David Lee, MD, MBA, SFHM, FACP

Elevated levels of circulating enzymes that are frequently of hepatic origin (aminotransferases and alkaline phosphatase) and bilirubin in the absence of symptoms are common in clinical practice. A dogmatic but true statement holds that there are no trivial elevations in these substances. All persistent elevations of liver enzymes need a methodical evaluation and an appropriate working diagnosis.¹

Here, we outline a framework for the workup and treatment of common causes of liver enzyme elevations.

PATTERN OF ELEVATION: CHOLESTATIC OR HEPATOCELLULAR

Based on the pattern of elevation, causes of elevated liver enzymes can be sorted into disorders of cholestasis and disorders of hepatocellular injury (Table 1).¹

Cholestatic disorders tend to cause elevations in alkaline phosphatase, bilirubin, and gamma-glutamyl transferase (GGT).

Hepatocellular injury raises levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

HOW SHOULD ABNORMAL RESULTS BE EVALUATED?

When approaching liver enzyme elevations, the clinician should develop a working differential diagnosis based on the medical and social history and physical examination.

Think about alcohol, drugs, and fat

The most common causes of liver enzyme elevation are alcohol toxicity, medication overdose, and fatty liver disease.

Alcohol intake should be ascertained. “Significant” consumption is defined as more than 21 drinks per week in men or more than 14 drinks per week in women, over a period of at least 2 years.²

The exact pathogenesis of alcoholic hepatitis is incompletely understood, but alcohol is primarily metabolized by the liver, and damage likely occurs during metabolism of the ingested alcohol. AST elevations tend to be higher than ALT elevations; the reason is ascribed to hepatic deficiency of pyridoxal 5´-phosphate, a cofactor of the enzymatic activity of ALT, which leads to a lesser increase in ALT than in AST.

Alcoholic liver disease can be difficult to diagnose, as many people are initially reluctant to fully disclose how much they drink, but it should be suspected when the ratio of AST to ALT is 2 or greater.

In a classic study, a ratio greater than 2 was found in 70% of patients with alcoholic hepatitis and cirrhosis, compared with 26% of patients with postnecrotic cirrhosis, 8% with chronic hepatitis, 4% with viral hepatitis, and none with obstructive jaundice.³ Importantly, the disorder is often correctable if the patient is able to remain abstinent from alcohol over time.

A detailed medication history is important and should focus especially on recently added medications, dosage changes, medication overuse, and use of nonprescription drugs and herbal supplements. Common medications that affect liver enzyme levels include statins, which cause hepatic dysfunction primarily during the first 3 months of therapy, nonsteroidal anti-inflammatory drugs, antiep­ileptic drugs, antibiotics, anabolic steroids, and acetaminophen (Table 2).¹ Use of illicit drugs and herbal remedies should be discussed, as they may cause toxin-mediated hepatitis.

Although inflammation from drug toxicity will resolve if the offending agent is discontinued, complete recovery may take weeks to months.⁴

A pertinent social history includes exposure to environmental hepatotoxins such as amatoxin (contained in some wild mushrooms) and occupational hazards (eg, vinyl chloride). Risk factors for viral hepatitis should be evaluated, including intravenous drug use, blood transfusions, unprotected sexual contact, organ transplant, perinatal transmission, and a history of work in healthcare facilities or travel to regions in which hepatitis A or E is endemic.

The medical and family history should include details of associated conditions, such as:

• Right heart failure (a cause of congestive hepatopathy)
• Metabolic syndrome (associated with fatty liver disease)
• Inflammatory bowel disease and primary sclerosing cholangitis
• Early-onset emphysema and alpha-1 antitrypsin deficiency.

The physical examination should be thorough, with emphasis on the abdomen, and search for stigmata of advanced liver disease such as hepatomegaly, splenomegaly, ascites, edema, spider angiomata, jaundice, and asterixis. Any patient with evidence of chronic liver disease should be referred to a subspecialist for further evaluation.

Abnormal liver enzyme findings or physical examination findings should direct the subsequent diagnostic workup with laboratory testing and imaging.⁵

For cholestasis. If laboratory data are consistent with cholestasis or abnormal bile flow, it should be further characterized as extrahepatic or intrahepatic. Common causes of extrahepatic cholestasis include biliary tree obstruction due to stones or malignancy, often visualized as intraductal biliary dilation on ultrasonography of the right upper quadrant. Common causes of intrahepatic cholestasis include viral and alcoholic hepatitis, nonalcoholic steatohepatitis, certain drugs and toxins such as alkylated steroids and herbal medications, infiltrative diseases such as amyloid, sarcoid, lymphoma, and tuberculosis, and primary biliary cholangitis.

Abnormal findings on ultrasonography should be further pursued with advanced imaging, ie, computed tomography or magnetic resonance cholangiopancreatography (MRCP). The confirmation of a lesion on imaging is often followed by endoscopic retrograde cholangiopancreatography (ERCP) in an attempt to obtain biopsy samples, remove obstructions, and place therapeutic stents. In instances when endoscopic attempts fail to relieve the obstruction, surgical referral may be appropriate.

For nonhepatobiliary problems. Depending on clinical presentation, it may also be important to consider nonhepatobiliary causes of elevated liver enzymes.

Alkaline phosphatase is found in many other tissue types, including bone, kidney, and the placenta, and can be elevated during pregnancy, adolescence, and even after fatty meals due to intestinal release.⁶ After screening for the aforementioned physiologic conditions, isolated elevated alkaline phosphatase should be further evaluated by obtaining GGT or 5-nucleotidase levels, which are more specifically of hepatic origin. If these levels are within normal limits, further evaluation for conditions of bone growth and cellular turnover such as Paget disease, hyperparathyroidism, and malignancy should be considered. Specifically, Stauffer syndrome should be considered when there is a paraneoplastic rise in the alkaline phosphatase level in the setting of renal cell carcinoma without liver metastases.

AST and ALT levels may also be elevated in clinical situations and syndromes unrelated to liver disease. Rhabdomyolysis, for instance, may be associated with elevations of AST in more than 90% of cases, and ALT in more than 75%.⁷ Markers of muscle injury including serum creatine kinase should be obtained in the setting of heat stroke, muscle weakness, strenuous activity, or seizures, as related elevations in AST and ALT may not always be clinically indicative of liver injury.

Given the many conditions that may cause elevated liver enzymes, evaluation and treatment should focus on identifying and removing offending agents and targeting the underlying process with appropriate medical therapy.

