physiology :
? hepatic blood flow is maintained at a constant rate in pregnancy despite marked changes in the cardiovascular system.
? blood flow increases to the kidneys and other organs, but hepatic blood flow is unaltered, which results in a decline of approximately 35% in the proportion of cardiac output delivered to the liver.
summary of physiological changes in the liver during pregnancy :
increased:
? blood volume and cardiac ouput rise by 35%–50%
? alkaline phosphatase levels rise threefold or fourfold due to placental production
? clotting factor changes create a hypercoagulable state
decreased:
? gallbladder contractility
? hemoglobin
? uric acid levels
? albumin, total protein, and antithrombin iii concentrations
no change:
? liver aminotransferase levels (aspartate aminotransferase,alanine aminotransferase, gamma-glutamyl transferase)
? bilirubin level
? prothrombin time
abnormal liver function tests in pregnancy :
liver function tests: alt levels and albumin normally fall in pregnancy. alp levels can rise due to the contribution of placental alp.
pre-existing liver disease: pregnancy is uncommon in cirrhosis due to infertility. variceal bleeding can occur if varices present prior to conception, and ascites or polyhydramnios should be treated with amiloride rather than spironolactone. penicillamine for wilson s disease and azathioprine for autoimmune liver disease should be continued during pregnancy. autoimmune liver disease can flare up post-partum.
unrelated liver disease: viral- and drug-induced hepatitis must be excluded in the presence of an elevated alt. immunoglobulin/vaccination given to the fetus at birth prevents transmission of hepatitis b to the fetus if the mother is infected. gallstones are more common in pregnancy and post-partum, and are a cause of a raised alp level. biliary imaging with ultrasound and mrcp is safe. ercp can be performed safely to remove stones with shielding of the fetus from radiation.
pregnancy-related liver diseases: occur predominantly in the third trimester and resolve post-partum. maternal and fetal mortality and morbidity are prevented by early delivery.
spectrum of liver diseases in pregnancy :
? preexistent liver diseases
– portal hypertension, cirrhosis, primary biliary cirrhosis
– autoimmune hepatitis
– wilson disease
– chronic infection with hepatitis b or hepatitis c virus
– alcoholic liver disease
– gall stones ( also might be coincidental )
preexistent liver diseases:
? pregnancy may be associated with both worsening and improvement of autoimmune liver disease (e.g. autoimmune hepatitis). cirrhosis often leads to infertility, but full-term delivery can occur. complications of portal hypertension may be a particular issue in the second and third trimesters. treating bleeding esophageal varices with nonselective beta-blockers, band ligation, and octreotide is safe and effective during pregnancy. gallstones are more common during pregnancy, and may present with cholecystitis or biliary obstruction. the diagnosis can usually be made with ultrasound. in biliary obstruction due to gallstones, therapeutic ercp can be safely performed, but lead protection for the fetus is essential and x-ray screening must be kept to an absolute minimum . pregnancy is a risk factor for sludge and gallstone formation. by the end of the third trimester, 10% to 12% of pregnant women have gallstones. most gallstones disappear spontaneously without causing symptoms. if symptoms develop, the treatment may be conservative or surgical, depending on the severity of the symptoms. also lap chole can be done during 2nd trimester .
in pbc ursodeoxycholic acid at doses of 10 to 13 mg/kg is treatment of choice for primary biliary cirrhosis and may be continued during pregnancy and breastfeeding. in aih corticosteroids& azothioprine are the treatment of choice in autoimmune hepatitis and appear to be safe in pregnancy.
wilson’s disease is a rare disorder characterized by cirrhosis, neurological abnormalities, and less commonly hematological and renal dysfunction. d-penicillamine and trientine have been used during pregnancy. however, the dosage should be reduced to the minimum necessary dose, which is about 25% to 50% of the dose the patient had been taking before the pregnancy.zinc is the agent of choice for wilson disease during pregnancy because of its safety for the fetus. it should be maintained throughout the pregnancy at 50 mg three times a day.
liver diseases coincidental with but not induced by pregnancy:
acute viral hepatitis and other viral infections
when elevated serum transaminases are present, acute viral hepatitis and drug causes need to be excluded.
