Autoimmune Hepatitis and Pregnancy


Article Author:
Jiten Kothadia


Article Editor:
Jamil Shah


Editors In Chief:
Sisira Reddy
Joseph Nahas
CHOKKALINGAM SIVA


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
9/30/2019 6:22:31 PM

Introduction

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disorder that is usually characterized by circulating autoantibodies and elevated serum globulin levels. The pathology of the disease is that of a gradual hepatocellular inflammation that cannot be explained by more common etiologies of chronic liver disease, such as alcohol-related liver disease, viral hepatitis, hereditary liver disorders or exposure to hepatotoxic substances.[1] The natural history of AIH may progress from acute hepatitis to chronic liver disease and ultimately to cirrhosis. In the general population, it has a low incidence (1 per 100000).[2] The pathology more commonly affects women and manifests at childbearing age, but it can occur at any age.[1][3]

Autoimmune disorders and having positive autoantibodies are risk factors for obstetric complications as well as perinatal morbidity and mortality.[4] The data regarding pregnancy in women with AIH is limited, and few studies exist on pregnancy outcomes in these women.[5][6][7] However, the number of pregnancies reported in these patients is becoming more frequent due to better clinical management as well as high-quality prenatal and antenatal care. Currently, pregnancy and childbirth in AIH appear to be safe for both mother and child.[8] In this review article, we aim to report on the diagnosis and management of AIH during pregnancy.

Etiology

The probable theory for the pathogenesis of autoimmune hepatitis – in both pregnant women and the general population – is that the disease results from an environmental trigger in an individual who is genetically predisposed. The precise mechanism between the genes and the autoimmune process are still unknown. However, at the molecular level, they are believed to involve an antigen, a major histocompatibility complex (MHC), and a T cell receptor, which together form a complex in which complementary-determining regions identify and contact the antigen-MHC complex.[9] The suggested environmental triggers that lead to this T cell-mediated immune response targeting the liver include viruses, medications, herbal supplements, and even immunizations.[10] However, in most cases, the particular inducer of autoimmunity is never identified.

Epidemiology

In the general population, autoimmune hepatitis has a low incidence (1 per 100000)[2]. The disease more commonly affects women and manifests at childbearing age, but the first episode of AIH can occur at any age.[1][3] For type 1 AIH, the female to male ratio is 4 to 1, but, for type 2 AIH, the ratio is 10 to 1.[11][12]

Pathophysiology

The pathology of autoimmune hepatitis is that of a gradual hepatocellular inflammation that cannot be explained by the common etiologies of chronic liver disease, such as alcohol-related liver disease, viral hepatitis, exposure to hepatotoxic substances, and hereditary liver disorders.[1] The natural history of the disease may progress from acute hepatitis to chronic liver disease and ultimately to cirrhosis. The probable mechanism of obstetric complications in women with AIH is target involvement of the maternal-fetal interface structures by autoantibodies and natural immune cells activated by the disease.[4] These interface structures that get targeted include cellular components of intervillous space, endothelial tissue of spiral veins, and superficial epithelial cells of the decidua. This process leads to increased risk of first-trimester miscarriage and preterm delivery.[4][13][1] Thrombosis is another complication that occurs due to endothelial damage and complement system activation; these can lead to worse perinatal outcomes.

Histopathology

Histopathology showing the following typical features can confirm the diagnosis of autoimmune hepatitis:

  • The presence of interface hepatitis
  • Lymphocytic infiltration of the portal tracts and extending into the lobule
  • Emperipolesis, or active penetration of one cell into and through a large cell
  • Hepatic rosette formation

History and Physical

The clinical presentation of autoimmune hepatitis can be highly variable: it can present as either an acute or chronic illness with a fluctuating pattern. It can also be discovered incidentally in completely asymptomatic individuals on routine laboratory testing such as those required for insurance, for employment, or before blood donation.[14][15] Patients can present with debilitating symptoms such as malaise, anorexia, fatigue, and weight loss. The patients can also present with acute liver failure as an initial presentation with jaundice, ascites, and coagulopathy.[16][17][18]

Physical findings expected of AIH, in both pregnant women and the general population, range from a normal physical examination to findings suggestive of cirrhosis or liver failure (e.g., jaundice, ascites, splenomegaly).

