Hospital Medicine

Elevated Liver Enzymes (Hepatitis)

Elevated Liver Enzymes (Hepatitis)

I. Problem/Condition.

A complete liver panel should include the aminotransferases (AST, ALT), Alkaline Phosphatase, Total bilirubin as well as tests of liver function: Albumin, Prothrombin time (PT) and international normalized ratio (INR). In general,, a liver enzyme panel should not be used as a screening test because of its low sensitivity and specificity for identifying clinically significant liver disease. Only a portion of healthy volunteers with a mild transaminitis will have clinically significant liver disease. Similarly, a significant degree of chronic liver injury can be hidden within mildly abnormal liver enzymes.

The initial approach to elevated liver enzymes should determine the pattern of liver injury as either hepatocellular, cholestatic or both. Hepatocellular injury will typically cause elevated transaminases (AST/ALT) that are released into the serum as a result of liver cell injury or death. A cholestatic injury will cause an elevated alkaline phosphatase and bilirubin out of proportion to the level of transaminitis. This discussion will focus mainly on the interpretation of elevated transaminases or hepatocellular injury.

While the transaminases are considered markers of acute hepatocellular injury, they can also become elevated in the setting of injury to muscle, kidney, brain, red blood cells and small bowel. The serum albumin, PT and INR are used to assess the synthetic function of liver and are most often elevated in the setting of chronic liver injury with fibrosis. The synthetic function of the liver can also become impaired in the setting of severe acute liver injury and these patients will have a mixed picture with both hepatocellular injury and cholestasis.

For the hospitalized patient, it is important to determine whether the noted liver enzyme abnormality is acute or if it was present prior to admission. Any liver function abnormalities need to be assessed within the clinical context of the patient and their underlying reason for admission. Mild chronic liver enzyme abnormalities may be innocent bystanders and ideally pursued non-urgently in the outpatient setting.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

The differential diagnosis for elevated liver enzymes is broad and the injury is not always hepatic in origin. Transaminases can be released as a result of injury to muscle, kidney, brain, bowel and red blood cells. For liver specific injury, the differential is best categorized into seven potential etiologies.

  1. Toxic (ex. medications, alcohol, non-alcoholic steatohepatitis);

  2. Infectious (ex. viral hepatitis);

  3. Vascular (ex. portal venous clot, congestive heart failure [CHF] related congestive hepatopathy);

  4. Obstructive (ex. acute cholestasis causing a secondary transaminitis);

  5. Autoimmune (ex. autoimmune hepatitis);

  6. Malignant (ex. infiltrating lymphoma);

  7. Genetic (ex. Wilson's disease, alpha-1 antitrypsin deficiency).

B. Describe a diagnostic approach/method to the patient with this problem.

In the hospitalized patient, the approach to abnormal liver enzymes should begin with the question of acute versus chronic injury to help triage the urgency of further evaluation. A mild asymptomatic transaminitis can often be trended and if stable, deferred for outpatient follow up with communication to the primary care provider. The evaluation of an acute transaminitis requires a review of chronic illnesses, social, family and travel history with a complete medication and ingestion history.

The differential can be narrowed by the degree of abnormality from the labs upper limit of normal. A transaminitis greater than 1000 is suggestive of acute viral hepatitis, ischemic injury, medication/toxin induced injury (most commonly acetaminophen) or autoimmune hepatitis. More rare causes of transaminitis greater than 1000 include Wilson's disease and acute biliary obstruction.

By comparison, the differential for mild transaminitis (less than 5 times the upper limit of normal) is broad and must be narrowed by further clinical history including specific risk factors for hepatitis exposure. The most common causes for mild transaminitis of hepatic origin include alcohol, acute/chronic viral hepatitis, non-alcoholic steatohepatitis, cirrhosis, medication/toxins and celiac disease. The less common causes include Wilson's disease, hemochromatosis, autoimmune hepatitis and alpha-1 antitrypsin deficiency.

It is important to consider clinical context of abnormal liver enzymes because they are not necessarily due to primary hepatic injury. For example, a patient who presents with biliary obstruction, systemic viral illness, pancreatitis or acute myocardial infarction may have abnormal liver enzymes as result of the primary process. In a pregnant patient with abnormal liver enzymes, it is important to consider the possibility of hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome and review the peripheral blood smear for evidence of microangiopathic hemolytic anemia.

1. Historical information important in the diagnosis of this problem.

Patients with mildly abnormal liver enzymes can often be asymptomatic. However, the symptoms that are associated with hepatitis or acute liver injury include fever, fatigue, jaundice, nausea, abdominal distension, right upper quadrant pain, dark urine, pale stools, pruritis, and referred right shoulder pain or right sided pleuritic pain due to inflammation of the liver capsule.

