Assessment of Liver Disease in Pregnancy

Most women with pregnancy-related liver diseases present acutely to the emergency room with nausea, vomiting, abdominal pain, jaundice, pruritus, and even drowsiness. The pattern of liver disease in pregnant women varies greatly both at presentation and in subsequent follow up. The trimester of their pregnancy needs to be established as this will suggest which liver disease may be present should their symptoms be pregnancy related.

Both in the emergency room and the physician’s office it is essential to collect historical details of prior pregnancies and to perform both a thorough history (including a list of all medications) and examination (including a check for easy bruising, spider nevi, jaundice, scratch marks (from pruritus), and abdominal and/or ankle swelling) (Box 24.1). Surprisingly though it may seem, some women don’t know that they are pregnant—this therefore has to be taken into consideration if any premenopausal woman arrives at the ER with any of the above symptoms (i.e. need to avoid exposure to X-rays, CT scans). Full evaluation of cardiac, respiratory, as well as neurological status, is required. Examination of the abdomen should look for evidence of hepatomegaly and/or splenomegaly as well as ascites. Risk factors for recent exposure to viral hepatitis, for example new sexual partner (hepatitis B and/or D), recent travel (hepatitis A and E) or recurrent vaginal herpes simplex and prior medical (and surgical) history, may all be potentially relevant (Box 24.1).

For those who present with an acute onset of symptoms, physical examination must include a careful evaluation of the patient’s mental status. If there is any evidence of impairment then regular (1 hourly) evaluation of their state of cognition is required. Adequate fluid and electrolyte replacement should be given to maintain systemic blood pressure, renal output, and blood glucose and electrolyte balance. Viability of the fetus must be closely monitored. The process of investigation depends both on the presenting symptoms and the timing of the clinical presentation (Box 24.2).

Liver Diseases As a Consequence of Pregnancy

First Trimester: Hyperemesis Gravidarium

Pregnant women who present with severe nausea and varying degrees of vomiting with consequent dehydration and weight loss, that is hyperemesis gravidarium, may be noted to have abnormal liver biochemistry, that is aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) (Table 24.1). This condition occurs in 1–20 per 1000 pregnancies and is more common in young obese mothers pregnant with their first baby or with multiple pregnancies; recurrence with subsequent pregnancies is common. Pre-existing diabetes is not unusual. Jaundice is rare but when present is all unconjugated (secondary to starvation). Elevation in AST and ALT is generally less than 250 IU/mL and values should return to normal with rehydration. Both fluid and electrolyte (phosphate, magnesium, and potassium) replacement must be attended to. Vitamin supplements, particularly thiamine must be administered. In severely compromised mothers, sublingual odansetron may reduce symptoms. Symptoms usually lessen with progression of the pregnancy.

Table 24.1 Acute liver disease caused by pregnancy

ALT, aspartate aminotransferase; AST, aspartate aminotransferase; HELLP, hemolysis, elevated liver enzymes and low platelet count; UDCA, ursodeoxycholic acid.

Very, very rarely mothers with severe, continued vomiting and consequent malnutrition develop serious complications such as esophageal rupture, retinal hemorrhage, and Wernicke encephalopathy or central pontine myelinosis.

Second to Third Trimester

Cholestasis of Pregnancy

Anywhere from midsecond trimester onwards some pregnant women may start to complain of generalized pruritus despite no evidence of background liver disease. Unless the pruritus becomes intense and disturbs their sleep, the mother remains well.

Typically, the pattern of abnormality of the biochemical tests reflecting cholestatic symptoms in pregnancy show a “mixed” picture with elevation of both serum transaminase and alkaline phosphatase levels although typically GGT remains normal (as is the case with other biliary transporter defects). A conjugated hyperbilirubinemia may be present. Prolonged cholestasis with jaundice results in malabsorption manifested by marked weight loss and a coagulopathy (the latter is correctable with parenteral administration of vitamin K). Elevated serum bile acid levels in the absence of any prior history of liver disease clinches the diagnosis (typically >10 µmol/L but in this condition levels exceed 40 µmol/L in symptomatic patients). Intrahepatic cholestasis of pregnancy is associated with increased rates of fetal loss from placental insufficiency. Treatment with ursodeoxycholic acid (UDCA, 1–2 g/day) is mandatory as it not only abrogates the pruritus but also reduces fetal loss—there are no untoward side effects of UDCA on the mother or fetus.

Pruritus spontaneously resolves within 2 weeks of delivery, unless there is background chronic cholestatic liver disease (the usual culprit being primary biliary cirrhosis (PBC)).

There is a genetic component to many causes of cholestasis including that related to pregnancy. Many different mutations of the bile acid transporters have been described—mutation in the MDR3 gene (the patient is usually a heretozygote) seems to be what promotes cholestasis of pregnancy; thus the condition recurs with subsequent pregnancies. It is not associated with any permanent hepatic consequences although recurrent intraductal stones may develop in those with mutations in the MDR3 gene.

Third Trimester

There are three serious pregnancy-related conditions that affect the liver, fortunately they are rare (1 in 14 000) births. These are: acute fatty liver, pregnancy-related toxemia (systemic hypertension, proteinuria, and fluid retention), and the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). It may be particularly hard to distinguish these latter two conditions. Rarely, acute fatty liver may accompany one of the two other syndromes! However, the more common causes of acute jaundice must not be forgotten.

Acute Jaundice with Biochemical Evidence of Cholestasis

Bile becomes more lithogenic during pregnancy and gall bladder emptying is reduced—this promotes cholelithiasis, which is rarely problematic during pregnancy. If choledocolithiasis is suspected on the basis of an ultrasound examination of the biliary tree then once into the second trimester it is safe (in terms of exposure to radiation to the fetus) for the mother to undergo endoscopic retrograde cholangiopancreatography (ERCP) and stone removal. Cholecystectomy if required is also safe in pregnancy.

