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GI and Hepatobiliary
disorders in Pregnancy
Ermias D (MD)
Approach to Liver Disease in
Pregnancy
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Liver disease occurs in approximately 3% of
deliveries
There are unique and other common liver
diseases seen during pregnancy
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Acute fatty liver of pregnancy
Intrahepatic cholestasis of pregnancy
Toxemia of pregnancy – HELLP
Hepatitis
Gall stone disease
The Liver in Normal Pregnancy
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Physical Examination
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Skin - palmar erythema and spider angiomas
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are usually signs of chronic liver disease, but can be
normal findings in pregnancy
secondary to high estrogen levels
Liver
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In the third trimester, the enlarging uterus displaces the
liver superiorly and posteriorly
a palpable liver is abnormal
The Liver in Normal Pregnancy
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Hemodynamics
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cardiac output increases until the 30 wk, then
plateaus until delivery
absolute hepatic blood flow remains unchanged,
as the percentage of cardiac output to the liver
decreases
The Liver in Normal Pregnancy
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Liver function tests
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Albumin
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Alkaline Phosphatase
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unchanged
ALT
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2-4 times normal in the third trimester
increases secondary to placental ALP
Alkaline phosphatase may remain elevated for up to six weeks
after delivery
AST
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decreases secondary to hemodilution
slightly higher in second trimester but still within normal range
LDH
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unchanged
The Liver in Normal Pregnancy
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Liver function tests
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Bilirubin
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Bile acids
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Alteration in bile composition, cholesterol super saturation,
increased bile acid pool, precipitation of cholesterol crystal
and stone formation.
Coagulation Factors
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Total and Free are lower throughout pregnancy
Conjugated is lower during T2 and T3
PTT/INR - unchanged
Fibrinogen - slightly elevated
Total cholesterol and triglycerides
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increase markedly during pregnancy
The Liver in Normal Pregnancy
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Ultrasound
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biliary tract is usually normal
Pathology
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standard and ultra structural examination of the
liver during normal pregnancy reveals no specific
abnormalities
Acute Fatty Liver in
Pregnancy
Acute Fatty Liver of Pregnancy
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Affects 1 in 6,692 – 15,900 pregnancies
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M survival was 72%, maternal mortality of 18%, fetal
mortality of 23% (earlier reports)
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Prompt dx, delivery and ICU mx – m survival
approaches 100%, infant mortality rate <7%
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association with nulliparity, twin gestations, male
fetus and pre-eclampsia or eclampsia
Etiology
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Remains unknown
Similar histologically and clinically to Reye’s
syndrome and Jamaican vomiting sickness
These diseases are characterized by
microvesicular fatty infiltration of hepatocytes
without inflammation or necrosis
Etiology
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Presentation is also similar to those people
with metabolic defects in the intra
mitochondrial -oxidation pathway
Also occurs more frequently in women whose
fetuses have a deficiency of long chain 3hydroxyacyl-CoA (enzyme deficiency is
similar to that in Reye’s)
Clinical Manifestations
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Generally occurs in the third tm of pregnancy
Mean gestational age is 34.5 weeks (range
28-39 weeks)
The duration of prodromal symptoms and
signs is variable
Often presents with nausea and vomiting,
followed by severe abdominal pain and
headache; pruritis may occur early
Clinical Manifestations
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RUQ tenderness with out hepatomegally
Within a few days, jaundice appears, and the
patient becomes somnolent and eventually
comatose
Hematemesis and spontaneous bleeding
from hypo-prothrombinemia and DIC
Oliguria, metabolic acidosis, and eventually
anuria occur in approximately 50% of patients
Clinical Manifestations
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Diabetes insipidus may also accompany the
disease, but may not manifest itself until
postpartum
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These patients may respond to dDAVP after
delivery (1 deamino 8D vasopressin)
Pre-eclampsia in 21-64%
Clinical Manifestations
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If the disease is allowed to progress, labor
begins and the patient delivers a stillborn
infant
Uteroplacental insufficiency may be the
cause of fetal distress and fetal death in
these patients.
