Abnormal Liver Enzymes

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In Process

Author / Curator: Marianna Mavilia, DO

Faculty Advisor: William Rabitaille, MD

LEARNING OBJECTIVES:
• Interpret patterns of liver enzyme elevation

• Construct a differential diagnosis based on liver profile • Be able to take a focused history and physical for a patient with abnormal liver enzymes

• Learn which diagnostic tests are indicated for further workup of elevated liver enzymes


Top Teaching Points

• A predominant elevation in ALT and AST indicates hepatocellular liver disease whereas predominant elevation in ALP suggests cholestatic liver disease.

• A thorough history includes exposures to viral hepatitis, alcohol consumption, family history, complete list of medications and herbal supplements, and history of autoimmune disease.

• There are several exam findings which help identify liver disease including: jaundice, scleral icterus, hepatosplenomegaly, spider angioma, caput medusa, abdominal distension and fluid wave indicating ascites, bruising, palmar erythema, asterixis, testicular atrophy and gynecomastia in males, and Dupuytren’s contracture.

• Initial workup for hepatocellular liver disease should include CBC, PT, albumin, viral hepatitis panel, iron panel, ceruloplasmin ANA, ASMA, and an abdominal ultrasound.

• Initial work up for cholestatic disease should include GGT, and abdominal ultrasound.


Background

A liver profile or liver panel consists of alanine aminotransferaste (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TB), and direct bilirubin (DB). The liver panel is often incorrectly termed “liver function tests” or LFTs. Liver enzymes such as AST, ALT, ALP are released when the liver is damaged. True markers of liver function are albumin, platelet count and prothrombin time (PT), which are indicators of the liver’s synthetic function. Synthetic markers become abnormal if liver is impaired for at least 3 weeks (1). If these tests are abnormal, the clinician should be directed to a chronic disease process.

The pattern of elevation seen in liver enzymes can narrow the differential diagnosis. Hepatocellular liver disease is characterized by predominant elevation in ALT and AST, whereas in cholestatic liver disease, ALP is relatively more elevated. Elevated bilirubin can occur in either hepatocellular or cholestatic disease (1). If ALP alone is elevated, it can be useful to order a gamma-glutamyl transpeptidase (GGT) level. Because ALP can be elevated in liver, bone, intestine or placental pathologies, a GGT helps determine the source of the ALP elevation. Elevated ALP and GGT points to a liver pathology.

Hepatocellular Liver Disease Cholestatic Liver Disease
Acute viral hepatitis

Chronic viral hepatitis

Alcoholic hepatitis

Non-alcoholic fatty liver disease (NAFLD)

Autoimmune hepatitis

Wilson disease

Hemochromatosis

Alpha-antitrypsin deficiency

Hepatic ischemia

Congestive hepatopathy

Budd Chiari syndrome

Veno-occlusive disease

Drug- induced liver injury

Celiac disease

Liver trauma

Glycogen storage diseases

Choledodocolithiasis

Primary biliary cirrhosis

Primary sclerosing cholangitis

Malignant obstruction

Biliary flukes

Other biliary obstruction (stricture, polyp)

Infiltrative liver disease

AIDS cholangiopathy

Hepatic Abscess


The degree of elevation also guides work up. Elevation in AST or ALT that is less than 5 times the upper limit of normal is considered mild abnormality (1). With mild elevation the ACG guidelines recommend evaluation for viral hepatitis, alcoholic hepatitis, NAFLD, hemochromatosis, Wilson disease, alpha1- antitrypsin deficiency, autoimmune hepatitis, and drug-induced liver injury (2). If ALT or AST are moderately elevated, at 5-15 times the upper limit of normal, acute hepatitis A, B and C should be considered (2). In severely elevated ALT or AST, greater than 15 times the upper limit of normal, ischemic liver injury and acetaminophen toxicity are high on the differential (2). Additionally, the ratio of enzyme elevation can be helpful. In alcoholic liver disease, the ratio of AST:ALT is 2:1.