Also, individuals with AIH may present with a coexisting extrahepatic disorder, which may also be autoimmune-mediated. The common autoimmune disorders associated with AIH include autoimmune thyroiditis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, celiac disease, and ulcerative colitis.[19][20]

Evaluation

The diagnosis of autoimmune hepatitis is similar in both pregnant women and the general population and has its basis representative serologic and histologic findings as well as the exclusion of other types of chronic liver disease.[2] Often, the disease can be strongly suspected based upon clinical and laboratory features, and thus, a liver biopsy is not always necessary in patients with characteristic findings on non-invasive testing.[21]

For individuals with consistent clinical or laboratory features, it is recommended to obtain serum anti-nuclear (ANA), anti-smooth muscle (ASMA), anti-mitochondrial (AMA), and anti-liver/kidney microsomal-1 (ALKM-1) antibodies, as well as either an immunoglobulin G (IgG) or gamma globulin level. For those who are negative for these autoantibodies, it is recommended to obtain anti-soluble liver antigen/liver pancreas antibody, anti-actin antibodies, and atypical perinuclear antineutrophil cytoplasmic (p-ANCA) antibodies. 

Patients with AIH historically categorize into two disease subtypes according to the nature of autoantibodies [2]

  • Type 1 AIH: Anti-nuclear (ANA) and/or anti-smooth muscle (ASMA) antibodies with F-actin specificity
  • Type 2 AIH: Anti-liver/kidney microsomal antibody type 1 (ALKM-1) and/or anti-liver cytosol antibody type 1 (ALC-1)

Roughly 20 percent of individuals who present with features of AIH lack circulating ANA, ASMA, or ALKM-1 antibodies.[11] These individuals usually present as having autoantibody-negative autoimmune hepatitis. Often, the only indication that AIH is the underlying disease is a therapeutic response to anti-inflammatory therapy.

In specific instances, it may be preferable to obtain a liver biopsy in individuals in whom autoimmune hepatitis is suspected because histologic assessment can confirm the diagnosis and help to guide treatment. Histologic evaluation is especially useful as part of the diagnostic evaluation for those who have few or atypical findings, negative autoantibodies, and/or normal IgG levels. 

After obtaining a liver biopsy, the diagnostic confirmation is by histology showing typical features (see histopathology section).

Treatment / Management

The course of autoimmune hepatitis during pregnancy is unpredictable. Though the literature is limited, up to 20% of patients with AIH will flare during pregnancy, and this is associated with a high rate of fetal and maternal complications.[3][22] Thus, women with AIH should be counseled to delay pregnancy at least one year until their disease is under optimal control.[3]

Medical Treatment:

The preferred treatment for AIH during pregnancy include glucocorticoids at the lowest possible doses, alone or in combination with azathioprine.[22] Azathioprine is a US FDA pregnancy category D medication, and providers should prescribe it only if the benefit justifies the potential risks to the fetus. Meanwhile, prednisone is a US FDA pregnancy category C medication and does not extensively cross the placenta, is not associated with teratogenicity in humans, and is the preferred treatment for control of disease activity during pregnancy in women with AIH. Though the studies are limited, azathioprine and prednisone use in pregnant women with AIH did not increase the risk of adverse fetal and maternal outcomes, so optimal AIH control outweighs the risks associated with these medications.[3] Thus, treatment should continue, and the patient monitored closely for flares. Other medications used for the treatment of AIH, including mycophenolate mofetil (MMF) and tacrolimus, are contraindicated in pregnancy because they cause congenital malformations/congenital disabilities, premature birth, low birth weight, and severe infections in the expectant mother.[3][23]

AIH Treatment and Breastfeeding:

Breastfeeding is also safe with prednisone. Azathioprine gets excreted at low levels in breast milk, and the majority of experts recommend continuing azathioprine use during breastfeeding despite manufacturers’ recommendations against using them during lactation.[3] There are no data on budesonide and mycophenolate and breastfeeding.

Management of AIH Flare:

During flares, management of pregnant patients with AIH should be similar to non-pregnant patients, with higher doses of prednisone and/or the addition of azathioprine.