FATTY LIVER

With rates of obesity and type 2 diabetes on the rise in the general population, identifying and treating nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) require increased awareness and close coordination between primary care providers and subspecialists.

According to current estimates, up to one-third of the US population (100 million people) may have NAFLD, and 1% to 3% of the population (4–6 million people) likely have NASH, defined as steatosis with inflammation. Development of NASH places patients at a significantly higher risk of fibrosis, hepatocellular injury, and cancer.⁸

NAFLD is more common in men than in women. It is present in around 80% to 90% of obese adults, two-thirds of adults with type 2 diabetes, and many people with hyperlipidemia. It is also becoming more common in children, with 40% to 70% of obese children likely having some element of NAFLD.

Diagnosis of fatty liver

Although liver enzymes are more likely to be abnormal in individuals with NAFLD, many individuals with underlying NAFLD may have normal laboratory evaluations. ALT may be elevated in only up to 20% of cases and does not likely correlate with the level of underlying liver damage, although increasing GGT may serve as a marker of fibrosis over time.^9–11 In contrast to alcohol injury, however, the AST-ALT ratio is usually less than 1.0.

Noninvasive tools for diagnosing NAFLD include the NAFLD fibrosis score, which incorporates age, hyperglycemia, body mass index, platelet count, albumin level, and AST-ALT ratio. This and related scoring algorithms may be useful in differentiating patients with minimal fibrosis from those with advanced fibrosis.^12,13

Ultrasonography is a first-line diagnostic test for steatosis, although it may demonstrate fatty infiltration only around 60% of the time. Computed tomography and magnetic resonance imaging are more sensitive, but costlier. Transient elastography (FibroScan; Echosens, Paris, France) has become more popular and has been shown to correlate with findings on liver biopsy in diagnosing or excluding advanced liver fibrosis.^14,15

The gold standard for diagnosing NAFLD and NASH is identifying fat-laden hepatocytes or portal inflammation on biopsy; however, biopsy is generally reserved for cases in which the diagnosis remains uncertain.

Behavioral treatment

The primary treatment for NAFLD consists of behavioral modification including weight loss, exercise, and adherence to a low-fat diet, in addition to tight glycemic control and treatment of any underlying lipid abnormalities. Studies have shown that a reduction of 7% to 10% of body weight is associated with a decrease in the inflammation of NAFLD, though no strict guidelines have been established.¹⁶

Given the prevalence of NAFLD and the need for longitudinal treatment, primary care physicians will play a significant role in long-term monitoring and management of patients with fatty liver disease.

Hereditary hemochromatosis

Hereditary hemochromatosis is the most common inherited liver disorder in adults of European descent,¹⁷ and can be effectively treated if discovered early. But its clinical diagnosis can be challenging, as many patients have no symptoms at presentation despite abnormal liver enzyme levels. Early symptoms may include severe fatigue, arthralgias, and, in men, impotence, before the appearance of the classic triad of “bronze diabetes” with cirrhosis, diabetes, and darkening of the skin.¹⁸

If hemochromatosis is suspected, laboratory tests should include a calculation of percent transferrin saturation, with saturation greater than 45% warranting serum ferritin measurement to evaluate for iron overload (ferritin > 200–300 ng/mL in men, > 150–200 ng/mL in women).¹⁹ If iron overload is confirmed, referral to a gastroenterologist is recommended.

Genetic evaluation is often pursued, but patients may ultimately require liver biopsy regardless of the findings, as some patients homozygous for the HFE mutation C282Y may not have clinical hemochromatosis, whereas others with hereditary hemochromatosis may not have the HFE mutation.

Therapeutic phlebotomy is the treatment of choice, and most patients tolerate it well.

Chronic hepatitis B virus and hepatitis C virus infections

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are common in the United States, with HBV affecting more than 1 million people and HCV affecting an estimated 3.5 million.

Chronic HCV infection. Direct-acting antiviral drugs have revolutionized HCV treatment and have led to a sustained viral response and presumed cure at 12 weeks in more than 95% of cases across all HCV genotypes.²⁰ Given the recent development of effective and well-tolerated treatments, primary care physicians have assumed a pivotal role in screening for HCV.

The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America²¹ recommend screening for HCV in people who have risk factors for it, ie:

• HCV exposure
• HIV infection
• Behavioral or environmental risks for contracting the virus such as intravenous drug use or incarceration
• Birth between 1945 and 1965 (one-time testing).

If HCV antibody screening is positive, HCV RNA should be obtained to quantify the viral load and confirm active infection, and genotype testing should be performed to guide treatment. Among the 6 most common HCV genotypes, genotype 1 is the most common in North America, accounting for over 70% of cases in the United States.

Although recommendations and therapies are constantly evolving, the selection of a treatment regimen and the duration of therapy are determined by viral genotype, history of prior treatment, stage of liver fibrosis, potential drug interactions, and frequently, medication cost and insurance coverage.

HBV infection. The treatment for acute HBV infection is generally supportive, though viral suppression with tenofovir or entecavir may be required for those who develop coagulopathy, bilirubinemia, or liver failure. Treatment of chronic HBV infection may not be required and is generally considered for those with elevated ALT, high viral load, or evidence of liver fibrosis on noninvasive measurements such as transient elastography.

Autoimmune hepatitis

Autoimmune causes of liver enzyme elevations should also be considered during initial screening. Positive antinuclear antibody and positive antismooth muscle antibody tests are common in cases of autoimmune hepatitis.²² Autoimmune hepatitis affects women more often than men, with a ratio of 4:1. The peaks of incidence occur during adolescence and between ages 30 and 45.²³

Primary biliary cholangitis

Additionally, an elevated alkaline phosphatase level should raise concern for underlying primary biliary cholangitis (formerly called primary biliary cirrhosis), an autoimmune disorder that affects the small and medium intrahepatic bile ducts. Diagnosis of primary biliary cholangitis can be assisted by a positive test for antimitochondrial antibody, present in almost 90% of patients.²⁴

Primary sclerosing cholangitis

Elevated alkaline phosphatase is also the hallmark of primary sclerosing cholangitis, which is associated with inflammatory bowel disease.²⁵ Primary sclerosing cholangitis is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, which are visualized on MRCP and confirmed by biopsy if needed.

REFERRAL

Subspecialty referral should be considered if the cause remains ambiguous or unknown, if there is concern for a rare hepatic disorder such as an autoimmune condition, Wilson disease, or alpha-1 antitrypsin deficiency, or if there is evidence of advanced or chronic liver disease.