Severity Multiples of ULN Differential Diagnosis
Mild <5 Viral hepatitis, Alcoholic hepatitis, NAFLD, Hemochromatosis, Wilson disease, Alpha1-antitrypsin deficiency, Autoimmune hepatitis, Drug-induced liver injury
Moderate 5-10 Acute viral hepatitis, Drug-induced liver injury
Severe >10 Ischemic liver injury, Acetaminophen toxicity

There are extra-hepatic disease processes, which can also lead to elevation in LFTs. These include skeletal or cardiac muscle injuries, vigorous exercise, thyroid disease, heat stroke, hemolysis, and adrenal insufficiency (2). Additionally ALP may be elevated in pregnancy, malignancy, childhood growth, thyroid and parathyroid disease, infection and states of increased bone turnover (2).

It is also important to note that normal liver enzymes do not exclude liver disease (2).

Diagnosis

History A complete history is needed for evaluation of abnormal liver enzymes with particular focus on risk factors for hepatobiliary disease.

o Viral hepatitis-There is higher risk for hepatitis B and C in patient with history of intravenous or intranasal drug use, sexual exposures, men who have sex with men, history of blood transfusion, tattoos, medical professional with recent needle stick injury or other body fluid exposures, born between 1945-1965, travel to endemic areas. Hepatitis A can be transmitted via oral route and may be caused by contaminated drinking water, and certain foods such as oysters.

o Alcoholic liver disease- alcohol use (women >10 drinks/week, men >15 drinks/week)

o Drug-induced liver injury- You should collect a complete list of a patient’s medications, INCLUDING over the counter medications, herbal supplements, and vitamins. Since there are many medications that can affect the liver, these can be cross-referenced on the NIH’s DILI-Network (www.livertox.nih.gov).

o NAFLD- history of obesity, diabetes mellitus, hyperlipidemia, metabolic syndrome and certain medications

o Wilson disease, Hemochromatosis, Alpha Antitrypsin deficiency- family history of liver disease, genetic predisposition

o Autoimmune hepatitis- hx of other autoimmune conditions, female gender

o HELLP syndrome- current pregnancy

o Primary sclerosing cholangitis- history of inflammatory bowel disease


Physical exam Hepatomegaly can be appreciated on physically exam, however this finding is fairly nonspecific. Tenderness at the liver edge may be more suggestive of an acute etiology such as viral hepatitis. The eyes and skin should be examined for jaundice.

There are several findings on physical exam, which indicate chronic liver disease or cirrhosis. These include splenomegaly, spider angioma, caput medusa, abdominal distension and fluid wave indicating ascites, bruising, palmar erythema, asterixis, testicular atrophy and gynecomastia in males, and Dupuytren’s contracture.

How to assess for fluid wave

Spider Angioma
Caput Medusae (Photo Credit:Yang PM, Chen DS. Caput Medusae. Images in Clinical Medicine. NEJM 2005)
Kayser Fleischer Ring (Photo Credit:Schrag A, Schott JM. Kayser-Fleischer Rings in Wilson’s Disease. Images In Clinical Medicine NEJM 2012)


Certain exam findings may lead to a specific diagnosis: • A positive Murphy’s signs helps differentiate biliary process.

How to check for Murphy's sign

• Kayser-Fleischer rings are seen in Wilson disease.

• Bronzing of the skin is seen in hemochromatosis.

Initial laboratory work up Initial work up consists of a thorough history and physical. The findings here may lead to a specific diagnosis or may guide what further testing is warranted. If H&P is nonspecific, a general approach to hepatocellular disease is laboratory work up (including CBC, PT, albumin, viral hepatitis panel, iron panel, ceruloplasmin ANA, ASMA) and an abdominal ultrasound (2,3). For cholestatic disease, the general approach includes GGT, and abdominal ultrasound. Secondary workup includes MRCP/ERCP, and serologic testing for ANA, AMA, ASMA, ANCA (2,5).