It is important to ask about any history of intravenous (IV) or illicit drug use, quantify alcohol intake, acetaminophen intake and review all prescribed medications as well as any medications/herbal remedies obtained over the counter. Clinicians should review the travel history, sexual exposures, tattoos, history of blood transfusions, trauma or surgery. Pertinent clinical history includes any preceding gastrointestinal illness, pregnancy, blood borne exposures, fevers, food exposures and sick contacts.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Findings of acute liver injury:

Right upper quadrant tenderness, positive Murphy’s sign, hepatomegaly, splenomegaly, jaundice, pruritis, malaise and fever.

Findings of chronic liver injury (non-specific):

Proximal muscle wasting, palmar erythema, caput medusa (dilated abdominal veins), splenomegaly, spider angiomata, gynecomastia, lower extremity edema, ascites, Duputruyen’s contractures, testicular atrophy, altered mentation, hepatic Encephalopathy, and asterixis.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

  1. Basic liver panel (AST, ALT, Alk Phos, total bilirubin) will help determine the pattern of injury (hepatocellular versus cholestatic).

  2. Assess liver synthetic function with Albumin, PT and INR.

  3. Serum and urine toxicology screen for ingestions that could lead to acute liver injury (refer to the acetaminophen nomogram if there is any question of overdose given the potential reversibility of injury associated with administration of N-acetyl cysteine).

  4. AST:ALT ratio >2 suggests alcohol related liver injury.

  5. Viral Hepatitis panel to evaluate for chronic hepatitis B/C or acute hepatitis A/B.

  6. Right upper quadrant ultrasound can evaluate liver parenchyma for fatty infiltration associated with non-alcoholic steatohepatitis and rule out biliary obstruction.

  7. Iron indices will help to rule out hemochromatosis.

In order to evaluate for non-hepatic sources of transaminitis, check thyroid function, creatinine kinase for muscle injury, anti-tTG (transtissue glutaminase) for celiac disease and consider nutritional status as a potential source of liver injury.

Other common viral causes of transaminitis include Epstein Barr virus (EBV), acute human immunodeficiency virus (HIV), cytomegalovirus (CMV), and herpes simplex virus (HSV).

If the etiology of liver injury remains unclear after completing the evaluation above, consider checking antinuclear antibiody (ANA), Anti-smooth muscle antibody (Autoimmune hepatitis), Anti-mitochondrial antibody (Primary Biliary Cirrhosis) and ceruloplasmin with serum and urine copper levels (Wilson’s Disease). However, consultation with gastroenterology or a liver specialist is likely indicated at this point.

Imaging of the liver:

  1. Right upper quadrant ultrasound is used to evaluate for abnormalities of biliary tree and can often provide some assessment of liver parenchyma. The addition of doppler will help evaluate vascular abnormalities such as portal venous clot.

  2. Liver magnetic resonance imaging (MRI) is used to evaluate liver parenchyma, discrete liver lesions and to investigate infiltrative processes.

  3. Computed tomography (CT) abdomen will help identify mass lesions within the liver but these rarely cause a transaminitis unless they are diffusely infiltrating (ex. cholangiocarcinoma, lymphomatous liver infiltration and advanced hepatocellular carcinoma).

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Basic liver panel helps determine if the injury is primarily hepatocellular or cholestatic in nature. It is important to review baseline measurements to establish acuity of the injury.

A low albumin or elevated INR in absence of malnutrition should raise concern for a significant degree of acute liver injury or long standing cirrhosis.

The finding of acute liver injury with high serum acetaminophen level should prompt review of the acetaminophen nomogram with consideration of n-acetyl cysteine treatment. Gastroenterology should be involved early because these patients can progress rapidly to overwhelming liver failure.

An AST: ALT ratio of 2:1 is suggestive of alcohol related liver injury, but is less helpful in patients with cirrhosis. Serum AST levels are usually elevated to 2-6 times the upper limit of normal in severe alcoholic hepatitis. AST levels > 500 international units/liter (IU/L) or ALT > 200 IU/L suggest an alternative etiology.

Acute viral hepatitis A is diagnosed with a positive hepatitis A Immunoglobulin M (IgM), while a positive hepatitis A Immunoglobulin G (IgG) suggests a history of hepatitis A infection or prior vaccination for hepatitis A.

Acute viral hepatitis B is diagnosed with positive serum hepatitis B surface antigen or IgM Anti- hepatitis B core. A positive hepatitis B surface antibody suggests prior immunization for hepatitis B or prior infection with likely clearance. Please see the section on viral hepatitis B for further interpretation of hepatitis B serologies.

Acute conversion to hepatitis C is often asymptomatic and any patient with a positive hepatitis C antibody has been exposed to virus. Many of these patients will go on to develop chronic hepatitis C and may require a referral to gastroenterology to consider anti-viral treatment options.

Chronic infection with hepatitis C alone will not cause transaminases >1000 IU/L. However, when it is seen in combination with a second liver insult such as acute hepatitis A or acetaminophen related liver injury, the combined effect may result in transaminases >1000 IU/L.

