2 CME eligible articles. Transaminitis: What Does it Mean? NAFLD vs NASH: Is Your Patient at Risk?
Continuing Medical Education
Eligible for CME Credit
Transaminitis, What does it mean and what should be done when it occurs?
A Common Conundrum in Primary Care
Transaminitis CME - Part 1
Transaminitis Introduction / Signs and Symptoms
The term transaminitis, refers to an elevation in serum transaminases. These transaminases include alanine transaminase (ALT) and aspartate transaminase (AST). ALT is also known as SGPT (serum glutamic pyruvic transaminase), and AST as SGOT (serum
glutamic-oxaloacetic transaminase).
An elevation in these enzymes may indicate hepatocellular injury. ALT is a more specific marker of hepatocellular cell injury since it is found almost exclusively in liver tissue, whereas AST is also present in cardiac muscle, skeletal muscle, kidney, and brain. Both are released into the bloodstream during liver injury.
Transaminitis is a common occurrence in the primary care setting and can be discovered incidentally or as part of a workup for a symptomatic patient. Some symptoms that can be associated with transaminitis include fatigue, pruritis, jaundice, abdominal pain or swelling, nausea, vomiting, and edema of the legs/ankles. Asymptomatic transaminitis is also quite common. It has been estimated that approximately 1% to 9% of asymptomatic people have elevated liver enzyme levels at any given time. Thus, it is important to recognize when testing should be done for these patients and what to look for.
Causes
Nonalcoholic fatty liver disease(NAFLD) and nonalcoholic steatohepatitis (NASH) are among the most common causes of transaminitis. It can affect up to 30 percent of the population. Other causes include alcoholic liver disease, drug-induced liver injury (DILI), viral hepatitis (Hepatitis B and C), autoimmune hepatitis, hemochromatosis, Wilson’s Disease, alpha 1 antitrypsin deficiency, and infiltrative diseases. Below is a list of common medications associated with elevated liver transaminase levels.
Selected Medications Associated with Elevated Liver Transaminase Levels
(list not complete)
Ace Inhibitors (lisinopril (Prinivil, Zestril), captopril, enalapril)
Two possible causes, both rare- cholestasis or acute hepatitis2
Acetaminophen
Allopurinol (Zyloprim)
Amiodarone
Anabolic steroids
Anti-depressant medications3
Isoniazid (INH)
Kava kava4
Ketoconazole
Methotrexate
Phenytoin (Dilantin)- mild transaminase elevation usually transient but if significant elevation persists discontinuation is warranted5
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Rifampin
Statins
Tamoxifen6
Tetracyclines
Valproic acid (Depakene)
Diagnosis
The first step in evaluating a patient with abnormal liver enzymes is a thorough history and physical examination. Many causes of liver injury, such as alcoholic liver disease and DILI, can be identified by gathering a detailed history. Risk factors for other causes of liver injury that can be ascertained through a careful history include intravenous drug use, travel to areas endemic for viral hepatitis, weight gain, history of other autoimmune conditions, family history of liver disease, and occupational/recreational exposure to hepatotoxins.
Physical examination is crucial for identifying the etiology of transaminitis. Exam findings that may indicate cirrhosis include spider nevi, palmar erythema, gynecomastia, and caput medusae (enlarged superficial epigastric veins).
The presence of Virchow’s node (enlarged left supraclavicular node), Sister Mary Joseph’s nodule (periumbilical nodule), or an abdominal mass may suggest malignancy. The degree of aminotransferase elevation and ratio of AST to ALT can also provide clues. There are just a few conditions that can lead to very high aminotransferase levels, in the range of thousands of units/liter. In this scenario, the clinician should focus on acute viral hepatitis, toxins (most commonly acetaminophen), autoimmune hepatitis, liver ischemia and rarely, acute bile duct obstruction. If a patient’s AST to ALT ratio is 2:1 or greater, when both values are elevated, alcoholic liver disease should be considered, especially if the gamma-glutamyl transferase levels are elevated.
Initial testing for transaminitis should include Hepatitis A, B and C serologies, as well as serum ferritin and percent iron saturation(also known as percent transferrin saturation), to assess for hemochromatosis.
If the above tests are unrevealing and liver enzyme elevation persists, a right upper quadrant ultrasound should be ordered to rule out dilated bile ducts or masses. Anti-nuclear Antibody(ANA), anti-smooth muscle antibody, anti-mitochondrial M2 antibody, anti-liver kidney microsomal antibody and quantitative immunoglobulins should be checked to rule out autoimmune diseases of the liver. Wilson’s Disease and alpha 1 antitrypsin deficiency, two rare disorders, can be identified by checking ceruloplasmin and alpha-1 antitrypsin enzyme level (respectively). The patient’s medication list should be carefully reviewed using LiverTox produced by the National Institute of Diabetes and Digestive and Kidney Diseases or the FDA Liver Toxicity Knowledge Base .
If all of the above tests are unrevealing, the most likely diagnosis is nonalcoholic fatty liver disease. To make this diagnosis, there are two options. NASH Fibrosure is a panel of tests whose results are calculated to identify the degree of steatohepatitis and fibrosis. (For more information about this test use this hyperlink https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/604200). A more invasive option is a liver biopsy which has the added benefits of being more accurate than the NASH Fibrosure and can identify other pathologies that were not identified in the bloodwork. Liver elastography is an imaging study that can estimate the fibrotic content of the liver, though it is primarily available at large academic centers.
Management
If an underlying liver disease, such as Hepatitis C, NASH, autoimmune hepatitis or cirrhosis are discovered, referral to a hepatologist or gastroenterologist is a reasonable course of action. If LFTs remain mildly elevated for 6 months, referral is warranted as well.