acute hepatitis a can occur during pregnancy but has no effect on the fetus.
chronic hepatitis b requires identification in pregnancy, because of long-term health implications for the mother and the effectiveness of perinatal vaccination (with or without pre-delivery maternal antiviral therapy) in reducing neonatal acquisition of chronic hepatitis b.
maternal transmission of hepatitis c occurs in 1% of cases, and there is no convincing evidence that the mode of delivery affects this.
hepatitis e is reported to progress to acute liver failure much more commonly in pregnancy, with a 20% maternal mortality.
hav infection : there is substantial evidence that pregnancy does not alter the course of hav infection. however, a higher incidence of fulminant disease during pregnancy has been reported in developing nations. concurrent malnutrition has been a suspected cause. if the course of hav infection is severe, it may precipitate premature labor in women in the third trimester of pregnancy. there is no evidence that hav causes birth defects, and there is no evidence of maternal-fetal transmission
? the incidence of the hbv carrier state among pregnant women is variable and depends on the patient group studied. the incidence of hbv carriers is considerably higher in populations in which drug abuse is commonplace or with n high incidence of sexual promiscuity .evidence suggests that transmission of hbv to infants is common when mothers have acute infection in the third trimester or when they are chronic carriers of hbv infection and have positive results of serum tests for hbeag or hbv dna. the risk of transmission is highest in mothers who are hbeag - positive at the time of delivery. in women with chronic hepatitis b infection, taking lamivudine before becoming pregnant and continuing to take it throughout the pregnancy has been reported to lower rates of transmission of the virus from mother to newborn. lower transmission rates have also been seen in pregnant women with a high viral dna load.the administration of hyperimmune globulin and hbv vaccine protects 90% to 95% of infants from hbv infection. it is recommended that 0.5 ml, of hbig be given at birth and that three doses of hbv vaccine be given beginning at birth.
universal vaccination of all infants at birth for hbv is now the standard of care. vaccinations for all children previously not immunized is recommended as they enter puberty, in future generations, the specter of viral hepatitis b and its complications could be eliminated. vaccine for pregnant women exposed to hepatitis b is safe.
? the rate of vertical transmission of hepatitis c is less than 5%. the risk is higher if the mother is co-infected with human immunodeficiency virus (hiv), if she is viremic at the time of delivery, if her viral dna load is greater than 1 million copies/ml, and if the time from the rupture of membranes to delivery is more than 6 hours.
? the mode of delivery does not seem to influence the rate of transmission from mother to child.
? breastfeeding is not considered a risk factor for transmission, even though viral rna has been detected in breast milk. spontaneous resolution of infection in the mother and in the newborn may occur.
? newborns of infected mothers should be tested at 12 to 18 months of age, when igg antibodies to hepatitis c virus that may have passively transferred from the placenta to the fetus would have been lost, and the persistence of hepatitis c viral rna would indicate infection with hepatitis c.
? inf & ribaverine : both drugs are contraindicated in pregnancy. if a woman gets pregnant while on combination therapy, then both drugs should be stopped, and she should be advised that she has already put the fetus at risk of teratogenicity.
hepatitis e (hev) is a non enveloped, single-stranded rna virus. it is endemic in developing countries and shares the route of transmission, risk factors, and chronicity rate with hav. during pregnancy, hev can cause fulminant hepatitis indistinguishable from aflp. there is a significant mortality rate of 20% in pregnant women with acute hev infection.
hsv : it can cause fulminant liver failure and death if infection occurs during pregnancy, and the rate of transmission to the fetus can reach 30% to 50% if the primary episode occurs at delivery.about 90% of pregnant women with this infection have abnormal liver enzyme tests and an abnormal prothrombin time. acyclovir is very effective if promptly given at doses of 400 mg three times daily for 5 to 7 days, and early delivery is not required.
