Transaminitis, Elevated Liver Enzymes and The Fatty Liver
Two articles look at liver transaminase levels, signs, symptoms, causes, diagnosis, and management.
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WHAT DOES IT MEAN AND WHAT SHOULD BE DONE WHEN IT OCCURS?
A COMMON CONUNDRUM IN PRIMARY CARE
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by Eleni Florakis and Jeffrey R. Abergel, M.D.
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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
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.
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
Phenytoin (Dilantin)- mild transaminase elevation usually transient but if significant elevation persists discontinuation is warranted5
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Valproic acid (Depakene)
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.
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.
NAFLD vs NASH
IS YOUR PATIENT AT RISK?
Nonalcoholic fatty liver disease (NAFLD) vs Nonalcoholic steatohepatitis (NASH)
by Madeleine Beckman and David Kauvar, MD
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.
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.
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.
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
Lowering triglyceride and cholesterol levels
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.
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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ABOUT THE AUTHORS of Transaminitis - What Does it Mean and What Should be Done When it Occurs?
Eleni Florakis is currently a fourth-year medical student at the Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, PA. She is interested in pursuing a residency in Internal Medicine and possibly practicing as a Primary Care Physician or Gastroenterologist in the future.
Dr. Jeff Abergel is a board-certified gastroenterologist at New York-Presbyterian Medical Group Hudson Valley. After earning his medical degree at the Sackler School of Medicine in Israel, Dr. Abergel completed his internship and residency in internal medicine at the Mount Sinai School of Medicine in New York. He then completed his fellowship in gastroenterology at Robert Wood Johnson School of Medicine in New Jersey. In 2015, Dr. Abergel was honored by the Crohn’s and Colitis Foundation of America’s charity event, “Take Steps” Walk on Staten Island. His research has been published in both medical journals and textbooks. Additionally, his work has been presented at national meetings of the American College of Gastroenterology
ABOUT THE AUTHORS of NAFLD vs NASH: Is Your Patient at Risk?
Madeleine Beckman is a writer and editor specializing in medicine & wellness. She teaches Narrative & Reflective Writing at NYU School of Medicine in the Division of Medical Humanities, and Creative Nonfiction with Denver University. Her books are available online. madeleinebeckman.com
Dr. David Kauvar, Assistant Professor of Medicine at Columbia University Medical Center, is board-certified in Internal Medicine and Gastroenterology. Dr. Kauvar obtained his medical degree from the University of Colorado and completed his internship and residency in Internal Medicine at the University of California-San Diego. His fellowships in Gastroenterology were completed at the University of Colorado, Denver, and Beth Israel Hospital in Boston. Dr. Kauvar holds memberships in the American Society of Gastroenterology and American of Gastrointestinal Motility. .
References for Transaminitis
1 Devarbhavi H. An Update on Drug-induced Liver Injury. J Clin Exp Hepatol. 2012 Sep; 2(3): 247–259. Published online 2012 Sep 21. doi: 10.1016/j.jceh.2012.05.002
2 Lisinopril. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Last Update: February 11, 2018
3 Voican C, Corruble E, Naveau S, Perlemuter G. Antidepressant-induced liver injury: a review for clinicians.
Am J Psychiatry. 2014 Apr;171(4):404-15. doi: 10.1176/appi.ajp.2013.13050709.
4 Fu P, Xia Q, Guo L, Yu H and Chan P. Toxicity of Kava Kava. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2008 Jan-Mar; 26(1): 89–112. doi: 10.1080/10590500801907407
5 Phenytoin. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.
6 Tamoxifen. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Last Update: August 20, 2020.
ArAGon G, Younossi ZM. When and how to evaluate mildly elevated liver enzymes in apparently healthy patients. Cleve Clin J Med. 2010 Mar 1;77(3):195-204.