A Ferritin of >1000 nanograms/liter with a Fe/TIBC ratio >50% for women and >60% for men suggests the possibility of hemochromatosis and warrants referral to gastroenterology.

In the hospitalized patient, the finding of a new transaminitis can often be attributed to a newly introduced medication or an ischemic injury resulting from a hypotensive event. It is important to review the vital signs throughout hospitalization and perform a complete review of the administered medications to remove any potential offenders. The transaminitis from a medication adverse effect may take time to resolve and should be followed up 2-4 weeks after discharge by the primary provider. The transaminitis from ischemic injury will typically peak within a few days of the inciting event and should resolve within 7-10 days. The liver function tests should be trended to ensure resolution.

In the setting of acute hepatitis and prothrombin time prolonged by ~4-6 seconds or more (INR ≥ 1.5) with evidence of an altered sensorium the diagnosis of acute liver failure has been established. This necessitates a hospital admission, with consideration of intensive care unit management, and gastroenterology consult.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Hepatitis C IgM does not have much clinical utility because acute conversion is often asymptomatic.

Right upper quadrant ultrasound is an imaging modality best used to assess biliary tree abnormalities. It is an operator dependant study and it is not always a reliable test for liver parenchymal changes. RUQ ultrasound will often be unrevealing if the lab evaluation suggests hepatocellular injury without cholestasis.

CT abdomen is not a reliable method to assess the biliary tree.

An asymptomatic patient with a mild stable transaminitis (less than 2 x upper limit of normal) may be best worked up in the outpatient setting. It is important to investigate about the chronicity of this abnormality and communicate these lab findings with the primary care physician prior to discharge.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Elevated Liver Enzymes.

Management of acute liver failure

Acute liver failure refers to a rapid deterioration in liver function with evidence of altered mental status and impaired synthetic function with an elevated INR. The most common causes include drug induced liver injury, viral hepatitis, autoimmune hepatitis and hypoperfusion (shock liver). These patients can deteriorate rapidly and require close monitoring of synthetic function (INR) with serial assessment of mental status. The American Association for the Study of Liver Diseases (AASLD) suggest that all of these patients should be admitted to the hospital and often require intensive care unit level of monitoring.

In any patient presenting with acute liver failure, it is important to rule out acetaminophen overdose due to potential reversibility. The clinical history, serum/urine toxicology screens and liver synthetic function should be assessed rapidly. If these suggest the possibility of acetaminophen overdose, treatment with N-acetylcysteine should begin immediately based on the acetaminophen nomogram. Gastroenterology needs to be involved as these patients may need referral for liver transplant evaluation.

If the acute liver injury is attributed to acute viral hepatitis or hypoperfusion, the transaminases should be monitored regularly to establish peak levels. Patients require supportive care, nutrition and avoidance of any potential liver toxins especially acetaminophen. If the liver injury is due to an acute biliary obstruction, surgery or interventional GI should be involved to assist with decompression of the biliary tree. If the transaminitis is thought most likely due to autoimmune hepatitis, gastroenterology should be involved and immunosuppression considered.

In alcoholic hepatitis the management is based the severity of illness. To determine the severity and prognosis the patient’s Maddrey discriminant function (MDF) and Model for End-Stage Liver Disease (MELD) score need to be calculated. For patient’s with an MDF >32, a four week course of prednisolone should be considered. In patients with MDF >32 and contraindications to corticosteroid therapy, a four week course of pentoxifylline therapy should be considered.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

The discovery of a mild asymptomatic transaminitis is common in the hospitalized patient. Communication with the primary care provider will help establish chronicity and can help determine the urgency for inpatient work up. If acute, it is important to consider whether it is the side effect of a medication, the result of a hypotensive event or related to the primary process leading to hospitalization. Once all potential offending medications have been stopped, blood pressure normalized and primary process treated, the liver function tests should be trended to monitor for resolution.

IV. What's the evidence?

Green, RM, Flamm, S. "AGA Technical review on the evaluation of liver chemistry tests". Gastroenterology. vol. 123. 2002. pp. 1367-84.

Krier, M, Ahmed, A. "The asymptomatic outpatient with abnormal liver function tests". Clin Liver Dis. vol. 13. 2009 May. pp. 167-77.

Polson, J, Lee, WM. "AASLD Position Paper: the management of acute liver failure". Hepatology. vol. 41. 2005 May. pp. 1179-97.

Clark, JM, Brancati, FL, Diehl, AM. "The prevalence and etiology of elevated aminotransferase levels in the United States". Am J Gastroenterol. vol. 98. 2003. pp. 960-967.

Lee, WM, Larson, AM, Stravitz, RT. "AASLD Position Paper: The Management of Acute Liver Failure: Update 2011". Hepatology. 2011 Sept.

O’Shea, RS. "AASLD Practice Guidelines: Alcoholic Liver Disease". Hepatology. vol. 51. 2010 Jan. pp. 307-328.

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