liver diseases induced by or related to pregnancy or pregnancy-associated liver disease :these conditions only occur during pregnancy, may recur in subsequent pregnancies and resolve after delivery of the baby. the causes of abnormal lfts in pregnancy, which include pregnancy-associated liver disease:
first trimester ( hyperemesis gravidarum)
second and third trimesters
¢ intrahepatic cholestasis of pregnancy
¢ preeclampsia, eclampsia, and the hellp syndrome (hemolysis, elevated liver enzymes, low platelet counts)
¢ acute fatty liver of pregnancy
hyperemesis gravidarum can be defined as excessive nausea and vomiting in pregnancy that result in dehydration and ketosis, severe enough to necessitate hospitalization. although this is not primarily a liver disorder, it affects the liver in up to 50% of patients. factors thought to favor an increased risk for hyperemesis gravidarum include obesity, nulliparity, and twin gestation
the origin of the liver disease associated with hyperemesis gravidarum is unclear. not all affected patients have liver disease therefore, the vomiting does not appear to be secondary to the liver involvement. starvation alone does not seem to be an adequate explanation for the liver dysfunction, particularly in as much as biopsy in affected patients fails to show the fatty infiltration typical of starvation.affected patients present in the first trimester, usually by weeks 10 to 12. they have persistent nausea and vomiting and experience weight loss, often of significant amounts. they also have ptyalism (excessive spitting).laboratory testing demonstrates abnormal liver values in up to 50% of affected patients the most sensitive test is the alt, which may rise as high as 1000 u.severely affected patients also have elevations in bilirubin. improvement in the nausea and vomiting and resolution of the liver test abnormalities occur when most affected patients are given intravenous fluids and put to gut rest. antiemetic therapy is helpful. corticosteroid therapy has been reported with success. patients affected with hyperemesis gravidarum have no increased rate of prematurity, infants with low birth weight, or infants with birth defects.
intrahepatic cholestasis of prengnancy icp:
? epidemiology : the frequency of icp is clearly higher among certain ethnic groups, including scandinavians and chileans. in the latter group, icp may appear in 2.4% or more of pregnancies, the highest reported incidence in the world. the incidence is quite high (20.9%) in twin pregnancies.
? several studies have demonstrated a familial and genetic predisposition to the syndrome in sweden, chile, and the united states.
? this accounts for 20% of cases of jaundice in pregnancy it usually occurs in the third trimester of pregnancy but can occur earlier.
? it is associated with intrauterine growth retardation and premature birth.
? the condition characteristically presents with itching and cholestatic lfts however, the bilirubin may be normal and the liver biochemistry hepatitic. bile salts are elevated in the serum.
? delivery leads to resolution, and pregnancy should not continue beyond term.
? udca( urso ) effectively controls itching and probably prevents premature birth it should be given at a daily dose of 15 mg/kg.
? recurrence of cholestasis occurs in 60% of future pregnancies
? clinically many patients report the appearance of dark urine without frank jaundice shortly after the onset of pruritus. only a minority of patients develop obvious jaundice, and this is usually mild.
? it is notable that abdominal pain, biliary colic, fever, anorexia, nausea, vomiting, and arthralgias are absent.
? the improvement in both pruritus and jaundice begins to occur quite promptly after delivery, most often within 24 hours. however, jaundice may continue for several days after delivery, and some of the abnormal chemistry profiles persist for as long as several months.
? clinical features include pruritus ,jaundice* ,no anorexia or malasie 2nd or 3rd trimester onset* ,recurrent* & familial. lab features :
|
10-to 100 fold
7- to 10 fold
two folds
normal to slight
normal to 5 mg/dl
normal to twofolds
two to fourfolds
normal to twofolds
|
serum bile acid
alkaline phosphatase
5 nucleotidase
ggtp
bilirubin (total)
ast/alt
prothrombin time
cholesterol
triglyceride
|
*these clinical features are not invariably present. alt, alanine aminotransferase ast, aspartate aminotransferase ggtp, g-glutamyl-transpeptidase. ?, increase.
? effects on mother : although earlier reports suggested that the only effect of icp on the mother was related to the discomfort of pruritus, more recent studies have suggested more serious complications. these include an increased risk of postpartum hemorrhage, especially in those given cholestyramine, and an increased risk for the development of gallstones after pregnancy.