Primary care physicians are at the forefront of detecting and diagnosing liver disease, and close coordination with subspecialists will remain crucial in delivering patient care.

Elevated levels of circulating enzymes that are frequently of hepatic origin (aminotransferases and alkaline phosphatase) and bilirubin in the absence of symptoms are common in clinical practice. A dogmatic but true statement holds that there are no trivial elevations in these substances. All persistent elevations of liver enzymes need a methodical evaluation and an appropriate working diagnosis.¹

Here, we outline a framework for the workup and treatment of common causes of liver enzyme elevations.

PATTERN OF ELEVATION: CHOLESTATIC OR HEPATOCELLULAR

Based on the pattern of elevation, causes of elevated liver enzymes can be sorted into disorders of cholestasis and disorders of hepatocellular injury (Table 1).¹

Cholestatic disorders tend to cause elevations in alkaline phosphatase, bilirubin, and gamma-glutamyl transferase (GGT).

Hepatocellular injury raises levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

HOW SHOULD ABNORMAL RESULTS BE EVALUATED?

When approaching liver enzyme elevations, the clinician should develop a working differential diagnosis based on the medical and social history and physical examination.

Think about alcohol, drugs, and fat

The most common causes of liver enzyme elevation are alcohol toxicity, medication overdose, and fatty liver disease.

Alcohol intake should be ascertained. “Significant” consumption is defined as more than 21 drinks per week in men or more than 14 drinks per week in women, over a period of at least 2 years.²

The exact pathogenesis of alcoholic hepatitis is incompletely understood, but alcohol is primarily metabolized by the liver, and damage likely occurs during metabolism of the ingested alcohol. AST elevations tend to be higher than ALT elevations; the reason is ascribed to hepatic deficiency of pyridoxal 5´-phosphate, a cofactor of the enzymatic activity of ALT, which leads to a lesser increase in ALT than in AST.

Alcoholic liver disease can be difficult to diagnose, as many people are initially reluctant to fully disclose how much they drink, but it should be suspected when the ratio of AST to ALT is 2 or greater.

In a classic study, a ratio greater than 2 was found in 70% of patients with alcoholic hepatitis and cirrhosis, compared with 26% of patients with postnecrotic cirrhosis, 8% with chronic hepatitis, 4% with viral hepatitis, and none with obstructive jaundice.³ Importantly, the disorder is often correctable if the patient is able to remain abstinent from alcohol over time.

A detailed medication history is important and should focus especially on recently added medications, dosage changes, medication overuse, and use of nonprescription drugs and herbal supplements. Common medications that affect liver enzyme levels include statins, which cause hepatic dysfunction primarily during the first 3 months of therapy, nonsteroidal anti-inflammatory drugs, antiep­ileptic drugs, antibiotics, anabolic steroids, and acetaminophen (Table 2).¹ Use of illicit drugs and herbal remedies should be discussed, as they may cause toxin-mediated hepatitis.

Although inflammation from drug toxicity will resolve if the offending agent is discontinued, complete recovery may take weeks to months.⁴

A pertinent social history includes exposure to environmental hepatotoxins such as amatoxin (contained in some wild mushrooms) and occupational hazards (eg, vinyl chloride). Risk factors for viral hepatitis should be evaluated, including intravenous drug use, blood transfusions, unprotected sexual contact, organ transplant, perinatal transmission, and a history of work in healthcare facilities or travel to regions in which hepatitis A or E is endemic.

The medical and family history should include details of associated conditions, such as:

• Right heart failure (a cause of congestive hepatopathy)
• Metabolic syndrome (associated with fatty liver disease)
• Inflammatory bowel disease and primary sclerosing cholangitis
• Early-onset emphysema and alpha-1 antitrypsin deficiency.

The physical examination should be thorough, with emphasis on the abdomen, and search for stigmata of advanced liver disease such as hepatomegaly, splenomegaly, ascites, edema, spider angiomata, jaundice, and asterixis. Any patient with evidence of chronic liver disease should be referred to a subspecialist for further evaluation.

Abnormal liver enzyme findings or physical examination findings should direct the subsequent diagnostic workup with laboratory testing and imaging.⁵

For cholestasis. If laboratory data are consistent with cholestasis or abnormal bile flow, it should be further characterized as extrahepatic or intrahepatic. Common causes of extrahepatic cholestasis include biliary tree obstruction due to stones or malignancy, often visualized as intraductal biliary dilation on ultrasonography of the right upper quadrant. Common causes of intrahepatic cholestasis include viral and alcoholic hepatitis, nonalcoholic steatohepatitis, certain drugs and toxins such as alkylated steroids and herbal medications, infiltrative diseases such as amyloid, sarcoid, lymphoma, and tuberculosis, and primary biliary cholangitis.

Abnormal findings on ultrasonography should be further pursued with advanced imaging, ie, computed tomography or magnetic resonance cholangiopancreatography (MRCP). The confirmation of a lesion on imaging is often followed by endoscopic retrograde cholangiopancreatography (ERCP) in an attempt to obtain biopsy samples, remove obstructions, and place therapeutic stents. In instances when endoscopic attempts fail to relieve the obstruction, surgical referral may be appropriate.

For nonhepatobiliary problems. Depending on clinical presentation, it may also be important to consider nonhepatobiliary causes of elevated liver enzymes.

Alkaline phosphatase is found in many other tissue types, including bone, kidney, and the placenta, and can be elevated during pregnancy, adolescence, and even after fatty meals due to intestinal release.⁶ After screening for the aforementioned physiologic conditions, isolated elevated alkaline phosphatase should be further evaluated by obtaining GGT or 5-nucleotidase levels, which are more specifically of hepatic origin. If these levels are within normal limits, further evaluation for conditions of bone growth and cellular turnover such as Paget disease, hyperparathyroidism, and malignancy should be considered. Specifically, Stauffer syndrome should be considered when there is a paraneoplastic rise in the alkaline phosphatase level in the setting of renal cell carcinoma without liver metastases.

AST and ALT levels may also be elevated in clinical situations and syndromes unrelated to liver disease. Rhabdomyolysis, for instance, may be associated with elevations of AST in more than 90% of cases, and ALT in more than 75%.⁷ Markers of muscle injury including serum creatine kinase should be obtained in the setting of heat stroke, muscle weakness, strenuous activity, or seizures, as related elevations in AST and ALT may not always be clinically indicative of liver injury.

