A typical laboratory finding that I run into on a daily basis is elevated liver enzymes.  When I first started practicing, I did not know precisely how to work this finding up appropriately, and I was fearful that I was missing a diagnosis. 


Today we will talk about possible etiologies for elevated liver enzymes that are less than five times the normal upper limit, as well as the path to diagnosis.

Elevated liver enzymes (ELE) are seen in approximately ten percent of the United States population. However, only five percent of these cases have considerable or worrisome liver disease.1  Often these patients will be asymptomatic, and it is found on routine screening labs.


When the hepatocytes (liver cells) are damaged they release ALT and AST.  When the ALT is elevated, this is more likely due to liver injury.  When the AST is elevated, this can be related to liver injury, but can also be due to celiac disease, thyroid conditions, muscle conditions, or hemolysis.


The ratio of AST:ALT can point towards a specific disease as well.  If the AST:ALT ratio is greater than two this can suggest alcoholic liver disease.  If the ratio is less than one, this can point towards nonalcoholic fatty liver disease (NAFLD).


The causes of mildly elevated liver enzymes are split into category lists as below.  These being common, uncommon, and rare etiologies.



Nonalcoholic fatty liver disease (NAFLD) has been shown to be the most common cause of elevated liver enzymes.  Studies have shown that in patients with ELE, approximately 25 to 51 percent of these cases were due to NAFLD.  In my practice, NAFLD is largely the most common etiology of ELE.


NAFLD has two subsets, one being that the patient has fatty deposition of the liver without inflammation.  The other is fatty deposition of the liver with inflammation which can advance to fibrosis and cirrhosis.  This is known as nonalcoholic steatohepatitis (NASH).


NAFLD is typically benign and can be treated with conservative measures and lifestyle changes, whereas those with NASH have concerning risk factors for progression to cirrhosis or hepatocellular carcinoma.1



Regarding diagnosis of nonalcoholic fatty liver disease, ultrasonography is the first-line choice which reveals hepatic steatosis or fatty deposition of the liver.  Unfortunately, ultrasound does not differentiate between NAFLD and NASH.


It is essential to identify those with NAFLD who are at an increased risk of disease progression.  Liver fibrosis has been found to be the best predictor of progression of NAFLD towards NASH.1


Currently, numerous clinical tests can aid in finding those patients with fibrosis as opposed to a more invasive liver biopsy.  The NAFLD Fibrosis Score uses laboratory findings to calculate the potential risk of progression of liver disease and complications associated.1


The next step for patients who have ELE, with findings consistent with NAFLD on ultrasound, should be to calculate the NAFLD Fibrosis Score.  Patients with an elevated score should be referred to GI for further evaluation and treatment.


Gastroenterology may proceed with vibration-controlled transient elastography, which is a newer test that aids in the assessment of liver fibrosis, and can further narrow down and help determine which patients need a liver biopsy.1


In addition to strict dietary changes for the treatment of NAFLD, treating other comorbidities is essential as well.  Closely managing diabetes with medication such as metformin and hyperlipidemia with statins as long as liver enzymes are less than three times the upper limit of normal. 


Pioglitazone up to 45 mg daily has been shown to provide benefit in patients with both NAFLD and NASH by lowering inflammation, steatosis, and fibrosis, even in patients who do not have diabetes.  However, be aware of swelling and weight gain or other signs of heart failure with this medication.


Hypertension should be closely treated as well.  Data has shown that Angiotensin Receptor Blockers, such as Losartan, can be beneficial due to Angiotensin II being involved in the process of hepatic fibrosis.2  Other medications that may help are orlistat as well as Vitamin E taken at 800 IU per day.4  Bear in mind that this high of a dose of Vitamin E can be correlated to risk of prostate cancer and hemorrhagic stroke.


Alcoholic liver disease is another common etiology for elevated liver enzymes.  Often NAFLD versus alcoholic liver disease can be challenging to differentiate between unless there are history findings that point you towards the latter.  In these cases, the Alcoholic Liver Disease/NAFLD index can aid in diagnosis.


This tool distinguishes between the two based on the ALT, AST, and MCV levels, height, sex, and weight.


