The first step in the workup of a patient with a persistent asymptomatic alkaline phosphatase (ALP) elevation is to measure gamma-glutamyltranspeptidase to determine whether the elevation is liver-related or bone-related.
Although its differential diagnosis is less extensive than that of aminotransferase elevations, a persistent elevation of alkaline phosphatase (ALP) can still be a diagnostic challenge. The various types of biliary tract disease often present with nonspecific symptoms.
In a previous article (CONSULTANT, December 2007), we discussed the evaluation of patients with persistent aminotransferase elevations. Here we review the possible causes of ALP elevations and the tests needed to nail down each of these diagnoses (Table). We also discuss the unique differential diagnosis of liver function test abnormalities during pregnancy, and we present a systematic approach to the pregnant patient with a liver enzyme elevation.
|Table – Possible causes of liver-associated ALP elevations, with appropriate tests|
|Suspected diagnosis||Tests to include in the workup|
|Obstruction||U/S and/or MRC|
|Primary biliary cirrhosis||AMA, liver biopsy|
|Primary sclerosing cholangitis||MRC or ERC|
|Infiltrative and/or granulomatousdiseases (eg, amyloidosis, TB, sarcoidosis, fatty liver, lymphoma, leukemia)||Varies with specific suspected disease; liver biopsy is important|
|Cholestasis of pregnancy||Diagnosis is clinical|
CAUSES OF ALP ELEVATIONS: NARROWING THE DIFFERENTIAL
ALP elevations are seen in certain types of liver disease, in bone disease, in pregnancy, and in certain neoplastic disorders that do not involve the liver (eg, hypernephroma). When an ALP elevation is detected, the first step in the workup is to determine whether the elevation is liver-related or bone-related. A gamma-glutamyltranspeptidase (GGTP) measurement can establish this and should be ordered in any patient with an ALP elevation (an elevated level indicates that the ALP abnormality is liver-related). Once it is established that the elevation is associated with liver disease or injury, a careful history and review of systems can help narrow the differential.
Drugs. Like aminotransferase elevations, ALP elevations can be caused by a variety of agents. Drug-induced ALP elevations are usually associated with an agent that was started recently-a few weeks or at most a few months earlier. Thus, be sure to ask patients not only what medications they take but also how long they have been taking them. Common culprits include clavulanate and trimethoprim/sulfamethoxazole. Intra-arterial injections of chemotherapeutic agents may also be to blame.
Supplements, too, can cause ALP elevations; some anabolic steroids, for example, can cause a cholestatic jaundice that is often associated with an elevated ALP level. Be sure to ask patients about all agents used, not just prescription medications.
Symptoms and signs. Typical symptoms in patients with biliary disease include fatigue, joint pains, and in more advanced cases, pruritus that first develops on the palms and soles and that can eventually be quite profound and widespread. Because part of the pathophysiology of biliary disease is the inability of cholesterol to enter the bile, both low-density lipoprotein and high-density lipoprotein cholesterol levels may be elevated; depositions of cholesterol in the form of xanthelasmas and xanthomas are often seen as well.
Comorbidities. Ask about all forms of autoimmune disease, including hypothyroidism; autoimmune phenomena are very common in patients with primary biliary cirrhosis (PBC). Also ask about granulomatous and infiltrative illnesses. Sarcoidosis, drug-induced granulomatosis, tuberculosis-indeed, the whole spectrum of granulomas-can be associated with an elevated ALP level. (In fact, PBC is itself a granulomatous liver disease.) The presence of inflammatory bowel disease-particularly ulcerative colitis-raises suspicion of primary sclerosing cholangitis (PSC), which is often associated with the condition. Finally, determine whether the patient has a history of biliary tract surgery, which can cause partial biliary obstruction. For example, a duct incorrectly tied off during gallbladder surgery can have this result.
Epidemiology. The sex and age of a patient can make particular diagnoses more or less likely. PBC is most often seen in women, usually first presenting in middle age. When it does occur in men, it is usually at a more advanced age. PSC, on the other hand, is most common in younger men.
WORKUP FOR SUSPECTED PBC
If clues in the history and review of systems point to PBC, the next step is to order a test for antimitochondrial antibodies (AMA) (Algorithm I). A positive result heightens the suspicion of PBC but does not confirm the diagnosis (nor does a negative result necessarily rule out PBC; AMA results are sometimes negative in patients with an atypical form of PBC). For confirmatory testing, refer the patient to a specialist (a specialist is likely to order a liver biopsy to confirm the presence of PBC).
If PBC is diagnosed, a bone density scan is usually warranted as well. With any chronic cholestatic disorder, insufficient bile salts result in poor fat absorption, and because fat binds to calcium, osteoporosis is much more common in patients with PBC.
WORKUP FOR SUSPECTED PSC
PSC is best diagnosed by cholangiography, either endoscopic retrograde cholangiography (ERC) or magnetic resonance cholangiography (MRC) (Algorithm II). Although ERC is the more sensitive of the 2 tests and will unequivocally confirm the diagnosis, it usually makes sense to try MRC first. MRC is a noninvasive test and thus does not carry the risk of iatrogenic pancreatitis associated with ERC. Moreover, technological advances have made the MRC more sensitive than it used to be; today, the test will pick up most cases of PSC. Liver biopsy is generally not necessary. A negative result on MRC in a patient with an elevated ALP level and a negative AMA result suggests atypical PBC or autoimmune cholangiopathy.
EVALUATION OF LFT ABNORMALITIES IN PREGNANCY
Liver function test (LFT) elevations can occur in any phase of pregnancy. Different potential diagnoses assume greater prominence depending on how far along a woman's pregnancy is when the LFT elevation appears. Keep in mind that ALP levels normally rise during pregnancy (primarily during the third trimester-up to levels 2 or 3 times normal by term); these elevations are benign. Remember, too, that an elevated LFT level in a pregnant woman might have nothing to do with her pregnancy: for example, it could be caused by a viral hepatitis or gallbladder disease. Thus, always rule out benign and non-pregnancy-related causes before proceeding with any further workup (Algorithm III).
First trimester. LFT elevations early in pregnancy are usually caused by hyperemesis gravidarum. The levels usually go down once the patient stops vomiting.
Second and third trimesters. Several disorders seen later in pregnancy (usually the third trimester) are associated with elevated LFT levels. The least serious of these is cholestasis of pregnancy, typical symptoms of which include intense pruritus and jaundice. Cholestasis of pregnancy can be associated with an increased risk of fetal loss but by and large is a benign condition that resolves after delivery.
LFT elevations are also one of the laboratory abnormalities that characterize the HELLP (Hemolysis, Elevated Liver enzymes, and Low Platelet count) syndrome, a rare but serious complication of preeclampsia. The HELLP syndrome is an obstetrical emergency that requires prompt delivery.
Acute fatty liver of pregnancy is another rare disorder that is life-threatening and requires immediate delivery for its resolution. Acute fatty liver of pregnancy usually develops as a patient nears term; patients typically present in an acutely ill state, with nausea, vomiting, and jaundice (even though ALP levels are not strikingly high). The liver shows signs of mitochondrial injury similar to that seen in Reye syndrome. Liver disease may be accompanied by renal failure, hypoglycemia, or disseminated intravascular coagulation.
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