Given the many conditions that may cause elevated liver enzymes, evaluation and treatment should focus on identifying and removing offending agents and targeting the underlying process with appropriate medical therapy.

FATTY LIVER

With rates of obesity and type 2 diabetes on the rise in the general population, identifying and treating nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) require increased awareness and close coordination between primary care providers and subspecialists.

According to current estimates, up to one-third of the US population (100 million people) may have NAFLD, and 1% to 3% of the population (4–6 million people) likely have NASH, defined as steatosis with inflammation. Development of NASH places patients at a significantly higher risk of fibrosis, hepatocellular injury, and cancer.⁸

NAFLD is more common in men than in women. It is present in around 80% to 90% of obese adults, two-thirds of adults with type 2 diabetes, and many people with hyperlipidemia. It is also becoming more common in children, with 40% to 70% of obese children likely having some element of NAFLD.

Diagnosis of fatty liver

Although liver enzymes are more likely to be abnormal in individuals with NAFLD, many individuals with underlying NAFLD may have normal laboratory evaluations. ALT may be elevated in only up to 20% of cases and does not likely correlate with the level of underlying liver damage, although increasing GGT may serve as a marker of fibrosis over time.^9–11 In contrast to alcohol injury, however, the AST-ALT ratio is usually less than 1.0.

Noninvasive tools for diagnosing NAFLD include the NAFLD fibrosis score, which incorporates age, hyperglycemia, body mass index, platelet count, albumin level, and AST-ALT ratio. This and related scoring algorithms may be useful in differentiating patients with minimal fibrosis from those with advanced fibrosis.^12,13

Ultrasonography is a first-line diagnostic test for steatosis, although it may demonstrate fatty infiltration only around 60% of the time. Computed tomography and magnetic resonance imaging are more sensitive, but costlier. Transient elastography (FibroScan; Echosens, Paris, France) has become more popular and has been shown to correlate with findings on liver biopsy in diagnosing or excluding advanced liver fibrosis.^14,15

The gold standard for diagnosing NAFLD and NASH is identifying fat-laden hepatocytes or portal inflammation on biopsy; however, biopsy is generally reserved for cases in which the diagnosis remains uncertain.

Behavioral treatment

The primary treatment for NAFLD consists of behavioral modification including weight loss, exercise, and adherence to a low-fat diet, in addition to tight glycemic control and treatment of any underlying lipid abnormalities. Studies have shown that a reduction of 7% to 10% of body weight is associated with a decrease in the inflammation of NAFLD, though no strict guidelines have been established.¹⁶

Given the prevalence of NAFLD and the need for longitudinal treatment, primary care physicians will play a significant role in long-term monitoring and management of patients with fatty liver disease.

Hereditary hemochromatosis

Hereditary hemochromatosis is the most common inherited liver disorder in adults of European descent,¹⁷ and can be effectively treated if discovered early. But its clinical diagnosis can be challenging, as many patients have no symptoms at presentation despite abnormal liver enzyme levels. Early symptoms may include severe fatigue, arthralgias, and, in men, impotence, before the appearance of the classic triad of “bronze diabetes” with cirrhosis, diabetes, and darkening of the skin.¹⁸

If hemochromatosis is suspected, laboratory tests should include a calculation of percent transferrin saturation, with saturation greater than 45% warranting serum ferritin measurement to evaluate for iron overload (ferritin > 200–300 ng/mL in men, > 150–200 ng/mL in women).¹⁹ If iron overload is confirmed, referral to a gastroenterologist is recommended.

Genetic evaluation is often pursued, but patients may ultimately require liver biopsy regardless of the findings, as some patients homozygous for the HFE mutation C282Y may not have clinical hemochromatosis, whereas others with hereditary hemochromatosis may not have the HFE mutation.

Therapeutic phlebotomy is the treatment of choice, and most patients tolerate it well.

Chronic hepatitis B virus and hepatitis C virus infections

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are common in the United States, with HBV affecting more than 1 million people and HCV affecting an estimated 3.5 million.

Chronic HCV infection. Direct-acting antiviral drugs have revolutionized HCV treatment and have led to a sustained viral response and presumed cure at 12 weeks in more than 95% of cases across all HCV genotypes.²⁰ Given the recent development of effective and well-tolerated treatments, primary care physicians have assumed a pivotal role in screening for HCV.

The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America²¹ recommend screening for HCV in people who have risk factors for it, ie:

• HCV exposure
• HIV infection
• Behavioral or environmental risks for contracting the virus such as intravenous drug use or incarceration
• Birth between 1945 and 1965 (one-time testing).

If HCV antibody screening is positive, HCV RNA should be obtained to quantify the viral load and confirm active infection, and genotype testing should be performed to guide treatment. Among the 6 most common HCV genotypes, genotype 1 is the most common in North America, accounting for over 70% of cases in the United States.

Although recommendations and therapies are constantly evolving, the selection of a treatment regimen and the duration of therapy are determined by viral genotype, history of prior treatment, stage of liver fibrosis, potential drug interactions, and frequently, medication cost and insurance coverage.

HBV infection. The treatment for acute HBV infection is generally supportive, though viral suppression with tenofovir or entecavir may be required for those who develop coagulopathy, bilirubinemia, or liver failure. Treatment of chronic HBV infection may not be required and is generally considered for those with elevated ALT, high viral load, or evidence of liver fibrosis on noninvasive measurements such as transient elastography.

Autoimmune hepatitis

Autoimmune causes of liver enzyme elevations should also be considered during initial screening. Positive antinuclear antibody and positive antismooth muscle antibody tests are common in cases of autoimmune hepatitis.²² Autoimmune hepatitis affects women more often than men, with a ratio of 4:1. The peaks of incidence occur during adolescence and between ages 30 and 45.²³

Primary biliary cholangitis

Additionally, an elevated alkaline phosphatase level should raise concern for underlying primary biliary cholangitis (formerly called primary biliary cirrhosis), an autoimmune disorder that affects the small and medium intrahepatic bile ducts. Diagnosis of primary biliary cholangitis can be assisted by a positive test for antimitochondrial antibody, present in almost 90% of patients.²⁴

Primary sclerosing cholangitis

Elevated alkaline phosphatase is also the hallmark of primary sclerosing cholangitis, which is associated with inflammatory bowel disease.²⁵ Primary sclerosing cholangitis is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, which are visualized on MRCP and confirmed by biopsy if needed.