? effects on faetus : the implications of icp for the fetus are considerably more ominous. an increased incidence of prematurity and fetal death has been reported in several studies. fetal distress is reported in one third of patients, leading to cesarean section in 30% to 60% of cases and prematurity in over 50% in some series. stillbirths are recorded in more than 9%. these outcomes are more likely if the disorder begins earlier in pregnancy. thus, icp very clearly increases the risks to the fetus.
treatment :
? therapy is directed at alleviating pruritus in the mother. ursodeoxycholic acid has been used successfully in the treatment of cholestasis in other settings, most prominently primary biliary cirrhosis. improvement in both liver function test results and the symptom of pruritus has been documented in women with icp treated with a standard 15-mg/kg/day dosage. a larger dosage, 20 to 25 mg/kg/day has been shown to be effective with no adverse affects on either mother or baby.
? phenobarbital in a dosage of 100 mg/day has been reported to be effective in approximately 50% of patients. cholestyramine may be somewhat effective and is usually given in a dosage of 4 g four or five times per day.
? cholestyramine may worsen the malabsorption of fats and fat-soluble vitamins. therefore, the prothrombin time must be monitored in patients treated with this regimen, and parenteral vitamin k should be given before delivery.
? some investigators recommend elective induction at 38 weeks or as early as 36 weeks in the presence of jaundice or if the fetus s lungs have matured.
preeclampsia and eclampsia
preeclampsia affects up to 5% to 10% of pregnancies, usually occurring in the late second and third trimesters and less frequently occurring before 20 weeks’ gestation. preeclampsia commonly occurs in nulliparous women or multiparous women who are nonwhite are older than 34 or have new partners, past or current history of hypertension, or previous postpartum hemorrhage .
the disease is characterized by a triad of hypertension, proteinuria, and peripheral edema, and hypertension and proteinuria characteristically regress after delivery. eclampsia is characterized by seizures, coma, and other signs of preeclampsia, including hypereflexia, funduscopic changes in severe cases, cerebral edema, hepatic infarction, acute renal failure, congestive heart failure, and acute respiratory distress syndrome.
pathophsiology :
? a uteroplacental mismatch, whereby the demands of the fetal placenta exceeds the maternal circulatory supply leads to placenta hypoperfusion, local hypoxia, endothelial cell dysfunction, abnormal expression of inflammatory mediators, alteration of vasomotor tone, and activation of the coagulation cascade.
clinical manifestations :
? the clinical course of preeclampsia includes nausea, vomiting, and epigastric pain and is associated with elevated levels of ldh, alkaline phosphatase, ast, alt, and uric acid. the level of uric acid is an excellent marker for assessing disease severity and progression. liver function tests are abnormal in 20% to 30% of patients with preeclampsia and may be attributed to vasoconstriction of the hepatic vascular bed.
therapy & outcome :
? women who develop preeclampsia before 32 weeks of gestation are 22 fold more likely to die than women who develop the condition at term.
? the maternal mortality rate is less than 1% at institutions with special skills in treating preeclampsia. approximately 80% of maternal deaths are attributed to central nervous system complications, usually cerebral edema.
? hepatic complications, including sub-capsular hematoma and rupture, infarction, and hepatic failure, account for the remaining causes of mortality.
? fetal complications include abruptioplacenta, prematurity, and iugr. severe disseminated intravascular coagulation (dic) is a rare complication in the absence of placenta abruption.
? the only effective treatment for preeclampsia is : delivery of the fetus and placenta, particularly if the condition is severe or develops after 36 weeks of gestation or if the fetal lungs are mature. most authorities suggest that the presence of multi organ system dysfunction (mosd), fetal distress, or gestational age greater than 34 weeks warrants immediate delivery
? if mild preeclampsia is evident in the third trimester, expectant management with intensive monitoring may enhance fetal lung maturity however, any sign of maternal or fetal deterioration requires emergent delivery. if eclampsia develops, magnesium sulfate is a treatment of choice for seizure prophylaxis.
the hellp syndrome is a multi-system disease variant of severe preeclampsia that is characterized by:
? microangiopathic hemolytic anemia (mah),
? hepatic dysfunction (hepatic necrosis),causing elevated liver enzymes
? thrombocytopenia (platelet count, < 100,000/ mm3), and, in the syndrome’s most severe form, dic.