Patients with Cirrhosis and AIH:

Cirrhosis can occur as an initial presentation at the time of diagnosis of AIH in up to 40% of patients. Therefore, providers will not infrequently encounter pregnant females with cirrhosis secondary to AIH.[3][23] Pregnancy in compensated cirrhotic women is no longer feared, nor is it contraindicated, but it correlates with increased rates of preeclampsia, low birth weight, preterm delivery, and neonatal death with increased risk of maternal mortality and complications.[24][25] In contrast, patients with a MELD (Model for End-Stage Liver Disease) score of greater than 10 are at higher risk for poor maternal and fetal outcomes, with increased risk of decompensation and maternal mortality of up to 7.8%.[24] This group of patients should have thorough discussions with their obstetrician and hepatologist regarding elective termination of pregnancy, surrogate pregnancy, and delaying pregnancy until after liver transplantation.[23] During pregnancy, compensatory dilation of collateral veins that join the portal circulation and the azygos vein occurs, causing expansion of the circulating blood volume and extrinsic compression of the inferior vena cava by the pregnant uterus, leading to increased portal hypertension and variceal bleeding, especially during the third trimester and labor and delivery.[23] This situation is the most common complication and cause of maternal morbidity and mortality. Thus, all patients should have an upper endoscopy for identification of, and potential prophylactic endoscopic variceal ligation of high-risk varices – especially around 28 weeks of gestation when maximum volume expansion occurs.[3] Management of other complications of portal hypertension such as hepatic encephalopathy and ascites should be per the guidelines established for the general population.

Postpartum Care:

AIH may flare with the return of normal immunity after delivery, and, in fact, flares are twice as frequent in the postpartum period during pregnancy.[3][23] The reported incidence of flares is around 20 to 50% of patients postpartum. Therefore, recommendations are that the patient should be followed by a hepatologist closely. The patient's liver function tests and immunoglobulin G (IgG) level should be monitored at delivery and then at 4-to-6 week intervals during the first three months postpartum.[3]

Differential Diagnosis

Autoimmune hepatitis has an array of clinical phenotypes. For this reason, it appears in the differential diagnosis for patients presenting with abnormal liver biochemical tests, cirrhosis, acute hepatitis, or acute liver failure[26]. Furthermore, even with the establishment of diagnostic criteria, there are still issues to be clarified attributable to its variability, such as autoantibody-negative AIH, drug-induced AIH, AIH sharing features with primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC)(i.e., overlap syndrome), and also rarely, post-transplant de novo AIH.

Prognosis

Pregnancy in patients with autoimmune hepatitis is associated with an increased risk of fetal complications and maternal complications.[3] However, data shows that the number of pregnancies reported in women with AIH is becoming more frequent due to better clinical management as well as high-quality prenatal and antenatal care. Currently, pregnancy and childbirth in AIH appear to be safe for both mother and child.[8]

Complications

Pregnant women with AIH should be counseled against pregnancy in the context of cirrhosis (MELD score greater than 10), primarily due to the risk of gastroesophageal variceal bleed, although ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, and hepatorenal syndrome can present as well.[27]

Deterrence and Patient Education

Given the elevated rate of fetal complications, including prematurity and death,[22] women with autoimmune hepatitis should be counseled to delay pregnancy until the AIH is under reasonable control for at least one year. Furthermore, these women should receive high-quality prenatal and antenatal care and follow closely with a specialist physician trained in the management of AIH during and after pregnancy. They should be advised to continue to take their medications under medical supervision and to see their healthcare provider regularly.

Patients should be counseled to eat a balanced, healthy diet and to avoid becoming obese, as obesity potentially increases the risk of fatty liver disease, which can worsen AIH. Patients should receive counsel to avoid all types of alcoholic beverages, including beer, wine, and liquor because they can all cause fatty liver and additional liver damage. Furthermore, certain herbs can cause severe liver injury, and some have links with triggering AIH. This reaction is why patients should be advised to avoid seeking any herbal treatment for their liver disease.

Enhancing Healthcare Team Outcomes

Women with autoimmune hepatitis have an increased risk of adverse outcomes in pregnancy and neonatal complications. It is important that these women undergo close surveillance, both prenatally and antenatally, by obstetricians, primary caregivers, nurse practitioners, and hepatologists working closely together. Therefore, autoimmune hepatitis requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. Pharmacists evaluate treatment regimens, check for drug-drug interactions, and provide patient education. Nurses monitor and educate patients and provide updates to the team. [Level V]

The outlook for women with AIH who get pregnant is guarded. Those with more severe disease tend to have poor fetal outcomes despite therapy.