REFERRAL

Subspecialty referral should be considered if the cause remains ambiguous or unknown, if there is concern for a rare hepatic disorder such as an autoimmune condition, Wilson disease, or alpha-1 antitrypsin deficiency, or if there is evidence of advanced or chronic liver disease.

Primary care physicians are at the forefront of detecting and diagnosing liver disease, and close coordination with subspecialists will remain crucial in delivering patient care.

Elevated levels of circulating enzymes that are frequently of hepatic origin (aminotransferases and alkaline phosphatase) and bilirubin in the absence of symptoms are common in clinical practice. A dogmatic but true statement holds that there are no trivial elevations in these substances. All persistent elevations of liver enzymes need a methodical evaluation and an appropriate working diagnosis.¹

Here, we outline a framework for the workup and treatment of common causes of liver enzyme elevations.

PATTERN OF ELEVATION: CHOLESTATIC OR HEPATOCELLULAR

Based on the pattern of elevation, causes of elevated liver enzymes can be sorted into disorders of cholestasis and disorders of hepatocellular injury (Table 1).¹

Cholestatic disorders tend to cause elevations in alkaline phosphatase, bilirubin, and gamma-glutamyl transferase (GGT).

Hepatocellular injury raises levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

HOW SHOULD ABNORMAL RESULTS BE EVALUATED?

When approaching liver enzyme elevations, the clinician should develop a working differential diagnosis based on the medical and social history and physical examination.

Think about alcohol, drugs, and fat

The most common causes of liver enzyme elevation are alcohol toxicity, medication overdose, and fatty liver disease.

Alcohol intake should be ascertained. “Significant” consumption is defined as more than 21 drinks per week in men or more than 14 drinks per week in women, over a period of at least 2 years.²

The exact pathogenesis of alcoholic hepatitis is incompletely understood, but alcohol is primarily metabolized by the liver, and damage likely occurs during metabolism of the ingested alcohol. AST elevations tend to be higher than ALT elevations; the reason is ascribed to hepatic deficiency of pyridoxal 5´-phosphate, a cofactor of the enzymatic activity of ALT, which leads to a lesser increase in ALT than in AST.

Alcoholic liver disease can be difficult to diagnose, as many people are initially reluctant to fully disclose how much they drink, but it should be suspected when the ratio of AST to ALT is 2 or greater.

In a classic study, a ratio greater than 2 was found in 70% of patients with alcoholic hepatitis and cirrhosis, compared with 26% of patients with postnecrotic cirrhosis, 8% with chronic hepatitis, 4% with viral hepatitis, and none with obstructive jaundice.³ Importantly, the disorder is often correctable if the patient is able to remain abstinent from alcohol over time.

A detailed medication history is important and should focus especially on recently added medications, dosage changes, medication overuse, and use of nonprescription drugs and herbal supplements. Common medications that affect liver enzyme levels include statins, which cause hepatic dysfunction primarily during the first 3 months of therapy, nonsteroidal anti-inflammatory drugs, antiep­ileptic drugs, antibiotics, anabolic steroids, and acetaminophen (Table 2).¹ Use of illicit drugs and herbal remedies should be discussed, as they may cause toxin-mediated hepatitis.

Although inflammation from drug toxicity will resolve if the offending agent is discontinued, complete recovery may take weeks to months.⁴

A pertinent social history includes exposure to environmental hepatotoxins such as amatoxin (contained in some wild mushrooms) and occupational hazards (eg, vinyl chloride). Risk factors for viral hepatitis should be evaluated, including intravenous drug use, blood transfusions, unprotected sexual contact, organ transplant, perinatal transmission, and a history of work in healthcare facilities or travel to regions in which hepatitis A or E is endemic.

The medical and family history should include details of associated conditions, such as:

• Right heart failure (a cause of congestive hepatopathy)
• Metabolic syndrome (associated with fatty liver disease)
• Inflammatory bowel disease and primary sclerosing cholangitis
• Early-onset emphysema and alpha-1 antitrypsin deficiency.

The physical examination should be thorough, with emphasis on the abdomen, and search for stigmata of advanced liver disease such as hepatomegaly, splenomegaly, ascites, edema, spider angiomata, jaundice, and asterixis. Any patient with evidence of chronic liver disease should be referred to a subspecialist for further evaluation.

Abnormal liver enzyme findings or physical examination findings should direct the subsequent diagnostic workup with laboratory testing and imaging.⁵

For cholestasis. If laboratory data are consistent with cholestasis or abnormal bile flow, it should be further characterized as extrahepatic or intrahepatic. Common causes of extrahepatic cholestasis include biliary tree obstruction due to stones or malignancy, often visualized as intraductal biliary dilation on ultrasonography of the right upper quadrant. Common causes of intrahepatic cholestasis include viral and alcoholic hepatitis, nonalcoholic steatohepatitis, certain drugs and toxins such as alkylated steroids and herbal medications, infiltrative diseases such as amyloid, sarcoid, lymphoma, and tuberculosis, and primary biliary cholangitis.

Abnormal findings on ultrasonography should be further pursued with advanced imaging, ie, computed tomography or magnetic resonance cholangiopancreatography (MRCP). The confirmation of a lesion on imaging is often followed by endoscopic retrograde cholangiopancreatography (ERCP) in an attempt to obtain biopsy samples, remove obstructions, and place therapeutic stents. In instances when endoscopic attempts fail to relieve the obstruction, surgical referral may be appropriate.

For nonhepatobiliary problems. Depending on clinical presentation, it may also be important to consider nonhepatobiliary causes of elevated liver enzymes.

Alkaline phosphatase is found in many other tissue types, including bone, kidney, and the placenta, and can be elevated during pregnancy, adolescence, and even after fatty meals due to intestinal release.⁶ After screening for the aforementioned physiologic conditions, isolated elevated alkaline phosphatase should be further evaluated by obtaining GGT or 5-nucleotidase levels, which are more specifically of hepatic origin. If these levels are within normal limits, further evaluation for conditions of bone growth and cellular turnover such as Paget disease, hyperparathyroidism, and malignancy should be considered. Specifically, Stauffer syndrome should be considered when there is a paraneoplastic rise in the alkaline phosphatase level in the setting of renal cell carcinoma without liver metastases.

