Liver function test and pregnancy

Liver function test and pregnancy

PRADUMNA JAMJUTE, AMIR AHMAD, TARUN GHOSH, & PHILIP BANFIELD

Department of Obstetrics & Gynaecology, Glan Clwyd Hospital, North Wales NHS Trust, Rhyl, North Wales, UK,

LL18 5UJ

(Received 11 February 2007; revised 20 March 2008; accepted 20 March 2008)

Abstract

The physiological changes in liver function in pregnancy are commonly transient, rarely permanent. Disorders arising inpregnancy, such as pre-eclampsia and eclampsia, acute fatty liver of pregnancy (AFLP), haemolysis, elevated liver enzymeand low pletelets (HELLP) syndrome, cholestasis, hyperemisis gravidarum and isolated cases of raised liver enzymes canhave serious implications. Proper interpretation of liver function tests (LFTs) at an early stage can lead to timelymanagement and may reduce complications in both mother and fetus. Normal LFTs do not always mean that the liver isnormal. A number of pitfalls can be encountered in the interpretation of basic blood LFTs. The commonly used LFTsprimarily assess liver injury rather than hepatic function. Abnormal LFTs may indicate that something is wrong with theliver, and they can provide clues to the nature of the problem but this is not always the case. The various biochemical tests,their pathophysiology, and an approach to the interpretation of abnormal LFTs are discussed in this review. Commonlyavailable tests include alanine transaminase, aspartate transaminase, alkaline phosphatase, bile acid, serum bilirubin, serumalbumin and prothrombin time.

Keywords: Liver function tests, pregnancy

Quantitative tests of liver function

Limitations of the various biochemical tests have

prompted the search for more sensitive and quanti-

tative tests of liver function. Though these tests are

currently limited to research centres they include [1]:

Indocyanine green clearance, C-aminopyrine breath

test [2], antipyrine clearance, galactose elimination

capacity, C-caffeine breath test [3].

Normal liver function in pregnancy

Although the increase in the cardiac output peaks at

32 weeks, the blood flow in the liver remains the

same or in some studies decreases.

In a prospective analysis of aspartate transaminase

(AST), alanine transaminase (ALT), bilirubin and

gamma-glutamyl transferase (GGT) in 430 pregnant

women it was found that these tests were about 20%

lower in pregnant women when compared with

laboratory reference ranges [4].

Liver disease in pregnancy should be considered in

three categories:

Pre-existing disease, disease specific to pregnancy

and coincidental acute liver or biliary tree disease.

Diseases specific to pregnancy have a characteristic

time of onset. In the last trimester, close obstetric

management is required in the presence of abnormal

liver function tests (LFTs), in association with

nausea and/or vomiting and abdominal pain. This

clinical picture may be seen in severe pre-eclampsia,

haemolysis, elevated liver enzyme and low pletelets

(HELLP) syndrome or acute fatty liver of pregnancy

(AFLP), management of which is early delivery as

soon and as safely as possible. These form a

spectrum of disease that ranges from having mild

Normal values of liver enzymes in pregnancy.

NonTrimester

Liver enzymes pregnant 1st 2nd 3rd

AST (IU/l) 7–40 10–28 10–29 11–30

ALT (IU/l) 0–40 6–32 6–32 6–32

Bilirubin (mmol/l) 0–17 4–16 3–13 3–14

Gamma GT (IU/l) 11–50 5–37 5–43 3–41

Alkaline phosphatase

(ALP) (IU/l)

30–130 32–100 43–135 133–418

Bile acid (mmol/l) 5–10 5.3–5.7 5.6–6.5

Correspondence: P. Jamjute, Specialist registrar, Ysbyty Glan Glwyd, Rhyl, LL18 5UJ, North Wales, UK. Tel: þ01745583910 BLEEP 6690.

E-mail: [email protected]

The Journal of Maternal-Fetal and Neonatal Medicine, March 2009; 22(3): 274–283

ISSN 1476-7058 print/ISSN 1476-4954 online � 2009 Informa Healthcare USA, Inc.

DOI: 10.1080/14767050802211929

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symptoms to severe life-threatening multi-organ

dysfunction.

Minor elevations in amino-transferases may be a

harbinger of life-threatening processes.