Alatalo PI, Koivisto HM, Hietala JP, Puukka KS, Bloigu R, Niemelä OJ. Effect of moderate alcohol consumption on liver enzymes increases with increasing body mass index. The American journal of clinical nutrition. 2008 Oct 1;88(4):1097-103.
Alempijevic T, Zec S, Milosavljevic T. Drug-induced liver injury: Do we know everything?. World J Hepatol. 2017;9(10):491-502. doi:10.4254/wjh.v9.i10.491
Coates P. Liver function tests. Australian Family Physician. March 2011;40(3):113-115.
Forlani G, Di Bonito P, Mannucci E, Capaldo B, Genovese S, Orrasch M, Scaldaferri L, Di Bartolo P, Melandri P, Dei Cas A, Zavaroni I. Prevalence of elevated liver enzymes in Type 2 diabetes mellitus and its association with the metabolic syndrome. Journal of endocrinological investigation. 2008 Feb;31(2):146-52.
Fox A, Sanderlin JB, McNamee S, Bajaj JS, Carne W, Cifu DX. Elevated liver enzymes following polytraumatic injury. Journal of Rehabilitation Research & Development. 2014 Jun 1;51(6).
Friedman L. Approach to the patient with abnormal liver biochemical and function tests. UpToDate Web site. Updated Jun 10, 2020. Accessed February 18, 2021.
Jeon CY, Roberts CK, Crespi CM, Zhang ZF. Elevated liver enzymes in individuals with undiagnosed diabetes in the US. Journal of Diabetes and its Complications. 2013 Jul 1;27(4):333-9.
Krier M, Ahmed A. The Asymptomatic Outpatient with Abnormal Liver Function Tests. Clinics in Liver Disease. 2009;13(2):167-177. https://doi.org/10.1016/j.cld.2009.02.001.
Lee, Tae Hoon, W. Ray Kim, and John J. Poterucha. Evaluation of elevated liver enzymes. Clinics in Liver Disease. 2012; 16(2):183-198.
Madan, Kaushal, et al. Role of polymerase chain reaction and liver biopsy in the evaluation of patients with asymptomatic transaminitis: implications in diagnostic approach. Journal of gastroenterology and hepatology. 2004;19(11): 1291-1299.
Mahady SE, Wong G, Turner RM, Mitchell P, Macaskill P, Craig JC, George J. Elevated Liver Enzymes and Mortality in Older Individuals. Journal of clinical gastroenterology. 2017 May 1;51(5):439-45.
Mainous AG, Diaz VA, King DE, Everett CJ, Player MS. The relationship of hepatitis antibodies and elevated liver enzymes with impaired fasting glucose and undiagnosed diabetes. The Journal of the American Board of Family Medicine. 2008 Nov 1;21(6):497-503.
Malakouti M, Kataria A, Ali SK, Schenker S. Elevated Liver Enzymes in Asymptomatic Patients - What Should I Do?. J Clin Transl Hepatol. 2017;5(4):394-403. doi:10.14218/JCTH.2017.00027
Oh R, Hustead TR, Ali SM, et al. Mildly Elevated Liver Transaminase Levels: Causes and Evaluation. Am Fam Physician. 2017 Dec 1;96(11):709-715.
Papatheodoridis GV, Goulis J, Christodoulou D, Manolakopoulos S, Raptopoulou M, Andrioti E, Alexandropoulos N, Savvidou S, Papachristou A, Zervou E, Seferiadis K. High prevalence of elevated liver enzymes in blood donors: associations with male gender and central adiposity. European journal of gastroenterology & hepatology. 2007 Apr 1;19(4):281-7.
Rahmani J, Miri A, Namjoo I, Zamaninour N, Maljaei MB, Zhou K, Cerneviciute R, Mousavi SM, Varkaneh HK, Salehisahlabadi A, Zhang Y. Elevated liver enzymes and cardiovascular mortality: a systematic review and dose–response meta-analysis of more than one million participants. European journal of gastroenterology & hepatology. 2019 May 1;31(5):555-62.