Specific laboratory testing

Hepatitis B- HBsAg, HBsAb, HBeAg, HBcAb, HBV DNA

Hepatitis C -Hepatitis C Ab, HCV RNA

Autoimmune hepatitis- ANA, Anti-smooth muscle Ab (ASMA), Anti liver/kidney microsome type 1 Ab (LKM1)

Primary biliary cirrhosis- AMA

Wilson disease- Ceruloplasmin, 24-hour urine copper level

Hemochromatosis- Ferritin, transferrin saturation, HFE genotype

Alpha1 Antitrypsin- alpha1-antitrypsin level, alpha1-antitrypsin phenotype

Drug-induced injury- Serum drug levels (acetaminophen level), urine toxicology


Imaging Imaging modalities for hepatobililary evaluation include: US, CT, MRI, MRCP, and ERCP. Cholestatic disorders may warrant further investigation with MRCP or ERCP, however these are not often the initial modality. The benefit of ERCP is that this is a procedure that can be therapeutic as well as diagnostic. Liver Doppler is another investigation that is useful if vascular disorders, such as Budd Chiari syndrome are suspected. If patients have risk factors for fibrosis, further evaluation can be done with elastography or FibroScan.

Diagnostic Modality Sensitivity Specificity Strengths Limitations
US 90% 79-90% Inexpensive, widely available, no radiation exposure Non-contrast, Limited evaluation in obesity
CT >90% 70% Widely available, contrast enhancement can provide more information Radiation exposure, complications from contrast agents
MRI 90-100% 95-100% No radiation exposure, contrast enhancement can provide more information Expensive, time consuming


Biopsy Liver biopsy should be considered if laboratory and imaging examinations do not yield a diagnosis (2). It can be performed percutaneously or via transjugular approach. Histologic examination of each zone of the portal triad can help identify etiology. Ischemic or drug induced injury causes histologic change in a centrilobular distribution, whereas viral and autoimmune hepatitis induce necrosis in periportal areas (4).


Management

The management is dependent on the underlying etiology. The first step is to identify the cause of abnormal enzymes. In many cases, laboratory values will normalize as the underlying disease is treated.

Liver enzyme values may also become normal in chronic disease states.

If severely elevated, treatment with N-acetylcysteine should be considered.


Ongoing controversies / New updates

Is it safe to prescribe hepatic- cleared medications in patients with abnormal liver tests? Because elevated liver tests signify liver damage, its reasonable to assume some of the liver’s metabolic function is compromised. Its important to consider the underlying etiology for the elevated liver tests as well as the degree of liver damage that might be present when prescribing any medications. Currently there are no clear guidelines about prescribing medications to this population (6).

How can we be cost conscious in our evaluation of abnormal liver tests? In one study, 10,000 patients with elevated liver tests were studied to compare an extensive approach to evaluation which included testing for all possible liver diseases at one time with a limited approach which tested only for the most likely disease in a specific patient and then expanded testing as needed. They found that when history and physical were nonspecific, it is more cost-effective to take an extensive approach. However when there are clues in the history that suggest an etiology, limited testing was more cost effective in this scenario (7).


Teaching Resources

DILI Network by NIH. https://livertox.nih.gov/aboutus.html

References

1. Muir AJ. Evaluating The Patient with Liver Disease. Scientific American Medicine, 2014.

2. Kwo PY, Cohen SM, Lim JK. Evlauation or Abnormal Liver Tests. The American Journal of Gastroenterology, 2016.

3. Newsome PN, Cramb R, Davidson SM, Dillon JF, Foulerton M, Godfrey EM, Hall R, et al. Guidelines on the management of abnormal liver blood tests. Gut 2017, 0: 1-14.

4. Krishna, M. Patterns of Necrosis in Liver Disease. Clinical Liver Disease 2017, 10: 53-57.

5. Gianni EG, Tzesta R, Savarino V. Liver enzyme alteration: a guide for clinicans. CMAJ 2005; 172: 367-369.

6. Smith E, Desmond P. Prescribing in patients with abnormal liver tests. Aust Fam Physician 2013; 42: 30-33.

7. Tapper EB, Saini SD, Sengupta N. Extensive testing or focused testing of patients with elevated liver enzymes. J Hepatol 2017; 66: 313-319.

8. Florani I, Torri V, Rulli E, Garavaglia D, et al. Performance of Imaging Modalities in Diagnosis of liver metastases from colorectal cancer: a systematic review and meta-analysis. J Magn Reson Imaging 2010; 31: 19-31.

9. Allan R, Thoris K, Phillips M. Accuracy of ultrasound to identify chronic liver disease. World J of Gastroenterol 2010; 16: 3510-3520.

Contributors

Alexey, Marianna Mavilia