Changes in individual enzymes specific

to liver disease in pregnancy

(see Tables I, II, III and IV)

Aspartate transaminase and alanine transaminase

Markers of hepatocellular injury. The most com-

monly used markers of hepatocyte injury are AST

(formerly serum glutamic-oxaloacetic transaminase)

and ALT (formerly serum glutamate-pyruvate trans-

aminase).

AST is present in cytosolic and mitochondrial

isoenzymes and is found in the liver, cardiac muscle

skeletal muscle, kidneys, brain, pancreas, lungs,

leucocytes and red cells [5]. It is less sensitive and

specific for the liver.

ALT, a cytosolic enzyme is found in its highest

concentrations in the liver and is more specific to the

liver [5].

Hepatocyte necrosis in acute hepatitis, toxic

injury or ischemic injury results in the leakage of

enzymes into the circulation. As markers of hepa-

tocellular injury, AST and ALT also lack some

specificity because they are found in skeletal muscle.

Levels of these aminotransferases can rise to several

times normal after severe muscular exertion or other

muscle injury, as in polymyositis [6], or in the

presence of hypothyroidism. In fact, AST and ALT

were once used in the diagnosis of myocardial

infarction.

Slight AST or ALT elevations (within 1.5 times

the upper limits of normal) do not necessarily

indicate liver disease. Part of this ambiguity has to

do with the fact that unlike the values in many other

biochemical tests, serum AST and ALT levels do not

follow a normal bell-shaped distribution in the

population [7]. Instead, AST and ALT values have

a skewed distribution characterised by a long ‘tail’ at

the high end of the scale [8]. The ALT distributions

in males and nonwhites (i.e. blacks and Hispanics)

tend to have a larger tail at the high end, so that more

values fall above the upper limits of normal set for the

average population [9,10].

AST and ALT values are higher in obese patients,

probably because these persons commonly have fatty

livers [11]. ALT levels have been noted to decline

with weight loss [12]. Depending on the physician’s

point of view, the upper limits of normal for AST and

ALT levels could be set higher for more obese

persons.

Rare individuals have chronically elevated AST

levels because of a defect in clearance of the enzyme

from the circulation [13]. For both AST and ALT,

the average values and upper limits of normal in

patients undergoing renal dialysis are about one half

of those found in the general population [14]. Mild

elevations of ALT or AST in asymptomatic patients

can be evaluated efficiently by considering alcohol

abuse, hepatitis B, hepatitis C and several other

possible diagnoses [6].

Various liver diseases are associated with typical

ranges of AST and ALT levels. ALT levels often rise

to several thousand units per litre in patients with

acute viral hepatitis. The highest ALT levels (often

more than 10,000 IU/l) are usually found in patients

with acute toxic injury subsequent to, for example,

acetaminophen overdose or acute ischemic insult to

the liver. AST and ALT levels usually fall rapidly

after an acute insult.

Lactate dehydrogenase (LDH) is less specific

than AST and ALT as a marker of hepatocyte

injury. However, it is worth noting that LDH is

disproportionately elevated after an ischemic liver

injury [15].

Table I. Common liver disorders in different trimesters of

pregnancy.

Differential diagnosis Trimester of pregnancy

Hyperemesis gravidarum First

Gallstones

Viral hepatitis

Drug-induced hepatitis

Intrahepatic cholestasis of pregnancy*

Intrahepatic cholestasis of pregnancy Second

Gallstones

Viral hepatitis

Drug-induced hepatitis

Pre-eclampsia/eclampsia*

HELLP syndrome*

Intrahepatic cholestasis of pregnancy Third

Pre-eclampsia/eclampsia

HELLP syndrome

Acute fatty liver of pregnancy

Heptic rupture

Gallstones

Viral hepatitis

Drug-induced hepatitis

*Uncommon in this trimester.

Table II. Pregnancy associated liver disease-recurrence rates.

Pregnancy associated

liver disease

Rate of

recurrence (%)

Incidence

(%)

Intra-hepatic cholestasis

of pregnancy

40–60 0.7

HELLP 4–27 0.2–0.6

Acute fatty liver of pregnancy Occasionally 0.01

Pre-eclampsia 2–43 5–7

Liver function test and pregnancy 275

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It is especially important to remember that

in patients with acute alcoholic hepatitis, the

serum AST level is almost never greater than

500 IU/l and the serum ALT value is almost never

greater than 300 IU/l. The reasons for these limits on

AST and ALT elevations are not well understood. In

typical viral or toxic liver injury, the serum ALT level

rises more than the AST value, reflecting the relative

amounts of these enzymes in hepatocytes. However,

in alcoholic hepatitis, the ratio of AST to ALT is

greater than one in 90% of patients and is usually

greater than two [16]. The higher the AST/ALT

ratio, the greater the likelihood that alcohol is

contributing to the abnormal LFTs. In the absence

of alcohol intake, an increased AST/ALT ratio is

often found in patients with cirrhosis.

