Abnormal liver tests are a common occurrence in the United States.¹ Based on National Health and Nutrition Examination Survey III data, approximately 7.9% of the population has an elevated level of aspartate aminotransferase (AST) or alanine aminotransferase (ALT).² Because of this, abnormal liver tests are a common indication for referral to a gastroenterologist. This article outlines a stepwise, guideline-based approach to management of these patients.

The terms “liver function tests,” or “LFTs,” are not exactly correct. Although some liver tests—such as bilirubin, albumin, and international normalized ratio—do relate to liver function, liver tests such as AST, ALT, and alkaline phosphatase relate more to liver injury and/or other structural issues. For this reason, this article uses the terms abnormal liver chemistries, tests, or enzymes and specifically focuses on the evaluation of patients with abnormal ALT, AST, alkaline phosphatase, and/or bilirubin.

AST and ALT

Assessing a patient with abnormal AST and ALT requires delving further into the definition of normal versus abnormal. Normal lab values generally are defined as the mean value of a healthy population ± 2 SD, which is based on the control population that the various labs use. Upper limit of normal (ULN) levels for AST and ALT can vary by a factor of 2 to 4, depending on the lab.

Studies have demonstrated that individuals with higher AST and ALT have increased morbidity and/or mortality,^3-6 which likely represents underlying fatty liver disease and its associated metabolic risk factors as well as alcoholic liver disease. Some of the control populations used by labs to determine their specific ULN values have included individuals with these risk factors.

Because of this, many have proposed the concept of a true normal AST and ALT level based on a control population that excludes patients with fatty liver risk factors and alcohol use, which would result in much lower ULN levels for AST and ALT.

In the 2017 clinical guideline on abnormal liver chemistries from American College of Gastroenterology (ACG), based on many studies and surveys of many of the world’s leading hepatologists, we proposed that the true ULN for ALT should be 29 to 33 U/L in males and 19 to 25 U/L in females.⁷ However, using these lower ALT ULN values will significantly increase the number of patients defined as having elevated liver enzymes, up to 36% of men and 28% of women.⁸ This has clinical and financial implications, including more patients being referred for elevated liver enzymes, more testing, and increased costs.

AST and ALT are preformed in liver cells and released as a result of hepatocellular injury. However, AST also is found in skeletal muscle, cardiac muscle, the kidneys, and the brain. ALT is present mostly in the liver and, thus, is a more specific marker of liver injury than AST. There are no specific clarifying tests to determine whether AST or ALT elevations are from the liver.

Alkaline Phosphatase

Alkaline phosphatase is found in the hepatocytes on the canalicular membrane. It increases in patients with cholestatic liver disease, due to either mechanical obstruction (eg, extrahepatic cholestasis) or impairment of bile formation/flow/filtration by the liver (eg, intrahepatic cholestasis). Hepatic elevations of alkaline phosphatase can occur in obstructive liver diseases, infiltrative liver diseases, primary cholestatic diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), and granulomatous liver diseases. Alkaline phosphatase also is found in other organs including bone (the most common extrahepatic source), the placenta, the intestines, and the kidneys.

The most common clarifying test used is a gamma-glutamyl transferase (GGT). However, GGT can be elevated in patients with significant alcohol use, even in the absence of liver disease. Alkaline phosphatase isoenzymes also can be used as a clarifying test and can point to the specific origin of the elevation.

Bilirubin

Bilirubin is a breakdown product of senescent red blood cells and generally circulates in the unconjugated form tightly bound to albumin. Conjugation of bilirubin makes it water-soluble, allowing it to be excreted in the bile and converted in the colon to urobilinogen, which is excreted in urine and stool.

The main clarifying test for bilirubin elevation would be fractionation of the bilirubin. Fractionating the bilirubin may not be necessary in patients who present with obvious liver disease, including elevated AST, ALT, and/or alkaline phosphatase.

Elevated conjugated (direct) bilirubin occurs with liver disease and/or cholestasis, and should prompt a liver workup. Potential etiologies include biliary obstruction, acute alcoholic hepatitis, postoperative jaundice, drug-induced liver injury, hepatitis, and multifactorial/ICU jaundice. Elevated unconjugated (indirect) bilirubin can be seen in conditions such as Gilbert’s syndrome (about 6% of the US population)⁹ or hemolysis and should prompt an initial assessment for nonhepatic causes.

Algorithmic Approach to Diagnosis In Setting of Elevated Liver Enzymes

Unless there is obvious evidence of liver damage, clinicians may want to start with repeat liver tests to confirm elevations. Clinicians then should consider several factors, including ruling out nonhepatic causes of elevations, assessing the various common/uncommon causes of elevated liver enzymes, defining the pattern of elevations, assessing the magnitude of elevations, and looking into the timing of the elevations.

