Introduction
Pregnancy induces numerous physiological changes aimed at ensuring the proper development of the foetus and preparing the maternal body for delivery. These changes affect the function of multiple organs and biochemical parameters, including liver function markers. While most of these adaptations are predictable and pose no threat, some may mimic pathological conditions, complicating accurate diagnosis. A key challenge for clinicians is to distinguish physiological changes from pathological states requiring medical intervention. One of the most significant physiological changes is the increase in plasma volume and cardiac output by 35–50%, accompanied by a reduction in systemic vascular resistance. Consequently, haemoglobin levels, haematocrit, and red blood cell counts decrease due to physiological haemodilution. Simultaneously, there is an increased demand for iron, vitamin B12, and folic acid. Changes in the coagulation system favour a hypercoagulable state. Elevated levels of clotting factors such as VII, IX, and X, along with increased fibrinogen production (by up to 50%), represent an adaptive mechanism preparing the body for potential haemorrhage during delivery. Glucose metabolism also undergoes modifications: hepatic glucose synthesis decreases, maternal glucose demand rises, and insulin resistance develops due to hormonal changes. During pregnancy, the liver increases the production of cholesterol and triglycerides, linked to heightened lipid metabolism. Despite significant haemodynamic changes, hepatic blood flow remains unchanged during pregnancy. However, increased blood flow is observed in organs such as the kidneys, skin, and uterus.
Hormonal changes, particularly elevated progesterone levels, affect the smooth muscle function of the gastrointestinal tract, leading to reduced intestinal peristalsis, gastroesophageal reflux, and gastroparesis. Significant changes also occur in the respiratory system. The increased oxygen demand leads to a rise in tidal volume and minute ventilation by 30–50%. Consequently, mild respiratory alkalosis, characteristic of physiological pregnancy, develops [1, 2]. Approximately 3% of pregnant women present with abnormal biochemical markers of liver function in laboratory tests, although these findings are not always indicative of pathology [3]. During physiological pregnancy, a 2–4-fold increase in alkaline phosphatase (ALP) levels can be observed in the third trimester, attributed to the production of placental isoenzyme. Additionally, elevated levels of certain coagulation factors lead to a hypercoagulable state. Decreased concentrations of albumin and total bilirubin are primarily due to haemodilution and changes in hepatic metabolism. Liver enzymes such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and g-glutamyl transferase (GGT) typically remain within reference ranges, providing an important diagnostic baseline. Occasionally, these enzymes may be slightly reduced. Elevated oestrogen levels during pregnancy contribute to reduced bile acid secretion and slower bile flow in the biliary tract, which can lead to stasis and potentially to the development of intrahepatic cholestasis of pregnancy (ICP), discussed later in this article [4]. It is essential to emphasise, however, that not all laboratory deviations from normal values indicate pathology. The primary challenge for clinicians is distinguishing physiological changes characteristic of pregnancy from those signalling serious pathological conditions requiring further diagnostics and intervention.
This article focuses primarily on liver diseases closely associated with pregnancy, including hyperemesis gravidarum (HG), HELLP syndrome, preeclampsia and eclampsia, ICP, and acute fatty liver of pregnancy (AFLP). Special attention is given to the pathogenesis, diagnostics, and clinical presentation of these conditions. Additionally, autoimmune liver diseases, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH), are discussed, with an emphasis on their diagnosis and progression during pregnancy. The article highlights the diagnostic challenges resulting from the overlap of clinical symptoms of these diseases with the physiological changes occurring in pregnant women. It underscores the importance of a thorough medical history and a detailed evaluation of biochemical parameters, which are critical for differentiating pregnancy-related liver diseases from other pathological conditions. A comparison of the aforementioned liver diseases and the physiological adaptive changes occurring in pregnancy is presented in custom tables (Tables I and II), summarising the data discussed in this article.