The elevated AST/ALT ratio in alcoholic liver

disease results in part from the depletion of vitamin

B6 (pyridoxine) in chronic alcoholics [17]. ALT and

AST both use pyridoxine as a coenzyme, but the

synthesis of ALT is more strongly inhibited by

pyridoxine deficiency. Alcohol also causes mitochon-

drial injury, which releases the mitochondrial iso-

enzyme of AST.

Pre-eclampsia. Hepatic dysfunction with pre-

eclampsia has long been recognised [18]. More

recently, this dysfunction has been associated with

other findings in the HELLP syndrome. This

syndrome may complicate the course in 3–10% of

patients with pre-eclampsia and is noted in 0.1%

of all pregnancies [19,20]. The pathophysiology of

Table III. Pregnancy associated liver disease and derangement of liver functions.

Pregnancy associated liver disease

Amino-

transferases Bile acids Bilirubin

Alkaline

phosphatase Uric acid Platelets PT/PTT

Urine

protein

Hyperemesis gravidarum 1–26 Normal 55 mg/dl 1–26 Normal Normal Normal Normal

Intra-hepatic cholestasis of pregnancy 1–46 30–1006 55 mg/dl 1–26 Normal Normal Normal Normal

Acute fatty liver of pregnancy 1–56 Normal 510 mg/dl 1–26 " þ7# þ7" þ7"Pre-eclampsia/eclampsia 1–1006 Normal 55 mg/dl 1–26 " þ7# þ7" "HELLP 1–1006 Normal 55 mg/dl 1–26 " # þ7" þ7"Hepatic rupture 2–1006 Normal þ7" " Normal þ7# þ7" Normal

", increases; #, decreases.

Table IV. Liver disease specific to pregnancy & maternal and fetal outcome.

Liver diseases specificMaternal outcome Fetal outcome

Neonatal

to pregnancy Maternal mortality Morbidity Perinatal mortality Morbidity outcome

Obstretic cholestasis 10.6/1000 Prematurity: 7–25%

Caeseran section rates: 10–36% Passage meconium:12% (T)

Postpartum haemorrhage: 2–22% 25% (PT)

Recurrence rate: 60–70%

Pre-eclampsia mortality: 1.8%

HELLP syndrome Mortality: 2% Hepatic failure:15% 7–20% Prematurity: 70%

Abruptio placenta: 16% 14% IUGR

Acute renal failure: 8%

Subcapsular liver Hematoma: 1%

Retinal detachment: 1%

DIC: 15%

Pulmonary edema: 8%

Recurrance: 2–6%

Acute fatty liver of pregnancy 10–21% Hepatic failure: 27–33% Mortality: 7%

Hypoglycemia

Renal failure:

pre-eclampsia: 20–40%

Deranged clotting:

Hyperemesis gravidarum Wernickes encephalopathy: Low birth weights

Korasakoffs psychosis:

Central pontine myelinolysis:

DVT:

Hepatic rupture and infarction 16–60% Shock 40–60%

Coagulopathy Prematurity

Hepatic abscess

Pleural effusion

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HELLP syndrome reflects that of pre-eclampsia,

with microvascular damage, platelet activation and

vasospasm. Liver biopsy reveals periportal hemor-

rhage and fibrin deposition [21]. Recent data suggest

that a defect in nitric oxide metabolism may

contribute to pre-eclampsia and HELLP syndrome

[22,23].

Notable hepatic abnormalities in the HELLP

syndrome include hemolysis (with elevated bilirubin

levels and LDH levels greater than 600 IU/l),

moderately elevated transaminase levels (AST and

ALT levels of 200–700 IU/l) and a platelet count

less than 100,000 per ml (1006 109 per litre)

[24,25]. Patients typically present with right upper

quadrant pain and malaise [24,25]. Sixty percent of

patients exhibit significant weight gain or oedema;

50% have nausea or vomiting [25]. No correlation

has been noted between extent of hypertension,

liver function test abnormalities or liver biopsy

findings [21].