? the hellp syndrome is a variant of pre-eclampsia affect multiparous women. it usually presents at 27-36 weeks of pregnancy with hypertension, proteinuria and fluid retention. jaundice only occurs in 5% of cases. blood tests may show low haemoglobin, with fragmented red cells, markedly elevated serum transaminases and raised d-dimers.
the condition can be complicated by hepatic infarction and rupture. maternal complications also include disseminated intravascular coagulation and placental abruption. maternal mortality is 1% and perinatal mortality can be up to 30%. delivery usually leads to prompt resolution, and disease recurs in < 5% of subsequent pregnancies.
acute fatty liver of pregnancy : sheehan, first recognized this disorder as a distinct syndrome in 1940. he named it acute yellow atrophy but it is now more commonly known as acute fatly liver of pregnancy. (aflp) is rare, encountered in a tertiary maternity hospital approximately once a year, with a reported incidence of 1 in 13,000 to 1 in 16,000 deliveries.preeclampsia is present in 50% or more of cases of aflp and may play a role in its origin.
clinical characteristics :aflp occurs in the latter half of pregnancy, usually close to term. as with hellp syndrome, affected patients may present after delivery. it is reported to occur more commonly in a first pregnancy and in the presence of multiple pregnancy, also prevalent in preeclampsia. there are reports of an association between aflp and gestation of a male fetus.affected women have nonspecific symptoms, including, prominently, nausea and vomiting, malaise and fatigue, jaundice, thirst, headache, and altered mental status. these can be signs and symptoms of acute hepatic failure. in severe cases that go untreated, there is progression over hours or days to fulminant hepatic failure, with hepaticcoma, hypo-glycemia, sever coagulopathy,,hemorrhage from the gastrointestinal tract or the uterus and death. most affected women have signs of coexistent preeclampsia, including modest elevations in blood pressure, hyperuricemia, and proteinuria.
slight , normal
normal to 1000 u
slight
¯¯
¯
«,
|
acute fatty liver of pregnancy : is more common in twin and first pregnancies it occurs in 1 in 14 000 pregnancies in the usa. it typically presents between 31 and 38 weeks of pregnancy with vomiting and abdominal pain followed by jaundice. in severe cases this may be followed by lactic acidosis, a coagulopathy, encephalopathy and renal failure. hypoglycaemia can also occur. the features are characteristic of a defect in beta-oxidation of fatty acids in the mitochondria that leads to the formation of small fat dropinglets in liver cells (known as microvesicular fatty liver). some women are heterozygous for loss-of-function mutations in the long-chain 3-hydroxyacyl-coa dehydrogenase (lchad) gene. other causes of microvesicular steatosis due to defects in mitochondrial beta-oxidation of fatty acids that have a similar clinical presentation.overlap between acute fatty liver of pregnancy, hellp and toxaemia of pregnancy can occur. early diagnosis, specialist care and delivery of the fetus have led to a fall in maternal and perinatal mortality to 1% and 7% respectively.polydepsia & with or without polyuria, frequently is an early symptom in aflp. the patient may drink 2 or 3 liters of liquids overnight. it often exceeds the magnitude of vomiting. it has been interpreted as a transient diabetes insipidus. laboratory tests : biochemical changes
bilirubin (total)
ast/alt
ggtp
prothrombin time
fibrinogen
uric acid
ammonia
glucose
leukocytes
platelets
in aflp imaging may be useful fat in the liver has been demonstrated in aflp with ultrasonography and ct scanning.liver biopsy is not indicated for diagnosis.
characteristics of heelp syndrome and aflp :
heelp
|
early
platelet count,50,000-150,000/mm3
ldh level, 600-1400 iu/l
bilirubin/pt levels, normal
|
|
late
platelet count, < 50,000/mm3
ldh level, > 1400 iu/l
bilirubin/pt levels, abnormal
|