Table I
Comparison of laboratory tests in physiological pregnancy and pregnancy complicated by liver disease
Table II
Comparison of pregnancy-related liver diseases
Liver diseases specific to pregnancy
Hyperemesis gravidarum (HG)
The occurrence of nausea and vomiting in pregnancy is a common phenomenon, affecting about 70% of pregnant women. The onset of symptoms usually takes place in the 6–8th week of pregnancy, and they usually resolve spontaneously around the 20th week of pregnancy [5]. The most dangerous form of nausea and vomiting in pregnancy is hyperemesis gravidarum. They occur much less frequently, complicating 1–1.5% of all pregnancies. However, they are associated with certain risks [6]. HG is defined as persistent, intractable vomiting leading to electrolyte imbalance, dehydration, and weight loss of at least 5%. The characteristic triad of symptoms may be accompanied by the following: ketosis, ketonuria, neurological disorders, liver and kidney damage, and retinal haemorrhage [7]. The pathogenesis of hyperemesis gravidarum is not fully understood. The main cause of these symptoms is considered to be increased levels of chorionic gonadotropin (hCG), the level of which peaks at 12–14 weeks of pregnancy. This temporal relationship correlates with the severity of symptoms during this period. Other potential causes of HG include changes in the expression of the GDF15 and IGFBP 7 genes, elevated thyroid hormone levels, Helicobacter pylori infection, gastrointestinal motility disorders, increased body mass index, history of diabetes, first pregnancy, younger age, and HG in the previous pregnancy, as well as psychological factors such as depression, anxiety disorders, mood changes, and stress. Prolonged vomiting during pregnancy can lead to transient liver function disorders, manifested by a slight increase in transaminase activity and mild jaundice. Although the exact pathogenesis of this phenomenon has not yet been fully understood, it is believed that one of the causes may be elevated levels of tumour necrosis factor a (TNF-a), the increased concentration of which is associated with pregnancy. In most cases, liver parameters return to normal after vomiting ceases. This usually occurs after the 20th week of pregnancy. However, if liver function tests remain abnormal, further diagnostics are necessary to exclude other causes of liver dysfunction. HG can also lead to dehydration, electrolyte imbalance, and significant weight loss, which requires a comprehensive therapeutic approach. Treatment primarily includes adequate hydration of patients, the use of antiemetics, and in the case of immobile patients, antithrombotic prophylaxis. This approach aims to minimise the risk of complications and improve the clinical condition of patients [8].
The therapeutic process includes four main stages:
The first focuses on preventing HG, which includes vitamin B6 supplementation. In women with a history of HG, doxylamine in combination with vitamin B6 is also recommended.
If there is no improvement, antihistamines such as diphenhydramine or hydroxyzine are introduced.
If these methods are insufficient, the next stage is the use of antiemetics. Some specialists recommend starting HG treatment from this stage. The most commonly used drugs include metoclopramide, promethazine, and ondansetron. However, a limitation of metoclopramide is that it should only be for short-term use – typically for no longer than about 5 days – due to the risk of extrapyramidal side effects.
In situations where symptoms worsen to the point that the patient is unable to take oral fluids, and previous outpatient treatment is ineffective, hospitalisation is necessary. In such cases, the priority becomes adequate hydration, carried out with intravenous fluids such as 0.9% NaCl solution, Ringer’s solution, or glucose solution. In particularly resistant cases, a short, three-day course of corticosteroid therapy may be considered.
Early implementation of appropriate interventions allows for effective symptom relief, improvement of the patient’s clinical condition, and avoidance of potential complications [8, 9]. Life-threatening complications of HG are extremely rare. Popa et al. in their study analysed the collected cases of these complications to date, indicating Wernicke’s encephalopathy as one of the most common complications of a potentially life-threatening nature. Other possible complications include ventricular arrhythmias resulting from electrolyte disturbances, preeclampsia, and vitamin K deficiency. Mortality associated with HG complications is currently very low, which is due to improved recognition and the ability to quickly implement appropriate treatment. Effective diagnostics and medical interventions, such as supplementation of missing nutrients and electrolytes, minimise the risk of serious clinical consequences [10].
HELLP syndrome
HELLP syndrome is a serious obstetric complication that is characterised by a triad of symptoms: haemolysis, decreased platelet count (PLT), and increased activity of liver enzymes. This complication affects 0.2% to 0.8% of pregnancies and is associated with a high risk of maternal mortality, which is up to 24%. Perinatal mortality associated with it reaches as much as 37% [11]. In approximately 70% of cases, HELLP syndrome occurs before delivery. It develops in 80% of patients before the 37th week of pregnancy and in 10% before the 27th week. In the postpartum period, symptoms primarily manifest within the first 48 h, although they can appear up to 7 days after delivery [12]. HELLP syndrome is considered a severe complication of preeclampsia. However, it is noteworthy that 15–20% of patients do not exhibit proteinuria or hypertension, which are hallmark features of preeclampsia. This observation suggests that HELLP syndrome may occur independently of preeclampsia, raising questions about the direct relationship between these conditions. Advanced maternal age, multiparity, a history of preeclampsia or HELLP syndrome, multiple pregnancies, and genetic factors are known to increase the risk of HELLP syndrome. Recent studies have also highlighted the potential influence of SARS-CoV-2 infection on the occurrence of this complication. These observations suggest that inflammatory processes and oxidative stress triggered by the infection may play a significant role in the pathogenesis of HELLP syndrome [13, 14]. The aetiology of HELLP syndrome is not fully understood, but systemic inflammation linked to complement cascade activation is believed to play a critical role. The condition may share pathogenic elements with inadequate remodeling of spiral arteries in preeclampsia, leading to placental ischaemia, endothelial activation, and microvascular injury. Mitochondrial dysfunction in the foetus and the release of intermediate metabolic products are also implicated, contributing to hepatic and vascular damage. Additionally, activation of the coagulation system results in thrombocytopaenia, microangiopathic haemolytic anaemia, and focal hepatic necrosis. Symptoms typically resolve after delivery [15].