The maternal and fetal complications of HELLP

syndrome are significant. The maternal mortality

rate is 2%, and the perinatal mortality rate is 33%

[26]. Among the hepatic consequences are a 2%

incidence of hepatic rupture (with frequent conco-

mitant mortality) and a 4–38% incidence of dis-

seminated intra-vascular coagulation [25].

The most effective treatment for HELLP syn-

drome is prompt delivery [24,25]. Postpartum

corticosteroids have proved efficacious in improving

maternal platelet counts, ALT levels and blood

pressure [27]. Therapies that have not proved

efficacious include plasmapheresis [28], antithrom-

botic agents and immunosuppression [25].

Following delivery, laboratory abnormalities peak

in the first 1–2 days postpartum and return to normal

within 3–11 days. The risk of recurrence of HELLP

syndrome in subsequent pregnancies has been

reported as 3.4% [20].

Acute fatty liver of pregnancy. AFLP most frequently

complicates the third trimester and is commonly

associated with pre-eclampsia (50–100%) [24,25].

Although rare (with an incidence of one in

13,000), AFLP is a life-threatening condition,

with an 18% maternal and a 23% fetal mortality

rate [29].

Symptoms associated with AFLP include anorex-

ia, nausea, vomiting, abdominal pain, jaundice,

headache and central nervous system disturbances

[25,29]. Hepatic histopathology reveals pericentral

microvesicular fat with minimal inflammation or

necrosis. Liver biopsy is not indicated for diagnosis

[30]. The laboratory abnormalities in AFLP include

moderate elevations of transaminase levels (AST

and ALT less than 1000 IU/l), prolongation of

prothrombin time and partial thromboplastin time,

decreased fibrinogen, renal failure, profound hypo-

glycemia and increased bilirubin levels of 1–10 mg

per dl (17.1–171.0 mmol/l).

Recurrent AFLP has been reported in mothers

expressing heterozygous long-chain 3-hydroxyacyl-

CoA dehydrogenase deficiency [30–32].

The treatment of AFLP is expeditious delivery

and intensive care. Patients usually improve

promptly following delivery and, in the absence of

long-chain 3-hydroxyacyl-CoA dehydrogenase defi-

ciency, the prognosis in pregnancies following

AFLP is good.

Hepatic rupture and infarction. Hepatic rupture and

infarction, extremely rare complications of pre-

eclamptic liver disease, usually occur in the third

trimester [33]. The incidence of hepatic rupture

varies from one in 40,000 to one in 250,000

pregnancies [34]; hepatic infarction is even more

rare. Older multigravid mothers with pre-eclampsia

are at highest risk. Hepatic rupture most commonly

involves the right lobe [33]. It is believed to be a

continuum of pre-eclampsia, in which areas of

coalescing hemorrhage result in thinning of the

capsule and intra-peritoneal hemorrhage [33]. Nu-

merous pseudoaneurysms in the area of hemorrhage

have been documented in case reports, raising the

possibility of a vasculopathy contributing to this rare

disorder [34].

Patients with hepatic rupture typically present in

shock, with preceding right upper quadrant pain,

hypertension, elevated transaminase levels (greater

than 1000 IU/l) and coagulopathy [33]. Therapy for

hepatic rupture has included transfusion of blood

products and intravenous fluids, surgical evacuation

and arterial embolisation [33]. These therapies have

met with only moderate success; a 59–70% maternal

mortality rate and a 75% perinatal mortality rate have

been noted in hepatic rupture [33]. Late complications

arising after treatment of hepatic rupture include

hepatic abscess formation and pleural effusions.

Hepatic infarction and hepatic rupture is best

detected by using computed tomographic scans or

magnetic resonance imaging [30,35]. Patients typi-

cally present with fever and marked elevations in

transaminase levels. In surviving patients, liver

function and histopathology are normal within 6

months of delivery [30,36]. Intra-hepatic hemor-

rhage has been reported to recur in a minority of

subsequent pregnancies [34].

Others common causes of raised transaminases.

Alcohol. Medications: non-steroidal anti-inflam-

matory drugs, antibiotics, HMG Co-A-reductase

inhibitors, antiepileptic drugs, antituberculous

drugs, herbal medications, illicit drug use.

Liver function test and pregnancy 277

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Non-alcoholic steatohepatosis.Chronic hepatitis

B and C.

Autoimmune diseases. Haemochromatosis.

Wilson’s disease.