AST and ALT levels may also be elevated in clinical situations and syndromes unrelated to liver disease. Rhabdomyolysis, for instance, may be associated with elevations of AST in more than 90% of cases, and ALT in more than 75%.⁷ Markers of muscle injury including serum creatine kinase should be obtained in the setting of heat stroke, muscle weakness, strenuous activity, or seizures, as related elevations in AST and ALT may not always be clinically indicative of liver injury.

Given the many conditions that may cause elevated liver enzymes, evaluation and treatment should focus on identifying and removing offending agents and targeting the underlying process with appropriate medical therapy.

FATTY LIVER

With rates of obesity and type 2 diabetes on the rise in the general population, identifying and treating nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) require increased awareness and close coordination between primary care providers and subspecialists.

According to current estimates, up to one-third of the US population (100 million people) may have NAFLD, and 1% to 3% of the population (4–6 million people) likely have NASH, defined as steatosis with inflammation. Development of NASH places patients at a significantly higher risk of fibrosis, hepatocellular injury, and cancer.⁸

NAFLD is more common in men than in women. It is present in around 80% to 90% of obese adults, two-thirds of adults with type 2 diabetes, and many people with hyperlipidemia. It is also becoming more common in children, with 40% to 70% of obese children likely having some element of NAFLD.

Diagnosis of fatty liver

Although liver enzymes are more likely to be abnormal in individuals with NAFLD, many individuals with underlying NAFLD may have normal laboratory evaluations. ALT may be elevated in only up to 20% of cases and does not likely correlate with the level of underlying liver damage, although increasing GGT may serve as a marker of fibrosis over time.^9–11 In contrast to alcohol injury, however, the AST-ALT ratio is usually less than 1.0.

Noninvasive tools for diagnosing NAFLD include the NAFLD fibrosis score, which incorporates age, hyperglycemia, body mass index, platelet count, albumin level, and AST-ALT ratio. This and related scoring algorithms may be useful in differentiating patients with minimal fibrosis from those with advanced fibrosis.^12,13

Ultrasonography is a first-line diagnostic test for steatosis, although it may demonstrate fatty infiltration only around 60% of the time. Computed tomography and magnetic resonance imaging are more sensitive, but costlier. Transient elastography (FibroScan; Echosens, Paris, France) has become more popular and has been shown to correlate with findings on liver biopsy in diagnosing or excluding advanced liver fibrosis.^14,15

The gold standard for diagnosing NAFLD and NASH is identifying fat-laden hepatocytes or portal inflammation on biopsy; however, biopsy is generally reserved for cases in which the diagnosis remains uncertain.

Behavioral treatment

The primary treatment for NAFLD consists of behavioral modification including weight loss, exercise, and adherence to a low-fat diet, in addition to tight glycemic control and treatment of any underlying lipid abnormalities. Studies have shown that a reduction of 7% to 10% of body weight is associated with a decrease in the inflammation of NAFLD, though no strict guidelines have been established.¹⁶

Given the prevalence of NAFLD and the need for longitudinal treatment, primary care physicians will play a significant role in long-term monitoring and management of patients with fatty liver disease.

Hereditary hemochromatosis

Hereditary hemochromatosis is the most common inherited liver disorder in adults of European descent,¹⁷ and can be effectively treated if discovered early. But its clinical diagnosis can be challenging, as many patients have no symptoms at presentation despite abnormal liver enzyme levels. Early symptoms may include severe fatigue, arthralgias, and, in men, impotence, before the appearance of the classic triad of “bronze diabetes” with cirrhosis, diabetes, and darkening of the skin.¹⁸

If hemochromatosis is suspected, laboratory tests should include a calculation of percent transferrin saturation, with saturation greater than 45% warranting serum ferritin measurement to evaluate for iron overload (ferritin > 200–300 ng/mL in men, > 150–200 ng/mL in women).¹⁹ If iron overload is confirmed, referral to a gastroenterologist is recommended.

Genetic evaluation is often pursued, but patients may ultimately require liver biopsy regardless of the findings, as some patients homozygous for the HFE mutation C282Y may not have clinical hemochromatosis, whereas others with hereditary hemochromatosis may not have the HFE mutation.

Therapeutic phlebotomy is the treatment of choice, and most patients tolerate it well.

Chronic hepatitis B virus and hepatitis C virus infections

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are common in the United States, with HBV affecting more than 1 million people and HCV affecting an estimated 3.5 million.

Chronic HCV infection. Direct-acting antiviral drugs have revolutionized HCV treatment and have led to a sustained viral response and presumed cure at 12 weeks in more than 95% of cases across all HCV genotypes.²⁰ Given the recent development of effective and well-tolerated treatments, primary care physicians have assumed a pivotal role in screening for HCV.

The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America²¹ recommend screening for HCV in people who have risk factors for it, ie:

• HCV exposure
• HIV infection
• Behavioral or environmental risks for contracting the virus such as intravenous drug use or incarceration
• Birth between 1945 and 1965 (one-time testing).

If HCV antibody screening is positive, HCV RNA should be obtained to quantify the viral load and confirm active infection, and genotype testing should be performed to guide treatment. Among the 6 most common HCV genotypes, genotype 1 is the most common in North America, accounting for over 70% of cases in the United States.

Although recommendations and therapies are constantly evolving, the selection of a treatment regimen and the duration of therapy are determined by viral genotype, history of prior treatment, stage of liver fibrosis, potential drug interactions, and frequently, medication cost and insurance coverage.

HBV infection. The treatment for acute HBV infection is generally supportive, though viral suppression with tenofovir or entecavir may be required for those who develop coagulopathy, bilirubinemia, or liver failure. Treatment of chronic HBV infection may not be required and is generally considered for those with elevated ALT, high viral load, or evidence of liver fibrosis on noninvasive measurements such as transient elastography.

Autoimmune hepatitis

Autoimmune causes of liver enzyme elevations should also be considered during initial screening. Positive antinuclear antibody and positive antismooth muscle antibody tests are common in cases of autoimmune hepatitis.²² Autoimmune hepatitis affects women more often than men, with a ratio of 4:1. The peaks of incidence occur during adolescence and between ages 30 and 45.²³

Primary biliary cholangitis

Additionally, an elevated alkaline phosphatase level should raise concern for underlying primary biliary cholangitis (formerly called primary biliary cirrhosis), an autoimmune disorder that affects the small and medium intrahepatic bile ducts. Diagnosis of primary biliary cholangitis can be assisted by a positive test for antimitochondrial antibody, present in almost 90% of patients.²⁴

Primary sclerosing cholangitis

Elevated alkaline phosphatase is also the hallmark of primary sclerosing cholangitis, which is associated with inflammatory bowel disease.²⁵ Primary sclerosing cholangitis is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, which are visualized on MRCP and confirmed by biopsy if needed.