Acute Fatty Liver of Pregnancy (AFLP)

The pregnant woman at about 34 to 36 weeks of pregnancy may suddenly complain of nausea accompanied by vomiting and abdominal pain complicated by hypoglycemia, lactic acidosis, and hyperammonemia. Jaundice is usually absent. It is more common in primipara, with twins, and/or male child (Box 24.3). These symptoms should prompt immediate admission to hospital where rehydration must be initiated promptly before hypoglycemia, lactic acidosis, and/or renal failure complicate the illness. If jaundice develops this often heralds subsequent hepatic encephalopathy and other serious complications such as disseminated intravascular coagulation, pulmonary emboli, ascites and rarely polydipsia and polyuria (diabetes insipidus) develops. About 50% of AFLP patients will have coexistent pre-eclampsia. Differential diagnosis includes viral hepatitis, drug-induced liver disease, and the HELLP syndrome.

The blood film often shows both thrombocytopenia and a leukocytosis. Other laboratory investigations are helpful in supporting the diagnosis, that is raised aminotransferases, bilirubin, and uric acid levels, with or without a prolonged prothrombin time. Monitoring of disease severity must include serial measurements of lactic acid, uric acid, and creatinine. Hypoglycemia and hyperammonemia reflect the severity of mitochondrial failure within hepatocytes.

Ultrasound of the liver does not help to make the diagnosis, although a sonographic pattern of fat deposition may be noted. Neither is a liver biopsy essential to make the diagnosis but should this be done the findings typically show a pattern of microvesicular fat within hepatocytes with a centrally placed nucleus (Plates 24.1–24.3). The patient needs to be closely observed in consultation with the obstetrician so that prompt delivery of the baby can be performed if there is any deterioration such as increasing coagulopathy, worsening renal function, hypoglycemia, increasing jaundice, and/or intractable vomiting. This disease carries with it a maternal mortality that ranges from 0 to 18% and a fetal mortality of 9 to 23%. Death of the mother is usually secondary to the complications of disseminated intravascular coagulation (DIC) with massive gastrointestinal hemorrhage. If a Cesarean section is performed this may be complicated postoperatively by an intra-abdominal hemorrhage. It is not unusual for a mother with AFLP to also have toxemia of pregnancy.

The etiology for AFLP may be related to a deficiency in long chain 3-hydroxyaceyl-coenzyme A dehydrogenase (LCHAD)—the baby is generally a homozygote and the mother a heterozygote for this inherited defect. The mother cannot metabolize the free fatty acids being delivered to her from the fetus. The child may develop hepatic failure and/or a myopathy.

The cure for AFLP in the mother is immediate delivery of the child. The latter should (if available) be tested for LCHAD deficiency. Early after delivery the baby may need steroid therapy to treat lung immaturity. The infant requires frequent feeds to prevent hypoglycemia and lifetime avoidance of fasting may be required. Additionally, the child requires supplements with carnitine. The mother may experience cholestasis (jaundice and/or pruritus) persisting for up to a month following delivery. Just occasionally, liver transplantation is necessary if the mother develops severe hepatic encephalopathy—hence all mothers thought to have AFLP should be transferred to a transplant centre if possible.

Pregnancy Toxemias (Hypertension-Related Liver Diseases of Pregnancy)

These must be suspected in a pregnant woman who after 20 weeks of gestation or within 48 h of delivery is found to have systemic hypertension, fluid retention, and proteinuria which defines pre-eclampsia if there is no other obvious cause for these findings.

The pathogenesis is presumed to be increased systemic vascular resistance due to excessive pressure responses to endogenous vasoconstrictors. This in turn leads to increased endothelial cell permeability, and deposition of platelets and fibrin in hepatic sinusoids, which causes both focal and diffuse hepatocellular necrosis with hemorrhage. Both are best seen on liver biopsy although this procedure is rarely necessary to make the diagnosis.

Evidence that the disease is hepatic in origin is obvious on routine blood testing as a marked elevation of serum aminotransferases (>10-fold elevation) and modest increase in serum alkaline phosphatase (ALP) is usual. Jaundice is rare unless disseminated intravascular coagulation has superseded, in which case there may be an unconjugated hyperbilirubinemia. The platelet count may be low. Ultrasound of the liver may show focal filling defects due to intrahepatic hematomas.

Strict control of systemic blood pressure is always required throughout pregnancy, but if the blood pressure goes out of control and there is also evidence of hepatic involvement (ALT 10-fold elevation) immediate delivery of the baby should be contemplated and supportive care maintained.

The HELLP Syndrome

The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet syndrome; Box 24.4) is a rare variant of pre-eclampsia (occurring in 5–10%) when hemolysis and thrombocytopenia are added to the complex described above (i.e. elevated serum aminotransferase and ALP levels). Sometimes there may have been no overt preceding pre-eclampsia. The mother may be quite asymptomatic; others complain of right upper quadrant pain, nausea, and vomiting. Hypertension and proteinuria are present in 85%, INR values usually remain normal and elevated serum uric acid levels are the best marker of disease severity (>464 µmol/L associated with both maternal and infant mortality). Sometimes there may also be an overlap with AFLP. A falling platelet count is the marker of this “mixed” syndrome. The degree of elevation in the liver biochemical tests does not reflect the severity of liver disease, so as soon as the diagnosis is made immediate arrangements for delivery of the fetus is essential as the perinatal mortality ranges from 10–60% with a maternal mortality 1.5–5%.