Congestive cardiac failure and ischaemic hepatitis.

a1-antitrypsin deficiency. Coeliac disease.

Endocrine disease: hypothyroidism, Addison’s

disease, Glycogen storage diseases.

For management protocol see Figure 1.

Alkaline phosphatase

ALP originates mainly from two sources: liver and

bone [37]. The enzymes may be present in a variety

of other tissues namely intestine, kidney placenta and

leucocytes. The serum ALP level rises during the 3rd

trimester of pregnancy because of a form of the

enzyme produced in the placenta. When serum ALP

originates from bone, clues to bone disease are often

present, such as recent fracture, bone pain or Paget’s

disease of the bone . Like the GGT value, the ALP

level can become mildly elevated in patients who are

taking phenytoin [35,38].

If the origin of an elevated serum ALP level is in

doubt, the isoenzymes of AP can be separated by

electrophoresis. However, this process is expensive

and usually unnecessary because an elevated GGT

level, an elevated 50-nucleotidase level and other

LFT abnormalities, usually accompanies an elevated

liver ALP value.

Persistently, elevated ALP values in asymptomatic

patients, especially women, can be caused by pri-

mary biliary cirrhosis, which is a chronic inflam-

matory disorder of the small bile ducts. Serum

Figure 1. Management of raised ALT in pregnancy.

Causes mild or moderate elevations of ALT and AST

Drug-induced

Hyperemesis gravidarum

Cholelithiasis

Acute fatty liver of pregnancy

Intra-hepatic cholestasis of pregnancy

Alcoholic hepatitis

Marked increase in ALT and AST

Viral hepatitis

Drugs or toxins

HELLP syndrome

Severe pre-eclampsia

Liver function and rupture

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antimitochondrial antibody is positive in almost all of

these patients.

It is also worth noting that ALP may be raised in

malignancies without liver or bone involvement. This

isoenzyme is called the ‘Regan isoenzyme’ and occurs

in various neoplasms for example lung cancers [1].

Common causes of raised ALP

Physiological

Women in the third trimester of pregnancy.

Adolescents.

Benign, familial (because of increased intestinal

ALP).

Pathological- bile duct obstruction, Primary biliary

cirrhosis, Primary sclerosing cholangitis, Drug in-

duced cholestasis – for example, anabolic steroids,

dult bile ductopenia, metastatic liver disease.

Bone disease.

For management protocol see Figure 2.

Bile acid

Bile acids are synthesised in the liver from cholester-

ol. The different bile acids are cholic, chenodoxy-

cholic and deoxycholic acids. Serum bile acids are

elevated in almost 92% of patients with obstetrics

cholestasis. While raised transaminase and bilirubin

is found in only 60% and 25%, respectively. The rate

of fetal complications increases when maternal

serum bile acid levels become elevated in women

who develop intra-hepatic cholestasis of pregnancy

(ICP). In a prospective cohort study conducted

between February 1999 and January 2002 in Sweden

ICP (defined as pruritus in pregnancy plus 10 mmol/l

or more of serum bile acids) occurred in 1.5% of

45,485 pregnancies recorded. The probability of the

fetal complications of spontaneous preterm deliv-

eries, asphyxial events, and meconium stainig of

Mild to moderate elevations in ALP

Acute fatty liver of pregnancy

Pre-eclampsia

HELLP syndrome

Cholestasis of pregnancy

Hyperemesis gravidarum

Phenytoin

Causes of markedly elevated ALP

Extrahepatic biliary obstruction

Hepatic rupture

Primary biliary cirrhosis

Drug induced cholestasis

Infiltrative processes (e.g. amyloid, granulomatous hepatitis,

neoplasm)

Sepsis

Figure 2. ALP protocol in pregnancy. *ALP rise with other raised liver enzymes can be seen in- cirrhosis, hepatitis, infiltrative disease of liver.

Liver function test and pregnancy 279

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aminotic fluid, placenta and membranes rose by

1.5–2% for each additional mmole/l of maternal

serum bile acids when the total level of bile acids

exceeded 40 mmol/l. No increase in fetal risks

was detected in ICP patients with bile acid

levels540 mmol/l. Most of the woman with ICP

(81%) had serum bile acids levels between 10 and

39 mmol/l (mild form), whereas the other 19% had

serum bile acid levels more than 40 mmol/l (severe

form) [39].