HELLP syndrome primarily manifests as pain in the epigastrium or upper right quadrant of the abdomen, often accompanied by nausea and vomiting. Most patients also experience hypertension and proteinuria. Additional symptoms may include jaundice, visual disturbances, and headaches, which may indicate the advanced stages of the disease. Diagnosis of HELLP syndrome is based on the analysis of laboratory test results, which are essential for confirming the diagnosis. Detailed diagnostic criteria – the Tennessee classification – are presented in Table III [12].
Table III
Criteria for the diagnosis of HELLP syndrome [12]
Platelet count is a key parameter in assessing the severity of HELLP syndrome. Based on its value, the Mississippi classification (Table IV) [12] distinguishes 3 stages of the disease, enabling accurate determination of the severity and appropriate therapeutic approach [12].
Table IV
Staging of HELLP syndrome [12]
| Mississippi classification |
|---|
| Class 1: Platelet count (PLT) < 50,000/mm3 |
| Class 2: PLT 50,000–100,000/mm3 |
| Class 3: PLT 100,000–150,000/mm3 |
Preliminary diagnosis in a woman suspected of having HELLP syndrome should include detailed laboratory tests, including complete blood count with a smear, coagulation factors, haptoglobin levels, liver function tests, and a urine examination. The elevation in aminotransferase activity is highly variable and may range from a slight increase to values 10–20 times above the normal range. Bilirubin levels typically do not exceed 5 mg/dl. A key marker for liver function is the prothrombin time, which in HELLP syndrome usually remains within normal limits. This is due to the characteristic activation of platelets in this syndrome, without clear involvement of coagulation factors. However, an abnormal prothrombin time result should prompt further investigation for disseminated intravascular coagulation (DIC), which may coexist with HELLP syndrome in more severe cases. A decreased fibrinogen level is an additional indicator of the development of DIC and requires immediate clinical intervention [16]. In differential diagnosis, autoimmune hepatitis (AIH) should also be considered because it is a disease that may develop before pregnancy. It has been documented that the course of AIH may worsen both during pregnancy and in the postpartum period. This diagnosis should be especially considered in women with a history of other autoimmune diseases. Both AIH and HELLP syndrome show significant elevation of liver enzyme activity. General symptoms such as abdominal pain or chronic fatigue may occur in both conditions, which further complicates differential diagnosis [17]. Treatment of HELLP syndrome depends mainly on gestational age. After 34 weeks of pregnancy, the standard is to immediately deliver the baby via caesarean section. In the case of platelet count below 50 × 109/l before delivery, platelet concentrate transfusion is recommended to reduce the risk of bleeding. In women between 27 and 34 weeks of pregnancy, the priority is to deliver the baby within 48 h, after administering corticosteroids. Corticosteroid therapy aims to accelerate foetal lung maturation, increasing the chances of survival in preterm conditions. In cases where HELLP syndrome develops before 27 weeks of pregnancy, a wait-and-see approach is adopted. This involves close monitoring of the patient’s condition, including water-electrolyte balance, blood pressure, blood count, and liver function. It is also important to prevent seizures and respond promptly to any deterioration in health that may threaten the life of the mother or foetus [18]. HELLP syndrome is associated with serious maternal and foetal complications. The most common maternal complications include placental abruption, eclampsia, disseminated intravascular coagulation (DIC), and subcapsular liver haematomas, which in some cases may lead to liver infarction or rupture. Other risks include acute kidney damage and severe liver failure. DIC affects about 20% of patients, and placental abruption occurs in about 16% of cases. The prognosis for patients is generally good, but several of these complications are associated with a maternal mortality rate of up to 24%. Foetal complications related to HELLP syndrome include intrauterine growth restriction (IUGR), preterm birth, neonatal thrombocytopaenia, respiratory distress syndrome, and in some cases, perinatal death [14, 19]. Early recognition of HELLP syndrome and immediate medical intervention are crucial for minimising risks to both the mother and the foetus. A quick response reduces the likelihood of complications, improving treatment outcomes and prognosis in these cases.