If DILI is suspected, nonessential medications that have the potential to cause elevations in transaminases should be held and alternatives to essential medications should be considered.
If alcoholic liver disease or DILI is suspected, transaminase levels should be reassessed after 6-8 weeks of abstinence.
Editor’s note: What do you do about a new elevation in transaminases after initiation of a statin? In our opinion, if less than 2 times normal, address the risk factors (alcohol, etc,), check hepatitis C Ab and other lab tests as described above, and continue the statin and monitor LFT's first after 3 months, then in 6 months and then yearly. Another approach is to stop the statin to see if LFTs improve. And if they do, consider restarting the statin and recheck every 6 months to make sure they are not continuing to rise.
PART 2
NAFLD vs NASH
IS YOUR PATIENT AT RISK?
Nonalcoholic fatty liver disease (NAFLD) vs Nonalcoholic steatohepatitis (NASH)
Nonalcoholic steatohepatitis (NASH), a form of liver disease, is associated with obesity, high blood pressure, type-2 diabetes, high cholesterol and triglyceride levels, use of certain medications, and genetics. In addition, it commonly is seen among patients with metabolic syndrome and insulin resistance. NASH is most prevalent during middle age, but it has been seen in pediatric populations. Primary complications of the disease include fibrosis, cirrhosis, and liver cancer.
Nonalcoholic fatty liver disease (NAFLD), a condition caused by fat accumulation in the liver, may progress to NASH, which includes further fat accumulation and progressive inflammation. Increased inflammation can lead to scarring of the liver and/or cirrhosis. Approximately 20% of people with NAFLD develop NASH, and some 12% of NASH patients develop cirrhosis.
Signs and symptoms associated with NAFLD include enlarged liver, obesity, elevated serum liver transaminase levels, and insulin resistance. Evidence of liver fibrosis can be identified by utilizing the NASH Fibrosure blood test, magnetic resonance elastography or vibration-controlled transient elastography. Consider one of these assessments if the patient is at higher risk for developing steatohepatitis (e.g., those with poorly controlled diabetes).
Fatty Liver Biopsy
Pathologic evaluation by biopsy is the most accurate way to truly distinguish NAFLD from NASH; however, the need for a biopsy should be decided by either a hepatologist or an experienced gastroenterologist. The primary physician should try to exclude other causes of elevated liver transaminases, such as alcohol consumption, viral hepatitis , autoimmune disease, or hemochromatosis.
Fatty Liver
The association between genetic variations and NAFLD and NASH is being widely studied. Results of one study by Speliotes et al. at the Massachusetts General Hospital showed that certain inherited variations in lipid metabolism precede and possibly lead to the development of liver disease. Variation of the PNPLA3 gene correlates with an increased risk of severe histologic features of NAFLD without having a strong effect on metabolic syndrome component traits. The PNPLA3 gene produces adiponutrin, a protein that seems to help regulate the production of adipocytes, lipogenesis, and lipolysis in hepatocytes and adipocytes. PNPLA3 appears to be part of a family of enzymes that affect lipid metabolism. Altered lipid metabolism, particularly within the liver, can affect fat accumulation, subsequent development of NAFLD, and possibly NASH. Genetic analyses may allow researchers to chart the causal pathways that lead to disease complications of NAFLD and other metabolic risk factors to potentially target them for therapeutic intervention.
Results from a recent Temple University study by Gerhard et al. showed that increased expression of the AEBP1 gene correlates with the severity of liver fibrosis in patients with NASH. Having the AEBP1 gene appears to correlate with the onset and severity of fibrosis in NASH patients, suggesting that AEBP1 may represent a specific therapeutic target to prevent development of NASH fibrosis.
DIAGNOSIS
NAFLD is usually asymptomatic. However, some patients report feeling tired or experience discomfort in the right upper quadrant of the abdomen if they have progressed to NASH or cirrhosis. NASH can be diagnosed using bloodwork (NASH Fibrosure) or imaging (Elastography) ; however, needle biopsy is considered to be the diagnostic “gold” standard.
MANAGEMENT
A serious concern with respect to diagnosis and treatment of NASH is the growing obesity rate. In 10 years, there may be more than a 50% annual increase in NASH patients needing a liver transplant.
The basic and most effective strategy for treating NASH is for patients to improve their overall health by changing their lifestyles. Steps include:
Lowering high blood pressure
Eating a low-fat diet
Restricting alcohol
Lowering triglyceride and cholesterol levels
Losing weight
Getting more exercise
In patients with type II Diabetes Mellitus, pioglitazone (Actos), should be considered as it has been shown to reduce fibrosis, steatosis, and inflammation. Vitamin-E supplementation may also be useful in noncirrhotic patients with biopsy confirmed steatohepatitis.
Recently, use of obeticholic acid (Ocaliva), an agonist of the farnesoid X receptor that was approved by the US Food and Drug Administration to treat primary biliary cholangitis, was shown to significantly improve regression of fibrosis in NASH patients. The Randomized Global Phase 3 Study to Evaluate the Impact on NASH with Fibrosis of Obeticholic Acid Treatment (REGENERATE) was conducted by the National Institutes of Health and is now in phase-III testing with 931 patients. Results have shown a 28% rate of fibrosis regression, and a significant number of study patients showed normalization of liver enzyme levels.
Conclusion
NASH, whether driven by genetics, body composition, dietary indiscretion, use of toxic medications, or possible viral infections, still remains a mostly elusive condition in cause, prognosis, and management. More complete information on its etiology, diagnosis, and treatment ultimately will lead to a healthier population and a lesser demand for liver transplantation.
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Initially published 8/1/2021