Markers of cholestasis

Cholestasis (lack of bile flow) results from the

blockage of bile ducts or from a disease that impairs

bile formation in the liver itself. AP and GGT levels

typically rise to several times the normal level after

several days of bile duct obstruction or intra-hepatic

cholestasis. The highest liver ALP elevations, often

greater than 1000 U per litre, or more than six times

the normal value, are found in diffuse infiltrative

diseases of the liver such as infiltrating tumors and

fungal infections.

Diagnostic confusion can occur when a pa-

tient presents within a few hours after acute

bile duct obstruction from a gallstone. In this

situation, AST and ALT levels often reach 500 U

per litre or more in the first hours and then decline,

whereas ALP and GGT levels can take several days

to rise.

Both ALP and GGT levels are elevated in about

90% of patients with cholestasis [40]. The elevation

of GGT alone, with no other LFT abnormalities,

often results from enzyme induction by alcohol or

aromatic medications in the absence of liver

disease. The GGT level is often elevated in persons

who take three or more alcoholic drinks (45 g of

ethanol or more) per day [41]. Thus, GGT is a

useful marker for immoderate alcohol intake.

Phenobarbital, phenytoin and other aromatic drugs

typically cause GGT elevations of about twice

normal. A mildly elevated GGT level is a typical

finding in patients taking anticonvulsants and by

itself does not necessarily indicate liver disease

[42,43].

Intra-hepatic cholestasis of pregnancy

ICP occurs in 0.05% of pregnancies. It typically

arises in the third trimester of pregnancy, although

it has been reported as early as 13 weeks’

gestation [44–46]. The pathophysiology of ICP

remains poorly understood [45]. Pruritus alone

occurs in 80% of patients; pruritus and jaundice

develop in 20% of patients [46]. Laboratory

abnormalities include a bilirubin level less than

5 mg per dl (85.5 mmol/l), minimal or no elevation

in transaminase, cholesterol and triglyceride levels,

and infrequent, mild to moderate steatorrhea. Liver

histopathology reveals centrilobular bile stasis [46].

ICP is associated with a 12–44% incidence of

prematurity, a 16–25% incidence of fetal distress

and an increased perinatal mortality rate (1.3%–

3.5%) [25,44].

A clear racial and genetic predisposition for this

disorder has been described. Intra-hepatic choles-

tasis complicates 0.01%–0.02% of pregnancies in

North America, 1–1.5% of pregnancies in Sweden

and 5–21% of pregnancies in Chile [46]. The

disease is rare in black patients [46]. A strong

family history of cholestasis of pregnancy is typi-

cally described by the patient [46]. Kindred

studies reveal alterations in bromosulfophthalein

clearance following oestrogen treatment in both

male and female relatives of women affected by ICP

[45].

Patients exhibiting cholestasis of pregnancy should

receive close fetal surveillance at delivery [25,46]

Symptoms of cholestasis usually resolve within 2

days of delivery. Elevated serum bilirubin and ALP

levels return to normal 4–6 weeks after delivery [25].

Cholestasis of pregnancy recurs in 60–70% of

subsequent pregnancies [25].

For management protocol see Figure 3.

Figure 3. Bile acid protocol in pregnancy.

280 P. Jamjute et al.

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Albumin

Albumin synthesis is an important function of the

liver. Approximately 10 g is synthesised and se-

creted daily. With progressive liver disease serum

albumin levels fall, reflecting decreased synthesis.

Albumin levels are dependant on a number of other

factors such as the nutritional status, catabolism,

and urinary and gastrointestinal losses. These

should be taken into account when interpreting

low albumin levels. Having said that, albumin

concentration does correlate with the prognosis in

chronic liver disease.

Prothrombin time

The synthesis of coagulation factors (except factor

VIII) is an important function of the liver. The

prothrombin time measures the rate of conversion of

prothrombin to thrombin (requiring factors II, V, VII

and X) and thus reflects a vital synthetic function of

the liver. Vitamin K is required for the g carboxyla-

tion of the above named factors. Prothrombin time

may therefore be prolonged in vitamin K deficiency,

warfarin therapy, liver disease and consumptive

coagulopathy. It is important to distinguish a

prolonged prothrombin time because of hepatocel-

lular disease from that due to chronic cholestasis

with fat malabsorption. In practice, a useful way of

differentiating the two is the administration of

vitamin K, which will reduce a prolonged prothrom-

bin time due to fat malabsorption, but not due to

intrinsic liver disease.