Preeclampsia and eclampsia
Preeclampsia (PE) is a multi-organ pregnancy disorder characterised by the onset of hypertension (above 140/90 mm Hg) in women without a prior history of hypertension. Alternatively, it may present as an increase in blood pressure of 30 mm Hg systolic and 15 mm Hg diastolic in patients with preexisting hypertension. A key diagnostic criterion is the presence of proteinuria exceeding 300 mg/day. Additionally, preeclampsia may manifest with a range of nonspecific symptoms, such as headaches, visual disturbances, right upper quadrant or epigastric pain, and peripheral oedema. Although these symptoms are varied, they reflect the multi-organ nature of the disease and are important for the diagnostic process. All symptoms appear after the 20th week of pregnancy, typically resolving before the end of the sixth week postpartum [20]. Detailed diagnostic criteria are outlined in Table V [21]. The incidence of preeclampsia is estimated to be around 3–5% of all pregnancies [22].
Table V
Criteria for the diagnosis of preeclampsia developed by the American College of Obstetricians and Gynecologists (ACOG) [21]
Eclampsia is defined as tonic-clonic seizures associated with loss of consciousness, occurring in a patient with preeclampsia. This complication affects approximately 1% of pregnant women with this diagnosis. Preeclampsia is associated with abnormal placental implantation, uteroplacental vascular insufficiency, oxidative stress, and endoplasmic reticulum stress. It also involves the release of anti-angiogenic molecules and syncytiotrophoblast fragments that lead to endothelial dysfunction and an exacerbated inflammatory response, particularly evident in early-onset cases. Endothelial damage in the liver during preeclampsia contributes to liver injury and the development of HELLP syndrome. Conditions that predispose to preeclampsia include antiphospholipid syndrome, kidney disease, a history of preeclampsia, preexisting hypertension, multiple gestation, obesity, diabetes, and advanced maternal age [23].
The guidelines from the National Institute for Health and Care Excellence (NICE) categorise the risk of preeclampsia as high or moderate, allowing for appropriate management (Table VI). Prophylactic administration of 75–150 mg of acetylsalicylic acid, the effectiveness of which in reducing the risk of preeclampsia has been proven, is recommended for women with at least one high-risk factor or two moderate-risk factors, provided it is started before the 16th week of pregnancy. Preeclampsia and eclampsia are extremely dangerous conditions that can threaten both maternal and foetal health. These disorders significantly impact the health of the mother and foetus both in the short and long term. For the mother, there is a 2–4-fold increased risk of chronic hypertension, increased cardiovascular mortality, major cardiovascular events, and a 1.5-fold higher risk of stroke. Liver dysfunction occurs in approximately 75% of pregnant women with preeclampsia. During diagnosis, abnormalities in other organs, such as the kidneys (glomeruloendotheliosis) or the brain (thrombosis and inflammatory infiltrates in the middle cerebral arteries), may also be observed [24]. Foetal consequences include the risk of intrauterine growth restriction (IUGR), preterm birth (most often medically induced), oligohydramnios, placental abruption, life-threatening conditions, and intrauterine death. The maternal mortality rate due to the development of preeclampsia and eclampsia is estimated at around 1% [25]. Management of suspected preeclampsia is based on monitoring the health of the patient and assessing foetal well-being. Laboratory tests (evaluation of liver and kidney function, and coagulation system) are essential for making the diagnosis, and imaging studies such as ultrasonography and cardiotocography are used to assess foetal status. Therapeutic decisions depend on the clinical picture and the stage of pregnancy. In most cases, hospitalisation is necessary. The primary treatment for preeclampsia is the termination of pregnancy. After 37 weeks of gestation, labour induction is recommended for all patients. In earlier weeks of pregnancy, depending on the condition of the mother and foetus, a watchful waiting approach may be adopted. However, in severe cases, pregnancy is usually terminated after 34 weeks of gestation. Pharmacological treatment is focused on controlling blood pressure, using medications such as methyldopa, labetalol, nifedipine, metoprolol, hydralazine, or prazosin. In the case of eclampsia, intravenous magnesium sulphate is used as an anticonvulsant treatment [26]. Preeclampsia can also manifest postpartum, as demonstrated by a case described by McBride et al. In this case, a woman at 39 weeks of gestation developed symptoms suggestive of HELLP syndrome, which led to a caesarean section. During the procedure, massive haemoperitoneum was found due to a liver haematoma, and postpartum, the patient developed preeclampsia. This case highlights the need for heightened vigilance in patients with subtle symptoms, such as right upper quadrant pain, which can indicate potentially severe complications, even in the absence of hypertension at the time of hospital admission [27]. Early diagnosis, close monitoring, and appropriate treatment (including timely termination of pregnancy) are critical for improving prognosis for both the mother and the foetus.