Senadhi V. A paradigm shift in the outpatient approach to liver function tests. Southern Medical Journal.2011 Jul;104(7):521-525. DOI: 10.1097/smj.0b013e31821e8ff5.
Singh, Wg Cdr Vishal, and Wg Cdr Prateek Kinra. Mild Transaminitis in asymptomatic aircrew-a clinical dilemma. Ind J Aerospace Med 52 (2008): 2.
St. George A, Bauman A, Johnston A, Farrell G, Chey T, George J. Effect of a lifestyle intervention in patients with abnormal liver enzymes and metabolic risk factors. Journal of gastroenterology and hepatology. 2009 Mar;24(3):399-407.
Tapper EB, Saini SD, Sengupta N. Extensive testing or focused testing of patients with elevated liver enzymes. Journal of hepatology. 2017 Feb 1;66(2):313-9.
References for NAFLD vs NASH
Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology. 2001;33:1358–1364.
Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs–II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol. 1993;46:1331–1336.
Boettcher E, Csako G, Pucino F, et al. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2012; 35:66-75.
Bril F, Kalavalapalli S, Clark VC, et al. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes. Clin Gastroenterol Hepatol. 2018;16:558-566.e2.
Chopra S, Lai M. Management of nonalcoholic fatty liver disease in adults. UpToDate Web site. Updated June 24, 2019. Accessed August 15, 2019.
Danan G, Benichou C. Causality assessment of adverse reactions to drugs–I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46:1323–1330.
Gerhard GS, Hanson A, Wilhelmsen D, et al. AEBP1 expression increases with severity of fibrosis in NASH and is regulated by glucose, palmitate, and miR-372-3p. PLoS One. 2019;14:e0219764.
Harrison SA. Correlation between insulin resistance and hepatitis C viral load. Hepatology. 2006;43:1168.
Houglum K, Venkataramani A, Lyche K, Chojkier M. A pilot study of the effects of D-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C. Gastroenterology. 1997;113:1069–1073.
Kirkendoll SM. NASH may overtake hepatitis C as top liver transplant cause. M Health Lab Web site. October 31, 2017. Accessed August 15, 2019.
Kotronen A, Juurinen L, Hakkarainen A, et al. Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects. Diabetes Care. 2008;31:165–169.
Molloy JW, Calcagno CJ, Williams CD, Jones FJ, Torres DM, Harrison SA. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology. 2012;55:429-436.
Moucari R, Asselah T, Cazals-Hatem D, et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008;134:412–423.
Nonalcoholic fatty liver disease. Barnes-Jewish St. Peters Hospital Web site. Accessed August 15, 2019.
Patel A, Harrison SA. Hepatitis C virus infection and nonalcoholic steatohepatitis. Gastroenterol Hepatol (N.Y.) 2012;8:305-312.
Patal B, Sanyal AJ. Drug-induced steatohepatitis. Clin Liver Dis. 2013;17:533-vii.
Pessayre D, Fromenty B, Berson A, et al. Central role of mitochondria in drug-induced liver injury. Drug Metab Rev. 2012;44:34–87
Rivera C. Risk factors and mechanisms of non-alcoholic steatohepatitis. Pathophysiology. 2008;15:109-114.
Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010; 362:1675-1685.
Shteyer E, Villenchik R, Mahamid M, Mator N, Safadi R. Low serum lysosomal acid lipase activity correlates with advanced liver disease. Int J Mol Sci. 2016;17:312.
Sookoian S, Pirola CJ. Genetic predisposition in nonalcoholic fatty liver disease. Clin Mol Hepatol. 2017;23:1-12.
Speliotes EK, Butler JL, Palmer CD, et al. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology. 2010;52:904-912.
Younossi Z, Lavine JE, Charlton M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67:328–357.
Zoler ML. Obeticholic acid reversed NASH liver fibrosis in phase 3 trial. MDEdge Web site. April 12, 2019. Accessed August 15, 2019.
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