An uncommon cause of ELE is drug-induced liver injury.  The incidence of this is believed to be around 19.1 per 100,000 persons annually, but it is considered to be underreported.  With the ever-increasing use of OTC supplements, this is now seen as 9 percent of drug-induced liver injury cases.


Tylenol use, even at normal doses can cause ELE.  Medications that are associated with elevated liver enzymes and liver injury are as listed below.



Statins have been known to cause ELE, but this is believed to be rare.  The United States FDA currently recommends checking liver function studies before the initiation of statin therapy but does not recommend routine monitoring.  If there is suspicion of this occurring in your patient, however, these labs should be checked.


Viral hepatitis is  a common cause of ELE.  In the U.S. around 3.5 million people have hepatitis C, and an additional 2.2 million with hepatitis B.1  The USPSTF recommends screening with a hepatitis B surface antigen and hepatitis C virus antibody test.1


Due to the number of cases of hepatitis in the United States as above, if a patient has unexplained ELE in my practice I will regularly run a hepatitis panel.  I have run upon several cases of patients with ELE who have hepatitis C that was unknown prior.


Another uncommon cause of elevated liver enzymes is hereditary hemochromatosis.  This is an autosomal recessive condition which leads to increased iron absorption as well as increased iron release from the tissue macrophages.1


In patients with ELE, iron studies should be completed, specifically looking at the TIBC and ferritin, and calculating the iron saturation.  If the saturation is higher than 50 percent, then I will often refer to hematology for further evaluation and testing for the HFE gene.  Treatment for this condition is therapeutic phlebotomy.


Rare causes of ELE include alpha1 antitrypsin deficiency, autoimmune hepatitis, and Wilson disease.  Extrahepatic causes such as rhabdomyolysis, thyroid disorders, celiac disease, and polymyositis can cause elevated liver enzymes as well.


Workup for mildly elevated liver enzymes has been hit on as above with the many different potential etiologies, but we will put it all together now.


When mild (less than five times the normal upper limit) ALT and AST elevation are seen on blood work you should look at the patient as a whole.  Do they have findings that would be consistent with NAFLD such as obesity, hyperlipidemia, or diabetes?  Look at their medication list, is there a drug that could be the cause of this lab finding?


The initial lab testing should include a lipid panel, A1c, and TSH if not completed with the initial CMP that likely found the ELE in the first place.  Also, iron studies including serum iron, ferritin, TIBC, a CBC, and hepatitis panel should be ordered.  If clinical findings are consistent with potential NAFLD, you could consider ordering a right upper quadrant ultrasound at that time as well.


If the initial workup does not find a cause, then an ultrasound would be a good idea to complete at that point.  If findings on this study are consistent with NAFLD, lifestyle changes and comorbid disease management should be addressed.  Additionally, a NAFLD fibrosis score should be calculated, and if elevated referral to gastroenterology should be considered.


If the initial laboratory results and imaging are negative, you can consider monitoring and repeating liver function studies.  If the elevation persists, then further investigation of less likely etiologies as mentioned above should be completed.


This includes looking at a TSH if not done initially, ANA, anti-smooth muscle antibodies, and anti-liver microsomal antibodies.  Further testing such as ceruloplasmin, CPK, SPEP, peripheral blood smear, and a celiac panel can be completed if clinical findings are suggestive.  Referral to gastroenterology would be appropriate for further evaluation and treatment at this point of the workup as well.



Overall, just like most things in medicine, there is more than one way to skin the proverbial cat.  This is just an overview of one way and a general outline of how I go about working up mildly elevated liver function studies.



Resources


  1. Am Fam Physician. Mildly Elevated Liver Transaminase Levels: Causes and Evaluation. 2017 Dec 1;96(11):709-715.
  2. UpToDate. Natural History and Management of Nonalcoholic Fatty Liver Disease in Adults. Accessed: January 31, 2018.
  3. Am Fam Physician. Causes and Evaluation of Mildly Elevated Liver Transaminase Levels. 2011 Nov 1;84(9):1003-1008.
  4. Family Practice Notebook. Nonalcoholic Fatty Liver Disease. Accessed: January 31, 2018.
  5. Family Practice Notebook. Liver Function Test Abnormality. Accessed: January 31, 2018.


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