Table VI
Risk assessment for preeclampsia [24]
| Risk assessment for preeclampsia | Risk factors |
|---|---|
| High risk (at least one of the following) | |
| Moderate risk (at least one of the following) |
Intrahepatic cholestasis of pregnancy
Intrahepatic cholestasis of pregnancy is characterised by an increase in bile acids in the blood, accompanied by intense pruritus, which typically appears in the second half of pregnancy. These symptoms usually resolve after delivery, but there is a high risk of recurrence in subsequent pregnancies (up to 50–60%). This disease is one of the most common liver pathologies during pregnancy, with an incidence in Europe ranging from 0.5% to 1.5% and the highest rates observed in Scandinavian countries [28]. A seasonal increase in incidence is typically seen during the winter months [29]. Available data indicate that cholestasis is more commonly diagnosed in women who experienced it during previous pregnancies and in cases of multiple pregnancies. Clinically, it is primarily characterised by itching of the skin, which intensifies at night, especially on the palms and soles. This is due to the accumulation of bile acids in the subcutaneous tissue, which irritate nerve endings. Jaundice occurs in approximately 10–60% of cases, typically about 4 weeks after the onset of pruritus [30]. During a normal pregnancy, bile acid levels increase, but they usually do not exceed 3 µmol/l. A level above 10 µmol/l is a diagnostic criterion for intrahepatic cholestasis of pregnancy, indicating the development of the disease. Laboratory tests in cholestasis of pregnancy often reveal additional abnormalities, such as a 3–10-fold increase in liver transaminase activity, reflecting hepatocyte damage resulting from elevated bile acid levels. Furthermore, an increase in the activity of GGT and bilirubin levels, usually in the range of 1.5–4 mg/dl, is observed. The pathogenesis of this condition has not been fully explained. The main cause is believed to be elevated progesterone levels, which impair bile acid transport and slow their metabolism. Genetic polymorphisms in the ABCB4 and ABCB11 genes, which encode transport proteins like MDR3 and BSEP, have been implicated in the pathogenesis. These changes may affect the function of bile transporters, disrupting bile flow and contributing to disease development [31]. Bile transport disturbances can also lead to a deficiency of fat-soluble vitamins, particularly vitamin K, due to impaired absorption, increasing the risk of bleeding complications. In such cases, vitamin K supplementation is recommended to minimise the bleeding risks for both the mother and the newborn. Furthermore, cholestasis during pregnancy is estimated to increase the risk of gallstones threefold. Intrahepatic cholestasis of pregnancy is associated with an increased risk of serious complications for the foetus, including preterm delivery (20–60%), intrauterine hypoxia (up to 44%), meconium in the amniotic fluid, and respiratory complications such as respiratory distress syndrome (RDS), chemical pneumonia, and atelectasis. Perinatal mortality can be as high as 4% of pregnancies. Additionally, some studies show a strong correlation between elevated bile acid levels in the mother and an increased risk of foetal complications, emphasising the importance of monitoring bile acids to assess foetal risks [32]. Management in pregnant women with cholestasis mainly involves administering ursodeoxycholic acid (UDCA) at a dose of 10–16 mg/kg/day until the end of pregnancy. Regular monitoring of both foetal status (via CTG and ultrasound) and the health of the pregnant woman is recommended. A light, low-fat diet is advised. For women with confirmed cholestasis, the minimum frequency of tests should be once a week, including measurements of bile acids, liver enzymes, and coagulation parameters [33]. If there is no improvement in biochemistry or if clinical symptoms worsen, early delivery should be considered. The decision regarding the timing of delivery should be based on the level of bile acids in the blood (Table VII). In exceptional cases, delivery before the 34th week of gestation may be considered, with corticosteroids administered to accelerate foetal lung maturation.
