Liver enzymes: No trivial elevations, even if asymptomatic
ABSTRACT
Primary care physicians are at the forefront in screening for abnormal levels of liver enzymes and investigating the likely causes by obtaining a detailed history and physical examination, followed by appropriate laboratory and diagnostic workup. This review outlines common causes for the two main mechanisms of liver injury—cholestasis and hepatocellular insult—and explores the associated risk factors, methods of diagnosis, and management, with a focus on nonalcoholic fatty liver disease, one of the most often encountered causes of abnormal liver enzyme levels.
KEY POINTS
- Disorders of hepatocellular injury tend to elevate levels of aminotransferases, whereas cholestatic disorders cause elevations of alkaline phosphatase and bilirubin.
- The three most common causes of liver enzyme elevation are alcohol toxicity, medication overdose, and fatty liver disease.
- Other disorders of liver dysfunction include hereditary hemochromatosis, viral hepatitis, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and alpha-1 antitrypsin disease.
- Nonhepatic causes of elevated “liver enzymes” also need to be considered. For instance, rhabdomyolysis causes elevations in aminotransferase levels.
OTHER DISORDERS OF LIVER FUNCTION
Hereditary hemochromatosis
Hereditary hemochromatosis is the most common inherited liver disorder in adults of European descent,17 and can be effectively treated if discovered early. But its clinical diagnosis can be challenging, as many patients have no symptoms at presentation despite abnormal liver enzyme levels. Early symptoms may include severe fatigue, arthralgias, and, in men, impotence, before the appearance of the classic triad of “bronze diabetes” with cirrhosis, diabetes, and darkening of the skin.18
If hemochromatosis is suspected, laboratory tests should include a calculation of percent transferrin saturation, with saturation greater than 45% warranting serum ferritin measurement to evaluate for iron overload (ferritin > 200–300 ng/mL in men, > 150–200 ng/mL in women).19 If iron overload is confirmed, referral to a gastroenterologist is recommended.
Genetic evaluation is often pursued, but patients may ultimately require liver biopsy regardless of the findings, as some patients homozygous for the HFE mutation C282Y may not have clinical hemochromatosis, whereas others with hereditary hemochromatosis may not have the HFE mutation.
Therapeutic phlebotomy is the treatment of choice, and most patients tolerate it well.
Chronic hepatitis B virus and hepatitis C virus infections
Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are common in the United States, with HBV affecting more than 1 million people and HCV affecting an estimated 3.5 million.
Chronic HCV infection. Direct-acting antiviral drugs have revolutionized HCV treatment and have led to a sustained viral response and presumed cure at 12 weeks in more than 95% of cases across all HCV genotypes.20 Given the recent development of effective and well-tolerated treatments, primary care physicians have assumed a pivotal role in screening for HCV.
The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America21 recommend screening for HCV in people who have risk factors for it, ie:
- HCV exposure
- HIV infection
- Behavioral or environmental risks for contracting the virus such as intravenous drug use or incarceration
- Birth between 1945 and 1965 (one-time testing).
If HCV antibody screening is positive, HCV RNA should be obtained to quantify the viral load and confirm active infection, and genotype testing should be performed to guide treatment. Among the 6 most common HCV genotypes, genotype 1 is the most common in North America, accounting for over 70% of cases in the United States.
Although recommendations and therapies are constantly evolving, the selection of a treatment regimen and the duration of therapy are determined by viral genotype, history of prior treatment, stage of liver fibrosis, potential drug interactions, and frequently, medication cost and insurance coverage.
HBV infection. The treatment for acute HBV infection is generally supportive, though viral suppression with tenofovir or entecavir may be required for those who develop coagulopathy, bilirubinemia, or liver failure. Treatment of chronic HBV infection may not be required and is generally considered for those with elevated ALT, high viral load, or evidence of liver fibrosis on noninvasive measurements such as transient elastography.
Autoimmune hepatitis
Autoimmune causes of liver enzyme elevations should also be considered during initial screening. Positive antinuclear antibody and positive antismooth muscle antibody tests are common in cases of autoimmune hepatitis.22 Autoimmune hepatitis affects women more often than men, with a ratio of 4:1. The peaks of incidence occur during adolescence and between ages 30 and 45.23
Primary biliary cholangitis
Additionally, an elevated alkaline phosphatase level should raise concern for underlying primary biliary cholangitis (formerly called primary biliary cirrhosis), an autoimmune disorder that affects the small and medium intrahepatic bile ducts. Diagnosis of primary biliary cholangitis can be assisted by a positive test for antimitochondrial antibody, present in almost 90% of patients.24
Primary sclerosing cholangitis
Elevated alkaline phosphatase is also the hallmark of primary sclerosing cholangitis, which is associated with inflammatory bowel disease.25 Primary sclerosing cholangitis is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, which are visualized on MRCP and confirmed by biopsy if needed.
REFERRAL
Subspecialty referral should be considered if the cause remains ambiguous or unknown, if there is concern for a rare hepatic disorder such as an autoimmune condition, Wilson disease, or alpha-1 antitrypsin deficiency, or if there is evidence of advanced or chronic liver disease.
Primary care physicians are at the forefront of detecting and diagnosing liver disease, and close coordination with subspecialists will remain crucial in delivering patient care.