REFERRAL

Subspecialty referral should be considered if the cause remains ambiguous or unknown, if there is concern for a rare hepatic disorder such as an autoimmune condition, Wilson disease, or alpha-1 antitrypsin deficiency, or if there is evidence of advanced or chronic liver disease.

Primary care physicians are at the forefront of detecting and diagnosing liver disease, and close coordination with subspecialists will remain crucial in delivering patient care.

More than 300 hospitalists and other clinicians recently attended the 13th annual Southern Hospital Medicine Conference in Atlanta. The conference is a joint collaboration between the Emory University School of Medicine in Atlanta and Ochsner Health System New Orleans. The meeting site has alternated between the two cities each year since 2005.

The prevailing conference theme in 2012 was “Value and Values in Hospital Medicine,” alluding to the value that hospitalists bring to the medical community and hospitals and the values shared by hospitalists. The conference offered five pre-courses and more than 50 sessions focused on educating hospitalists on current best practices within core topic areas, including clinical care, quality improvement, healthcare information technology, innovative care models, systems of care, and transitions of care. A judged poster competition featured research and clinical vignettes abstracts, with interesting clinical cases as well as new research in hospital medicine.

One of the highlights of this year’s conference was the keynote address delivered by Dr. William A. Bornstein, chief quality and medical officer of Emory Healthcare. Dr. Bornstein discussed the various aspects of quality and cost in hospital care. He described the challenges in defining quality and measuring cost when trying to calculate the “value” equation in medicine (value=quality/cost). He outlined the Institute of Medicine’s previously described STEEEP (safe, timely, effective, efficient, equitable, patient-centered) aims of quality in 2001.

Dr. Bornstein’s own definition for quality is “partnering with patients and families to reliably, 100% of the time, deliver when, where, and how they want it—and with minimal waste—care based on the best available evidence and consistent with patient and family values and preferences.” To measure outcome, he said, we need to address system structure (what’s in place before the patient arrives), process (what we do for the patient), and culture (how we can get the buy-in from all stakeholders). The sum of these factors achieves outcome, which requires risk adjustment and, ideally, long-term follow-up data, he said.

Dr. Bornstein also discussed the need to develop standard processes whereby equivalent clinicians can follow similar processes to achieve the same results. When physicians “do it the same” (i.e. standardized protocols), error rates and cost decrease, he explained.

Dr. Bornstein also focused on transformative solutions to address problems in healthcare as a whole, rather than attempting to fix problems piecemeal.

Jason Stein, MD, SFHM, offered another conference highlight: a pre-conference program and plenary session on an innovative approach to improve hospital outcomes through implementation of the accountable-care unit (ACU). Dr. Stein, director of the clinical research program at Emory School of Medicine, described the current state of hospital care as asynchronous, with various providers caring for the patient without much coordination. For example, the physician sees the patient at 9 a.m., followed by the nurse at 10 a.m., and then finally the visiting family at 11 a.m. The ACU model of care would involve all the providers rounding with the patient and family at a scheduled time daily to provide synchronous care.

Dr. Stein described an ACU as a geographic inpatient area consistently responsible for the clinical, service, and cost outcomes it produces. Features of this unit include:

• Assignment of physicians by units to enhance predictability;
• Cohesiveness and communication;
• Structured interdisciplinary bedside rounds to consistently deliver evidence-based, patient-centered care;
• Evaluation of performance data by unit instead of facility or service line; and
• A dyad partnership involving a nurse unit director and a physician unit medical director.

ACU implementation at Emory has led to decreased mortality, reduced length of stay, and improved patient satisfaction compared to traditional units, according to Dr. Stein. While the ACU might not be suited for all, he said, all hospitals can learn from various components of this innovative approach to deliver better patient care.

The ever-changing state of HM in the U.S. remains a challenge, but it continues to generate innovation and excitement. The high number of engaged participants from 30 different states attending the 13th annual Southern Hospital Medicine Conference demonstrates that hospitalists are eager to learn and ready to improve their practice in order to provide high-value healthcare in U.S. hospitals today.

Dr. Lee is vice chairman in the department of hospital medicine at Ochsner Health System. Dr. Smith is an assistant director for education in the division of hospital medicine at Emory University. Dr. Deitelzweig is system chairman in the department of hospital medicine and medical director for regional business development at Ochsner Health System. Dr. Wang is the division director of hospital medicine at Emory University. Dr. Dressler is director for education in the division of hospital medicine and an associate program director for the J. Willis Hurst Internal Medicine Residency Program at Emory University.

More than 300 hospitalists and other clinicians recently attended the 13th annual Southern Hospital Medicine Conference in Atlanta. The conference is a joint collaboration between the Emory University School of Medicine in Atlanta and Ochsner Health System New Orleans. The meeting site has alternated between the two cities each year since 2005.

The prevailing conference theme in 2012 was “Value and Values in Hospital Medicine,” alluding to the value that hospitalists bring to the medical community and hospitals and the values shared by hospitalists. The conference offered five pre-courses and more than 50 sessions focused on educating hospitalists on current best practices within core topic areas, including clinical care, quality improvement, healthcare information technology, innovative care models, systems of care, and transitions of care. A judged poster competition featured research and clinical vignettes abstracts, with interesting clinical cases as well as new research in hospital medicine.

One of the highlights of this year’s conference was the keynote address delivered by Dr. William A. Bornstein, chief quality and medical officer of Emory Healthcare. Dr. Bornstein discussed the various aspects of quality and cost in hospital care. He described the challenges in defining quality and measuring cost when trying to calculate the “value” equation in medicine (value=quality/cost). He outlined the Institute of Medicine’s previously described STEEEP (safe, timely, effective, efficient, equitable, patient-centered) aims of quality in 2001.

Dr. Bornstein’s own definition for quality is “partnering with patients and families to reliably, 100% of the time, deliver when, where, and how they want it—and with minimal waste—care based on the best available evidence and consistent with patient and family values and preferences.” To measure outcome, he said, we need to address system structure (what’s in place before the patient arrives), process (what we do for the patient), and culture (how we can get the buy-in from all stakeholders). The sum of these factors achieves outcome, which requires risk adjustment and, ideally, long-term follow-up data, he said.