Table VII
Recommended date of delivery for obstetric cholestasis depending on the level of bile acid concentration in the blood [33]
| Bile acids concentration | Recommended date of delivery |
|---|---|
| 10–39 µmol/l | After 38 weeks of pregnancy |
| 40–99 µmol/l | After 36 weeks of pregnancy |
| ≥ 100 µmol/l | After 34 weeks of pregnancy |
Due to the high frequency of recurrence of cholestasis in subsequent pregnancies, selenium supplementation, fat-soluble vitamins, and a low-fat diet are recommended for every subsequent pregnancy. Additionally, biochemical parameters of cholestasis should be assessed in pregnant women with a positive history starting from the second trimester, every 2 weeks. In justified cases, prophylactic administration of ursodeoxycholic acid at a dose of 2 × 300 mg from the second trimester may be considered [34].
Acute fatty liver of pregnancy
Acute fatty liver of pregnancy (AFLP) is one of the most dangerous yet rare liver diseases that can occur during pregnancy. Its incidence ranges from 0.005% to 0.01%, and the risk of recurrence may affect up to 20% of subsequent pregnancies [35]. According to available literature, AFLP is the most common cause of acute liver failure in pregnancy. The first symptoms of acute fatty liver of pregnancy usually appear in the third trimester of pregnancy, and less frequently at the end of the second trimester. In rare cases, the disease may develop within a few days after delivery. The clinical picture is typically nonspecific, with patients often reporting unclear symptoms such as pain in the right upper abdomen, nausea and vomiting, jaundice, or headache and loss of appetite. AFLP is sometimes manifested only as an isolated, asymptomatic increase in liver transaminases or mild jaundice. In rare instances, the disease can progress rapidly, leading to acute liver failure. Detailed diagnostic criteria are outlined in Table VIII [36]. In cases where AFLP is suspected, it is essential to perform an abdominal ultrasound, which in most cases will show fatty infiltration of the liver. The differential diagnosis should primarily consider HELLP syndrome and preeclampsia. It is also important not to overlook infectious causes of liver diseases, such as herpes virus or hepatitis E virus (HEV). If diagnostic difficulties arise, liver biopsy is recommended, which ultimately confirms the diagnosis.
Table VIII
Swansea criteria for diagnosing AFLP [36]
| Criterion | Description |
|---|---|
| Clinical symptoms | |
| Laboratory abnormalities | |
| Ultrasound image | Ascites or increased echogenicity of the liver |
| Histopathological image | Microvesicular steatosis on liver biopsy |
The pathogenesis of acute fatty liver of pregnancy is not fully understood. It is believed that certain factors predispose to its development, including multiple pregnancies, primiparity, male foetal sex, obesity, coexisting metabolic diseases such as diabetes, and liver diseases such as intrahepatic cholestasis of pregnancy. According to available data, genetic factors play an important role in the pathogenesis of AFLP. It is estimated that about 20% of cases result from disturbances in mitochondrial fatty acid metabolism with a genetic basis. The most commonly detected defect is a deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) in the foetus. This disorder is inherited in an autosomal recessive manner. As a result, abnormal fatty acid metabolism leads to hepatocyte damage in the pregnant woman, manifesting as microvesicular fat infiltration [35]. The diagnosis of acute fatty liver of pregnancy requires immediate implementation of comprehensive care for the pregnant woman and her baby. Every patient with this condition should be hospitalised, and both the mother’s condition and the foetal status must be closely monitored. To prevent the occurrence of preeclampsia and eclampsia, routine intravenous administration of magnesium sulphate is used, which is justified due to the frequent co-occurrence of these 2 diseases – up to 70% of women with AFLP also show signs of eclampsia [37]. The only effective treatment for AFLP is immediate termination of the pregnancy, most often by caesarean section. Symptoms of the disease typically resolve within a few days to weeks after delivery, but both the mother’s and the newborn’s conditions require further monitoring. Acute fatty liver of pregnancy can lead to numerous complications in the mother, including encephalopathy, hypoglycaemia, coagulopathy, and in about 15% of cases, acute pancreatitis. In rare situations, acute liver failure may develop, requiring liver transplantation. The maternal mortality rate is about 10%, while foetal mortality reaches 20%. The most common cause of foetal death is foetal hypoglycaemia, emphasising the importance of rapid therapeutic decision-making. In newborns with genetic disorders of fatty acid metabolism, close clinical observation is crucial [38].
Liver diseases occurring regardless of pregnancy
Autoimmune liver diseases
In addition to liver diseases specific to pregnancy, autoimmune liver diseases that occur in the general population should also be considered, as their course during pregnancy may worsen or mimic conditions typical for this period. These include autoimmune diseases such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).