The first step should be a thorough history and physical examination to assess for fatty liver disease risk factors, alcohol use, risk factors for autoimmune diseases, family history of liver disease, and a thorough evaluation of the patient’s medication history. Drug-induced liver injury can be precipitated by prescription medications, herbal supplements, and over-the-counter agents. Getting an accurate history of these potential agents can be very difficult. On exam, clinicians should look for obesity, stigmata of chronic liver disease, and any specific clues that may be related to liver disease, such as Kayser-Fleischer rings seen in Wilson’s disease. They also should make a quick assessment to ensure there is no evidence of liver failure, such as the development of coagulopathy and encephalopathy, because the workup is very different in that case and may require an emergent referral to a specialized liver center or liver transplant center.

Clinicians then need to consider the most common liver diagnoses and assess the pretest probability of finding a particular etiology for the abnormal liver tests. Depending on the patient population, the most common liver issues include fatty liver disease, alcoholic liver disease, viral hepatitis, and drug-induced liver injury. With fatty liver disease and alcoholic liver disease being so common and increasing in frequency, especially for patients with minimal or mild liver enzyme elevations, sometimes starting by just working on these risk factors and then reassessing liver tests a few months later is a reasonable first-line approach. In general, clues to the more prevalent diseases should be sought before searching for less common liver issues such as metabolic/genetic diseases, autoimmune diseases, or PBC and PSC.

Patients with milder liver enzyme elevations generally will start with basic workup, such as viral hepatitis testing, iron panel/ferritin, and ultrasound. If unrevealing and the liver test abnormalities persist, then further evaluation can be done. On the other hand, patients with more significant elevations of liver enzymes at presentation should get more thorough evaluation earlier.

Liver damage can be broken down into 4 patterns of liver enzyme elevations:

1. hepatocellular (disproportionate elevation of AST/ALT);
2. cholestatic (disproportionate elevation of alkaline phosphatase);
3. mixed (elevation of AST/ALT and alkaline phosphatase); and
4. isolated hyperbilirubinemia.

Clinicians usually can just look at the lab tests to determine the pattern, or an R value can be calculated (>5, hepatocellular; 2-5, mixed; and <2, cholestatic).

Table 1 shows the usual AST to ALT elevation patterns seen in multiple liver diseases. In many liver diseases, as cirrhosis develops, ALT levels will decrease and AST levels will increase proportionately. Thus, many liver diseases that begin as ALT predominant, such as viral hepatitis, can eventually show a pattern of AST > ALT in the later cirrhotic phases. Because this fact is not always understood, many patients are accused of having active ongoing alcohol use as the cause of their AST > ALT liver test pattern. In addition, many patients have multiple underlying liver issues that can complicate the AST/ALT ratio.

Table 1. Patterns of AST and ALT In Liver Disease
AST > ALT
Alcoholic liver disease Budd-Chiari syndrome Cardiac disease Cirrhosis Congestive hepatopathy Ischemic hepatitis/shock liver Muscle disease
ALT > AST
Alpha-1 antitrypsin deficiency Autoimmune hepatitis Drug-induced liver injury Fatty liver disease Hemochromatosis Toxic hepatitis Pregnancy-related liver Viral hepatitis Wilson’s disease
ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Table 2. Magnitude of AST and ALT Elevations in Liver Disease
Type of liver disease	AST/ALT elevation, IU/L
Alcoholic liver disease	Usually <200-300
Atypical viral hepatitis such as severe herpes hepatitis	Any level, even >10,000
Autoimmune hepatitis
Classic acute viral hepatitis A, B, C	Up to 3,000-5,000
Complete biliary obstruction	Up to 1,000
Fatty liver disease/NASH	Usually <200-300
Shock liver/ischemic hepatitis	Any level, even >10,000
Toxic hepatitis
ALT, alanine aminotransferase; AST, aspartate aminotransferase; NASH, nonalcoholic steatohepatitis.

In the 2017 ACG guideline, using our proposed levels for true normal ULN as discussed above, we broke down the magnitude of ALT elevations into 5 categories: borderline (<2 × ULN), mild (2-5 × ULN), moderate (5-15 × ULN), severe (>15 × ULN), and massive (>10,000 IU/L).⁶ These various categories are discussed in the ALT algorithms (Figures 1-4). Borderline and mild ALT elevations should be evaluated within a few months. Moderate, severe, and massive elevations should be evaluated immediately.

Figure 1. Borderline-mild ALT elevation (<2-5 x ULN).

CBC, complete blood count; NASH, nonalcoholic steatohepatitis; ULN, upper limit of normal.

Adapted from reference 7.

Figure 2. Moderate ALT elevation (5-15 × ULN).

ALT, alanine aminotransferase; IgM, immunoglobulin M; INR, international normalized ratio; ULN, upper limit of normal.

Adapted from reference 7.

Figure 3. Severe ALT elevation (>15 × ULN).

CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; LKM, liver-kidney microsomal; NAC, N-acetylcysteine; ULN, upper limit of normal.

Adapted from reference 7.

Figure 4. Massive ALT elevation (>10,000 IU/L).