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Autoimmune Hepatitis and Pregnancy - Questions

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A 26-year-old female (G1P1A0), just recently found that she is 8-weeks pregnant who came for initial evaluation. She does have a sister who is newly diagnosed with autoimmune hepatitis. Her last pregnancy was five years ago that was unremarkable. Her laboratory tests show the following: WBC 5200 / microL, hemoglobin 14.6 g/dL, platelets 240000 / microL, AST 220 IU, ALT 250 IU, alkaline phosphatase 178 IU, T. bilirubin 1.3 mg/dL, and GGT 190 IU. Ultrasound abdomen shows an intrauterine pregnancy with a liver normal in size and heterogeneous echogenicity with no intrahepatic or extrahepatic biliary ductal dilatation. Which of the following laboratory test should be ordered as the next step?



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A 28-year-old female with a history of autoimmune hepatitis (AIH) diagnosed three years ago, presents with a 7-week pregnancy. Her last pregnancy was five years ago, without any complications. Currently, she is taking azathioprine 75 mg and prednisone 5 mg daily. Her laboratory tests show WBCs 5200/microL, hemoglobin of 14.6 g/dL, platelets of 240000/mircoL, AST 30 IU, ALT 34 IU, alkaline phosphatase 126 IU, total bilirubin 0.8 mg/dL, and GGT 88 IU. Ultrasound abdomen shows an intrauterine pregnancy with a liver normal in size and echogenicity without any acute abnormalities. She is worried about the side effects of the medication. Which of the following is the next best step in the management of this patient?



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A 25-year-old female (G0P0A0) with a history of autoimmune hepatitis diagnosed three years ago presents to the clinic for follow up. She is married and monogamous. She is interested in having a child. Currently, she takes azathioprine 50 mg and prednisone 5 mg daily. Her last dose adjustment was six months ago. She denies any issues with medications. Her most recent laboratory tests show the following: WBC 4700/mircoL, hemoglobin 14.2 g/dL, platelets 250000/microL, AST 32 IU, ALT 30 IU, alkaline phosphatase 120 IU, total bilirubin 0.8 mg/dL, and GGT 80 IU. Ultrasound of the abdomen shows the liver is normal in size and echogenicity without any acute abnormalities. Which of the following is the most appropriate advice for the patient?



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A 30-year-old female with a history of autoimmune hepatitis (AIH) diagnosed eight years ago presents to the clinic for follow up. She had a liver biopsy done at the time of diagnosis of AIH, which showed stage 2 fibrosis. Her first pregnancy was five years ago, and she had an uneventful normal vaginal delivery. Last year, she had a flare-up of AIH requiring an increase in the dose of her immunosuppression medications and a one-time paracentesis. She was also noted to have esophageal varices which required banding. Currently, she takes azathioprine 100 mg daily and prednisone 5 mg daily. Her most recent laboratory tests showed WBC (white blood cell) count of 2500/microL, hemoglobin of 9.5 g/dL, platelet count of 75000/microL, AST is 89 IU, ALT is 125 IU, alkaline phosphatase is 187 IU, total bilirubin is mg/dL, GGT is 225 IU, sodium is 129 mEq/L, potassium is 3.7 mEq/L, BUN is 38 mg/dL, creatinine is 1.3 mg/dL, glucose is 90 mg/dL, calcium is 9.0 mg/dL, albumin is 2.3 g/dL, total protein is 5.6 mg/dL, PT is 13.1 and INR is 1.3. Her MELD-Na is around 23. Ultrasound abdomen with vascular doppler shows nodular liver suggestive of cirrhosis with mild to moderate ascites and splenic varices with other signs of portal hypertension. She is interested in having a second child. Which of the following is the most appropriate advice for this patient?



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A 30-year-old white female (G1P1A0) with a history of autoimmune hepatitis diagnosed three years ago, just recently had uneventful vaginal delivery three days ago. She had a baby girl with weight 7 lb 3 oz and 21 inches. Currently, she takes azathioprine and prednisone daily. Her laboratory tests show WBC count of 6200/microL, hemoglobin 13.6 g/dL, platelets 260000/microL, AST 30 IU/L, ALT 34 IU/L, alkaline phosphatase 120 IU/L, total bilirubin 0.7 mg/dL, and GGT 80 IU/L. She has questions regarding breastfeeding her baby and side effects of her autoimmune hepatitis medication. Which of the following is the most appropriate advice for this patient?



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Autoimmune Hepatitis and Pregnancy - References

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