Autoimmune hepatitis
Autoimmune hepatitis (AIH) is a chronic, inflammatory liver disease that leads to hepatocyte damage. It is characterised by increased levels of g-globulins in the plasma and the presence of tissue autoantibodies. The incidence ranges from 4.0 to 24.5 cases per 100,000 individuals annually, with the disease occurring 4 times more often in women than in men. The pathogenesis of AIH is not fully understood, but an abnormal immune response is believed to play a key role, leading to the release of pro-inflammatory cytokines and activation of Th1 and Th17 lymphocytes, which causes inflammatory changes in liver tissue. Additionally, genetic and environmental factors, such as viral infections, certain medications, or mutations in the HLA-DRB1 system, may play a significant role in the disease’s development [39]. The course of the disease can be highly variable. Existing data show that 25–34% of AIH cases are asymptomatic, and diagnosis is often made based on abnormal laboratory test results. Dominant symptoms can include chronic fatigue, loss of appetite, nausea, pruritus, or severe jaundice. However, AIH rarely manifests as acute liver failure with a fulminant course. Diagnosis of autoimmune hepatitis is based on criteria established by the International Autoimmune Hepatitis Group (IAIHG) in 2008 (Table IX).
Table IX
Simplified diagnostic criteria according to IHIHG for autoimmune hepatitis [39]
The goal of treating AIH is to induce remission. The therapy mainly involves the use of immunosuppressive medications, such as azathioprine (the drug of choice in pregnant women), mycophenolate mofetil, and glucocorticoids (GKS). After remission is achieved, usually after about 2 years of treatment, maintenance therapy with low doses of azathioprine or GKS is typically applied. In cases of liver cirrhosis, liver transplantation may be required. The recurrence rate of AIH is between 8% and 68% [39]. The impact of pregnancy on AIH is variable, but available data suggest that the disease may exacerbate or relapse during pregnancy or after childbirth. It is estimated that 21.7–45.0% of women experience worsening or recurrence of AIH during this period. A study by Westbrook et al. observed complications such as preterm birth (14.8%), and worsening of the disease during pregnancy (7.4%) and after delivery (24.6%). In rare cases, maternal death (4.9%) and perinatal death (3.7%) were reported, which were associated with a fulminant course of the disease leading to acute liver failure. Moreover, it was found that women whose AIH was poorly controlled or untreated for 12 months before conception were more likely to experience exacerbation of the disease during pregnancy or shortly after delivery [40]. Due to the risk of exacerbation of autoimmune hepatitis after delivery, some clinicians recommend increasing the dose of immunosuppressive drugs during this period. Additionally, it is recommended that liver enzyme activity be monitored for 6 months post-delivery, with checks typically conducted every month [39].
Primary biliary cholangitis
Primary biliary cholangitis (PBC) is an autoimmune disease that leads to the destruction of small bile ducts through T lymphocytes. This process results in cholestasis, and in later stages it may lead to acute liver failure or even cirrhosis [41]. Data regarding the course of PBC during pregnancy, treatment methods, and potential complications are limited because the primary age group for diagnosis is women around 50 years old. However, there are reports of earlier diagnoses of PBC, including during the reproductive period, with approximately 25% of cases diagnosed at this time or even during pregnancy or the peripartum period [42]. The disease course can vary greatly, ranging from asymptomatic to symptoms such as jaundice, pruritus, and chronic fatigue. Laboratory tests typically show elevated levels of ALP, GGT, and total bilirubin. In 95% of patients, antimitochondrial antibodies (AMA) are present in the serum. The diagnosis of PBC is based on specific diagnostic criteria (Table X) [43].
Table X
Criteria for the diagnosis of primary cholangitis [43]
Treatment of PBC mainly involves the use of ursodeoxycholic acid (UDCA), which has been shown in numerous studies to reduce the intensity of pruritus and improve biochemical outcomes [44]. PBC can resemble intrahepatic cholestasis of pregnancy, which can cause diagnostic difficulties. A key difference is the timing of symptom onset: intrahepatic cholestasis of pregnancy typically develops in the second or third trimester, while PBC may present before pregnancy. If PBC is diagnosed in a pregnant woman, monitoring of both maternal and foetal health is essential. Studies suggest that pregnancy should be terminated at 37–38 weeks to avoid complications for both the mother and foetus [41]. It is worth noting that studies on the impact of pregnancy on the course of PBC are still limited. Most available data suggest that pregnancy may have a beneficial effect on the course of some autoimmune diseases, including PBC. In pregnant women with a previous diagnosis of PBC, a decrease in the level of antimitochondrial antibodies has been observed [45]. However, around 60% of women experience disease exacerbation after childbirth, and the AMA levels return to pre-pregnancy values [41].