ALT, alanine aminotransferase; NAC, N-acetylcysteine.

Adapted from reference 7.

Clinicians also should try to define temporal relationships between potential liver insults and elevated liver enzymes. For example, although any medication theoretically can injure the liver, standardly, we would consider medications started more recently to be a more likely culprit. In addition, similar consideration would need to be given to risk factors such as recent foreign travel, recent parenteral risk factors, and recent evidence of hypotension and other cardiovascular instability that might correlate with ischemic hepatitis or shock liver.

Liver biopsy often is believed to be the gold standard for determining the etiology of elevated liver enzymes, but there are many potential issues associated with liver biopsy, including risk, adverse events, cost, and hesitancy, from the patient’s standpoint. In addition, the biopsy report often is descriptive rather than diagnostic. These various factors should influence liver biopsy decisions.

Approach to Elevated ALT

Because ALT is more liver specific than AST, the algorithms use ALT and are divided based on the magnitude of the elevations (Figures 1-4). The initial extent and rapidity of the workup is based on the severity of the elevations. Higher ALT levels warrant more testing, including for uncommon causes of liver disease, at the initial visit. The guideline also suggests evaluation for signs of liver failure in patients with higher ALT levels. In addition, there is a lower threshold to consider liver biopsy in patients with more significant elevations. The use of N-acetylcysteine in patients with severe and massive elevations of ALT can be considered if there is suspicion of possible primary acetaminophen toxicity, acetaminophen toxicity on top of another liver etiology, or concern for impending liver failure even in the absence of known acetaminophen use.

Approach to Elevated Alkaline Phosphatase

The elevated alkaline phosphatase algorithms start by determining whether it is likely a liver source or a nonhepatic source via assessment of other liver tests and/or using a clarifying test, such as GGT or alkaline phosphatase isoenzymes (Figures 5 and 6). In patients with otherwise normal liver tests, as shown in Figure 5, the first step would be the clarifying test and then proceeding with the workup if the cause is related to the liver. However, in patients with other abnormal liver tests (Figure 6), the elevated alkaline phosphatase is assumed to be from a liver source, and the workup is started without clarifying tests.

Figure 5. Elevated alkaline phosphatase with normal bilirubin/AST/ALT.

ALT, alanine aminotransferase; AMA, antimitochondrial antibody; AST, aspartate aminotransferase; ERCP, endoscopic retrograde cholangiopancreatography; GGT, gamma-glutamyl transferase; MRCP, magnetic resonance cholangiopancreatography; PBC, primary biliary cholangitis; ULN, upper limit of normal.

Adapted from reference 7.

Figure 6. Elevated alkaline phosphatase with elevated bilirubin/AST/ALT.

ALT, alanine aminotransferase; AMA, antimitochondrial antibody; AST, aspartate aminotransferase; ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance cholangiopancreatography; PBC, primary biliary cholangitis; ULN, upper limit of normal.

Adapted from reference 7.

Approach to Elevated Direct Bilirubin

The first step with elevated bilirubin is fractionation of the bilirubin to determine whether it is unconjugated (indirect) or conjugated (direct) (Figure 7). For elevated unconjugated (indirect) bilirubin, the approach is to look for causes of elevations not related to liver disease (classically Gilbert’s syndrome or hemolysis or occasionally medications). Usually, if the indirect bilirubin levels are mildly elevated and there is no other evidence of an obvious etiology, a presumptive diagnosis of Gilbert’s syndrome can be made, with no further follow-up necessary. However, if the elevations persist and are unexplained, symptomatic, worsening, and/or associated with abnormal ALT, then further workup could be considered. Figure 7 demonstrates the algorithm for elevated conjugated (direct) bilirubin. This workup is similar to that for patients with elevated alkaline phosphatase.

Figure 7. Elevated conjugated (direct) bilirubin.

ALT, alanine aminotransferase; AMA, antimitochondrial antibody; AST, aspartate aminotransferase; ERCP, endoscopic retrograde cholangiopancreatograpy; MRCP, magnetic resonance cholangiopancreatography.

Adapted from reference 7.

Conclusion

Elevated liver enzymes are a common consult for gastroenterology providers. The true healthy ULN for ALT should likely be much lower than that proposed by the standard reference lab, with levels of 29 to 33 IU/L and 19 to 25 IU/L defining a true healthy normal for men and women, respectively. Clinicians should focus on history, including all medications, herbal supplements, and over-the-counter preparations, and physical examination to point toward any obvious clues to the etiology of the elevations and rule out advanced liver disease and/or evidence of liver failure. Clinicians should consider the pretest probability of a particular liver disease. They also should use the pattern, magnitude, and timing of liver enzyme elevations to help define the most likely etiology. Liver biopsy should be reserved for cases with unclear etiology. Finally, patients with significantly elevated liver enzymes and/or potential liver failure should be considered for early referral to a specialized liver center or liver transplant centers.

References

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