Clinical Manifestations
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During the immediate postpartum period, the
mother becomes febrile, comatose and,
without therapy, dies within a few days
Common causes of death are:
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DIC,
renal failure,
profound hypoglycemia, and
occasionally pancreatitis
Lab Investigations
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Serum transaminases
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Coagulation factors
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INR increases before PTT because of vitamin K
dependent clotting factors made in the liver
fibrinogen decreases, D-dimer increases with DIC
Bilirubin
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elevated, but usually below 500 IU/L
mildly elevated
Serum ammonia - elevated
Serum glucose - decreased
Further Investigations
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Liver Biopsy
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liver biopsy not advised for diagnosis in most
cases due to coagulopathy
if biopsy is necessary, FFP can be administered to
correct coagulopathy
pericentral microvesicular fatty change
minimal inflammatory cell infiltration or hepatic
necrosis
periportal areas are usually preserved
Histology
Further Investigations
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Imaging - US, CT, MRI
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CT
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to detect hepatic hematoma, rupture, infarction
a large number of false-negatives
decreased attenuation over the liver is consistent
with fatty infiltration
MRI
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fatty infiltration can be visualized with T2-weighted
images
Management
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Once diagnosis is made, delivery should be
carried out as soon as possible
Need to ensure patient is stable
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invasive hemodynamic monitoring
correct coags
IV fluids containing adequate glucose
if ammonia levels are elevated, treat with
lactulose
Management
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Vaginal delivery is preferable
May use cervical ripening agents if needed
C/S can be performed if it appears vaginal
delivery cannot be carried out in a timely
fashion or if patient is deteriorating
Management
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If coagulopathy is corrected, regional
anesthesia is preferable because it allows
adequate assessment of LOC
GA should be avoided if possible because of
hepatotoxicity of some anesthetic agents
Narcotic doses need to be adjusted as
metabolized by the liver
prognosis
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If delivery is carried out before hepatic
encephalopathy and renal failure develop,
patients recover rapidly
Little risk of recurrence in subsequent
pregnancies
Liver disease of preeclampsia
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Pregnancy ass. HTNsive disorder affecting
multiple organs
complicates 3-10% of pregnancies
Occur In the second half of pregnancy period
Most commonly in primi, multiple gestation…
diagnosis
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Sustained BP > 140/90 in previously
normotensive, after 20 wk gestation
24 hrs urine protein 300mg or 30gm/dl(+1
dipstick)
Hyperreflexia
Edema
Severe preeclampsia
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SBP > 160, DBP> 110
Proteinuria >2gm/24hr
Serum Cr >1.2mg/dl
Persistent headache, neurologic or visual
disturbance
Pesistent epigastric pain
Platelet count < 100,000/mm3, or
microangiopathic hemolyic aneamia
HELLP
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Hemolysis, elevated liver enzymes, low
platelet
Described by Weinstein 1982
Underlie the development of hepatic
hematoma, rapture and infarction in
preeclamptic pt
Upto 30% occur post delivery
Dx
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Clinical
Hemolyis – fragmented RBC, elevated LDH
Elevated transaminases – variably
Elevated bilirubin ---- hemolysis
Glutathion S transferase, AST, D-dimer,
tissue polypeptide Ag, fibronectin rise predict
severe disease
imaging
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CT, MRI
To detect intrahepatic hemorrhage, infarction
For pts with severe abdominal pain, neck
shoulder pain, sudden drop of BP
Liver Biopsy – not necessary
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Periportal hemorrhage, intra sinusoidal fibrin
deposition, area of liver cell necrosis
No pericentral microvesicular fat like AFLP
No correlation with lab values of LFT
 DDX should be entertained
pathogenisis
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Unknown
? Abnormality of placental fromation,
trophoblast invasion and spiral artery
dilations
? Lipid peroxidation, oxidative stress
? Endothelial dysfunction
? Abnormal cell permeability to Ca
? molecular variant of angiotensin
management
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Usually resolve after delivery
Post partum liver failure, sepsis, DIC and
death is also possible
Supportive care in ICU set up
Platelet transfusions
Glucocorticoid for fetal lung maturity
Full recovery with out sequalae in majority
Intrahepatic Cholestasis of
Pregnancy
Background
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Incidence of 1 in 1,000-10,000 pregnancies
Uneven incidence worldwide
High incidence in Chile and Sweden
Seems to have a seasonal variation, peaking
in November (cold season)
Pathogenesis
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Cause is unknown
Evidence suggests both genetic and
hormonal factors play a role