Blood ammonia

Measurement of the blood ammonia concentration

is not always useful in patients with known or

suspected hepatic encephalopathy. Ammonia con-

tributes to hepatic encephalopathy; however, am-

monia concentrations are much higher in the brain

than in the blood and therefore do not correlate

well [29]. Furthermore, ammonia is not the only

waste product responsible for encephalopathy.

Thus, blood ammonia concentrations show only a

mediocre correlation with the level of mental status

in patients with liver disease. It is not unusual for

the blood ammonia concentration to be normal in a

patient who is in a coma from hepatic encephalo-

pathy.

Blood ammonia levels are best measured in arterial

blood, because venous concentrations can be ele-

vated as a result of muscle metabolism of amino

acids. Blood ammonia concentrations are most

useful in evaluating patients with stupor or coma of

unknown origin. It is not necessary to evaluate blood

ammonia levels routinely in patients with known

chronic liver disease who are responding to therapy

as expected [47].

Cholelithiasis and cholecystitis

Cholelithiasis is noted in as many as 6% of pregnant

women [33,48]. Pregnancy induced changes in bile

composition predispose these patients to cholelithia-

sis [49,50]. The bile salt pool decreases in the second

trimester, and biliary cholesterol levels may increase,

resulting in lithogenic bile [49]. In addition, gall-

bladder emptying slows in the second trimester,

increasing the risk of cholelithiasis.

Symptoms of cholelithiasis are similiar in preg-

nant and nonpregnant patients [49]. Patients

with cholecystitis typically present with laboratory

abnormalities, including leukocytosis and mild to

moderate elevations of transaminase and bilirubin

levels. The ALP level progressively increases during

normal pregnancy and is unhelpful in distinguishing

hepatobiliary disease. A liver ultrasound examina-

tion is most helpful in determining the presence

of cholelithiasis or sludge in symptomatic pa-

tients [49].

Surgical treatment (i.e. laparoscopic cholecystect-

omy) of biliary colic can be safely accomplished in

the first or second trimester [33].

As the uterus enlarges, surgery becomes more

difficult and should be avoided during the third

trimester [49].

A retrospective review [18] of 19,000 pregnancies

revealed that 11% of surgical emergencies were

attributable to biliary tract disease. Choledocho-

lithiasis accounts for *7% of patients with

jaundice in pregnancy [50] patients presenting

with pancreatitis during pregnancy, 90% have

choledocholithiasis [50]. Gallstone pancreatitis is

associated with a 15% maternal mortality rate and

a 60% fetal mortality rate. One group of investigators

[18] reported safely performing endoscopic retro-

grade cholangiopancreatography and endoscopic

retrograde sphincterotomy without complications in

five pregnant women (in the second and third

trimesters) with choledocholithiasis using minimal

fluoroscopy and lead aprons to shield the abdomen.

All of the women delivered healthy babies at term

[50].

When to refer for a specialist opinion

This would normally include [51] patients with:

1. Unexplained liver abnormalities more than 1.5

times normal on two occasions, a minimum of

6 weeks post pregnancy.

2. Unexplained liver disease with evidence

of hepatic dysfunction (hypoalbuminaemia,

Liver function test and pregnancy 281

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hyperbilirubinaemia, prolonged prothrombin

time or international normalised ratio).

3. Known liver disease where treatment beyond

the withdrawal of the implicating agent is

required.

What tests to do before referral [51]

Consider the following:

1. Screen for viral hepatitis: IgM antihepatitis

A virus, HbsAg, antihepatitis C virus.

2. Antinuclear antibodies.

3. Caeruloplasmin in patients younger than

40 years.

4. Ultrasound of the liver especially where fatty

infiltration is suspected (obese individuals, dia-

betics and/or hyperlipidaemic patients).

Key points

Abnormal liver tests may present in an asymptomatic

patient.

A good clinical history and physical examination

are often rewarding.

Liver tests often become abnormal in non-hepatic

diseases.

If a systematic approach is adopted the cause is

often apparent.

An ultrasound should also be performed in

symptomatic patients with liver enzyme abnormal-

ities or those with evidence of hepatic dysfunction

(increased bilirubin or prothrombin time, or de-

creased albumin) and in those with biochemical

evidence of cholestasis.

Declaration of interest: The authors report no

conflicts of interest. The authors alone are respon-

sible for the content and writing of the article.

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