Primary sclerosing cholangitis
Primary sclerosing cholangitis (PSC) is a disease characterised by chronic inflammation leading to fibrosis and obliteration of both intrahepatic and extrahepatic bile ducts [46]. Like primary biliary cholangitis, PSC can lead to acute liver failure and, in later stages, liver cirrhosis. This disease is more commonly diagnosed in men, especially those aged 25–40 years, and therefore, available data on the course of PSC in pregnant women are limited [47]. The clinical presentation of PSC in pregnant women is similar to that of PBC. PSC may be asymptomatic or cause intermittent symptoms such as pruritus, jaundice, chronic fatigue, and pain in the right upper quadrant of the abdomen. Cholestasis indicators such as elevated levels of ALP, GGT, and bilirubin may aid in diagnosis. In 33–85% of patients, antibodies against neutrophil cytoplasm (ANCA) are detectable. Additionally, in rare cases, antinuclear antibodies, smooth muscle antibodies, anticardiolipin antibodies, and rheumatoid factor may also be present. However, it is important to note that the presence of these antibodies has no diagnostic or prognostic significance [43]. Currently, there is no specific treatment for PSC. In women who experience severe pruritus, the use of ursodeoxycholic acid (UDCA) is recommended. Although it does not affect the disease course, it may help alleviate symptoms. Studies suggest that UDCA contributes to faster normalisation of liver enzyme levels compared to patients who did not use this drug [48]. In available studies on the impact of pregnancy on the course of PSC, there are no definitive conclusions. Meta-analyses do not show an association between pregnancy and exacerbation of PSC. However, documented cases indicate that pregnant women with PBC and PSC are more likely to experience severe pruritus – 25% of women with PBC and 14% of women with PSC. No maternal or foetal deaths have been reported in these conditions. Available data suggest that elevated bile acid levels in the mother, occurring in PBC and PSC, may increase the risk of preterm birth, with a slightly higher risk in PBC [49].
Summary
The detection of abnormal liver function indicators during pregnancy does not always indicate the presence of pathology. Many changes occurring in the pregnant body are physiological in nature. For example, biochemical changes such as elevated alkaline phosphatase levels towards the end of pregnancy or decreased albumin and bilirubin concentrations are results of natural adaptations of the body. However, due to the similarity of these changes to liver disease symptoms, their interpretation presents a diagnostic challenge. It is especially important to pay attention to the characteristic clinical course of specific diseases and the stage of pregnancy in which they most commonly begin. This article discusses liver diseases specific to pregnancy, as well as conditions that occur independently of pregnancy, including AIH, PBC, and PSC. Although available data suggest that the symptoms of PBC and PSC may improve during pregnancy, in the case of all 3 autoimmune liver diseases, including AIH, strict monitoring of liver function markers is necessary during pregnancy and postpartum. In AIH, it has been observed that some patients may experience disease exacerbation during pregnancy or the postpartum period, highlighting the importance of regular monitoring and appropriate adjustment of immunosuppressive treatment. There is an urgent need for further studies to better understand the impact of these diseases on pregnancy and to develop appropriate guidelines for managing such patients. Differential diagnosis of liver dysfunction in pregnant women should also consider drug-induced liver injury and viral infections such as hepatitis A, B, C, or E. A detailed medical history is essential because it can facilitate accurate diagnosis and reduce the risk of misdiagnosis. It is important to note that many liver diseases occurring during pregnancy present a similar clinical picture, which further complicates the diagnostic process. However, there are differentiating criteria for individual diseases. For example, jaundice rarely occurs in preeclampsia, while AFLP is characterised by hypoglycaemia. Symptoms such as upper abdominal pain, hypertension, thrombocytopaenia, or abnormal liver function tests should be analysed in detail, taking into account the patient’s clinical condition and the stage of pregnancy. Early diagnosis and prompt therapeutic action in diseases such as HELLP syndrome, AFLP, or preeclampsia are crucial to minimise the risk of complications. Close monitoring is also essential for women with autoimmune and other chronic liver diseases.
Conclusions
Further research is needed on the impact of liver diseases – both pregnancy-specific and coexisting – on the course of this unique period. A priority should be the development of effective diagnostic and therapeutic strategies that will allow for rapid diagnosis and the minimisation of risks to both the mother and foetus. It is also crucial to educate patients and maintain close surveillance of women with diagnosed conditions, to ensure the safety and proper development of pregnancy.