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Genetic
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could explain familial cases and a higher incidence in
some ethnic groups
heterozygous mutations in the MDR3 gene has been
found in a large consanguineous family
likely autosomal dominant
No HLA relation ship
Pathogenesis
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Hormonal
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Estrogens
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estrogens are known to cause cholestasis in both
experimental and clinical conditions
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ICP occurs mainly in the third trimester, when estrogens
reach their peak
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also more common in twin pregnancies, which have
higher circulating estrogen levels
Pathogenesis
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Hormonal
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Progesterone
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administration of progesterone may be a risk factor for
ICP
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the formation of large amounts of progesterone
metabolites may result in saturation of the hepatic
transport system utilized for biliary excretion
Clinical Manifestations
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Generally occurs in second and third
trimesters
Usually begins with pruritis at night
Pruritis is often generalized, but
predominates on palms and soles of feet
Progresses to continuous pruritis
Clinical Manifestations
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May have excoriations due to scratching
Abdominal pain is uncommon
Occasionally may have dark urine and pale
stool
Clinical Manifestations
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~2 weeks after start of symptoms, jaundice
develop in 50%
Accounts for 20-25% of cases of jaundice
during pregnancy
Jaundice is usually mild, but persists until
delivery
Symptoms usually abate about 2 days after
delivery
Differential Diagnosis for pruritis without
a primary skin lesion
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cholestasis
xerosis (dry skin)
medications
uremia
iron deficiency
leukemia
HIV
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polycythemia
lymphoma
thyroid disorders
diabetes
visceral malignancies
multiple sclerosis
Lab Investigations
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ALP
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Serum total bile acids
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may increase to more then 10x normal
Total bilirubin
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increases 5-10 fold
mildly increased
AST, ALT
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may increase to >1,000 U/L
Lab Investigations
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GGT
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normal or slightly elevated
Coagulation factors
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INR
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usually normal
may be increased secondary to Vitamin K deficiency due
to cholestasis or due to the use of bile acid sequestrants
Diagnosis
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Fasting serum bile acids must be more then 3
times the upper limit of normal
Clinical symptoms must also be present for
diagnosis
Need to exclude other causes of jaundice
and pruritus including viral hepatitis, primary
biliary cirrhosis and biliary tract disease
Diagnosis
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Ultrasound
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reveals no biliary duct dilation, hepatic
parenchyma appear normal
Liver Biopsy
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rarely necessary for diagnosis
histologically shows:
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centrilobular areas reveal dilated bile canaliculi
these changes tend to regress after delivery
Management
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Treatment focuses on reducing symptoms
Benadryl, hydroxyzine and other
antihistamines may help only slightly
Antihistamines may aggravate respiratory
difficulties in preterm babies
Management
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Cholestyramine
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anion binding resin that interrupts the
enterohepatic circulation, reducing reabsorption of
bile acids
dose 8-16 g/day in three to four divided doses
may take up to 2 weeks to work, so should start
as soon as pruritis is noted
check INR qweek, as affects vitamin K absorption
may cause bloating and constipation
Management
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Ursodeoxycholic acid (UDCA)
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increases bile flow
causes significant decrease in pruritus and
decrease liver function studies
dose 500 mg BID (15 – 20 – 25mg/kg/d)
Management
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Delivery
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In most cases, delivery should be accomplished
by 38 weeks
If cholestasis is severe, delivery should be
considered at 36 weeks if fetal lung maturity is
documented
Outcomes
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Perinatal Outcome
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Main complications are prematurity, meconuimstained amniotic fluid and intrauterine demise
Probability of fetal complications is directly related
to bile acid levels
Fetal complications are generally not seen until
bile acid levels are >40 mmol/L (further studies
needed)
Outcomes