Dr. Bornstein also discussed the need to develop standard processes whereby equivalent clinicians can follow similar processes to achieve the same results. When physicians “do it the same” (i.e. standardized protocols), error rates and cost decrease, he explained.

Dr. Bornstein also focused on transformative solutions to address problems in healthcare as a whole, rather than attempting to fix problems piecemeal.

Jason Stein, MD, SFHM, offered another conference highlight: a pre-conference program and plenary session on an innovative approach to improve hospital outcomes through implementation of the accountable-care unit (ACU). Dr. Stein, director of the clinical research program at Emory School of Medicine, described the current state of hospital care as asynchronous, with various providers caring for the patient without much coordination. For example, the physician sees the patient at 9 a.m., followed by the nurse at 10 a.m., and then finally the visiting family at 11 a.m. The ACU model of care would involve all the providers rounding with the patient and family at a scheduled time daily to provide synchronous care.

Dr. Stein described an ACU as a geographic inpatient area consistently responsible for the clinical, service, and cost outcomes it produces. Features of this unit include:

• Assignment of physicians by units to enhance predictability;
• Cohesiveness and communication;
• Structured interdisciplinary bedside rounds to consistently deliver evidence-based, patient-centered care;
• Evaluation of performance data by unit instead of facility or service line; and
• A dyad partnership involving a nurse unit director and a physician unit medical director.

ACU implementation at Emory has led to decreased mortality, reduced length of stay, and improved patient satisfaction compared to traditional units, according to Dr. Stein. While the ACU might not be suited for all, he said, all hospitals can learn from various components of this innovative approach to deliver better patient care.

The ever-changing state of HM in the U.S. remains a challenge, but it continues to generate innovation and excitement. The high number of engaged participants from 30 different states attending the 13th annual Southern Hospital Medicine Conference demonstrates that hospitalists are eager to learn and ready to improve their practice in order to provide high-value healthcare in U.S. hospitals today.

Dr. Lee is vice chairman in the department of hospital medicine at Ochsner Health System. Dr. Smith is an assistant director for education in the division of hospital medicine at Emory University. Dr. Deitelzweig is system chairman in the department of hospital medicine and medical director for regional business development at Ochsner Health System. Dr. Wang is the division director of hospital medicine at Emory University. Dr. Dressler is director for education in the division of hospital medicine and an associate program director for the J. Willis Hurst Internal Medicine Residency Program at Emory University.

More than 300 hospitalists and other clinicians recently attended the 13th annual Southern Hospital Medicine Conference in Atlanta. The conference is a joint collaboration between the Emory University School of Medicine in Atlanta and Ochsner Health System New Orleans. The meeting site has alternated between the two cities each year since 2005.

The prevailing conference theme in 2012 was “Value and Values in Hospital Medicine,” alluding to the value that hospitalists bring to the medical community and hospitals and the values shared by hospitalists. The conference offered five pre-courses and more than 50 sessions focused on educating hospitalists on current best practices within core topic areas, including clinical care, quality improvement, healthcare information technology, innovative care models, systems of care, and transitions of care. A judged poster competition featured research and clinical vignettes abstracts, with interesting clinical cases as well as new research in hospital medicine.

One of the highlights of this year’s conference was the keynote address delivered by Dr. William A. Bornstein, chief quality and medical officer of Emory Healthcare. Dr. Bornstein discussed the various aspects of quality and cost in hospital care. He described the challenges in defining quality and measuring cost when trying to calculate the “value” equation in medicine (value=quality/cost). He outlined the Institute of Medicine’s previously described STEEEP (safe, timely, effective, efficient, equitable, patient-centered) aims of quality in 2001.

Dr. Bornstein’s own definition for quality is “partnering with patients and families to reliably, 100% of the time, deliver when, where, and how they want it—and with minimal waste—care based on the best available evidence and consistent with patient and family values and preferences.” To measure outcome, he said, we need to address system structure (what’s in place before the patient arrives), process (what we do for the patient), and culture (how we can get the buy-in from all stakeholders). The sum of these factors achieves outcome, which requires risk adjustment and, ideally, long-term follow-up data, he said.

Dr. Bornstein also discussed the need to develop standard processes whereby equivalent clinicians can follow similar processes to achieve the same results. When physicians “do it the same” (i.e. standardized protocols), error rates and cost decrease, he explained.

Dr. Bornstein also focused on transformative solutions to address problems in healthcare as a whole, rather than attempting to fix problems piecemeal.

Jason Stein, MD, SFHM, offered another conference highlight: a pre-conference program and plenary session on an innovative approach to improve hospital outcomes through implementation of the accountable-care unit (ACU). Dr. Stein, director of the clinical research program at Emory School of Medicine, described the current state of hospital care as asynchronous, with various providers caring for the patient without much coordination. For example, the physician sees the patient at 9 a.m., followed by the nurse at 10 a.m., and then finally the visiting family at 11 a.m. The ACU model of care would involve all the providers rounding with the patient and family at a scheduled time daily to provide synchronous care.

Dr. Stein described an ACU as a geographic inpatient area consistently responsible for the clinical, service, and cost outcomes it produces. Features of this unit include:

• Assignment of physicians by units to enhance predictability;
• Cohesiveness and communication;
• Structured interdisciplinary bedside rounds to consistently deliver evidence-based, patient-centered care;
• Evaluation of performance data by unit instead of facility or service line; and
• A dyad partnership involving a nurse unit director and a physician unit medical director.

ACU implementation at Emory has led to decreased mortality, reduced length of stay, and improved patient satisfaction compared to traditional units, according to Dr. Stein. While the ACU might not be suited for all, he said, all hospitals can learn from various components of this innovative approach to deliver better patient care.

The ever-changing state of HM in the U.S. remains a challenge, but it continues to generate innovation and excitement. The high number of engaged participants from 30 different states attending the 13th annual Southern Hospital Medicine Conference demonstrates that hospitalists are eager to learn and ready to improve their practice in order to provide high-value healthcare in U.S. hospitals today.

Dr. Lee is vice chairman in the department of hospital medicine at Ochsner Health System. Dr. Smith is an assistant director for education in the division of hospital medicine at Emory University. Dr. Deitelzweig is system chairman in the department of hospital medicine and medical director for regional business development at Ochsner Health System. Dr. Wang is the division director of hospital medicine at Emory University. Dr. Dressler is director for education in the division of hospital medicine and an associate program director for the J. Willis Hurst Internal Medicine Residency Program at Emory University.