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Perinatal Outcome
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Antepartum FHR testing and fetal surveillance
should be undertaken
May induce labour at term, or when amniotic fluid
studies indicate FLM
Outcomes
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Maternal Outcome
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Maternal prognosis is good
Pruritis usually begins to resolve around 2 days
postpartum
There are generally no hepatic sequelae
Recurs in 60-70% of subsequent pregnancies
Recurrent episodes are variable in severity (u less
severe)
Outcomes
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Maternal Outcome
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May be at increased risk for gallstones
OCP – administration rarely results in recurrent
cholestasis, however LFTS should be checked
after 3-6 months
Viral hepatitis
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HAV - no difference with pregnancy status
HEV – cause of fulminant hepatic failure in third tm,
20% mortality, associated with IUFD, abortion
HBV – perinatal transmission, higher in those with
HBeAg positive (90% vs 10%), Ig at birth and
vaccine at first day, 1 and 6 month for the new born,
lamivudine for the mother
HDV – no difference from nonpreg
HCV – no effect bilaterally, vertical transmission is
uncommon except with high viremia, tx not possible
Chronic liver diseases
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Usually amenorrhea and infertility
Varices may worsen
Autoimmune hepatitis – worsen post partum
Neoplasms – may worsen, bleed
Thrombosis – may worsen, hepatic vein,
Transplantation – resulted in successful
delivery, continue immuno supressive tx
Differential Diagnosis of Liver Disease in
Pregnancy
Serum
Bilirubin
Transaminase
s
Coagulopat
hy
Histology
Other
Features
Acute
Hepatitis
B
>1000
>5
-
Hepatocellul
ar necrosis
Potential for
perinatal
transmissio
n
Acute
Fatty
Liver
<500
<5
+
Fatty
infiltration
Coma, renal
failure,
hypoglycem
ia
Intrahepa <300
tic
Cholesta
sis
<5,
mostly
direct
-
Dilated bile
canaliculi
Pruritis,
increased
bile acids
HELLP
<5
+
Variable
periportal
necrosis
HTN, edema,
thrombocyt
openia
>500
GI disorders
Physiology of pregnancy
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motility changes
Esophageal motility in distal part decreases by a
third, resting tone decreases progressively until
delivery due to progesterone effect
Stomach no effect on motility, delayed emptying at
term, normal basal and stimulated acid secretion
Intestines prolonged transit time, worsening with
increasing GA, progestrone effect
Increased villus height, mucosal hypertrophy,
increased brush border enzymes during lactation
and decrease after weaning
Animal studies – increase selective amino acid and
Vit B 12 absorption
Nausea and vomiting
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60-70% nausea, 40% vomiting in first trimester
Onset 4-6wks, peak 8-12 wks, resolution by 20wk
Hyperemesis gravidarum - 0.5-10/1000 preg.
Often with primi, multipleg, high maternal body
mass, unwanted preg, crowded living
May lead to hypotension, electrolyte disturbance, ….
Need hospitalization
25-40% slight transaminase and bilirubin rise
Recur in subsequent preg
H pylori – controversial roll
Chemoreceptor trigger – mediated by hCG, thyroxin,
cortisol, gestational steroid hormones, parathormon
Tx – hydration, metoclopromide, prochlorperazine,
vit B 6, TPN
GERD
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50-80% heart burn by the end of third trimester
Overt esophagitis is rare
Lower esophageal tone is decreased and with
advance of the pregnancy intra abdominal pressure
increases
EGD, pH monitoring are safe but unnecessary
TX- non pharmacologic antireflux measures, liquid
antiacids (avoid Mg containing near term). H2RB
pass the placenta but are safe, PPI are group B
except omeperazole ©
PUD
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Improves
Decrease use of NSAID, increase use of
antiacids for n, v, cytoprotective effect of
gestational steroids
Course of H pylori is the same
Cpx like bleeding, perforation and GOO are
reported but rare
EGD indicated in confusing cases
Tx – sucralfate (no absorbable), antibiotics
IBD
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IBD are common in female (by 30% > male)
Fertility is affected only in crohn’s ds with pelvic inflammations, or
post proctocolectomy for UC
Initial IBD presentation during preg is unusual, may occur in first
tm and usual is mild
Disease activity before conception determines the natural course
and effect on preg.
Surgical mx is ass with increased m and f mortality
Most drugs are safe – sulfasalazine (with folate), mesalamine is
ass with interstitial nephritis in the neonates, prednisone is safe
Azathioprine and 6-mercaptopurine safe in practice use
Metronidazole – reports of malformation
Methotrexate – teratogenic, inflixamab insufficient data
appendicitis
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1 in 1500 pregnancies, at any time of
gestation
Anatomic displacement makes dx difficult,
and delayed
Sx over lap eg nausea, vomiting
Graded compressive US, Helical CT
Tx – surgery, laparascopic
Gall stone disease
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2.5 – 12 % in asymptomatic preg, dx when
US is done for fetal assessment
Cpx are rare during preg.
Cholecystitis is more common during in post
partum
Conservative mx with iv fluid, antibiotics
analgesia, then surgery preferably
laparoscopic, endoscopic common bile duct
stone extraction (? Fluoroscopy use)
pancreatitis
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Rare
Due to gall stones or triglyceridemia
Similar to non pregnants