Cleveland Clinic Journal of Medicine

In Reply: We thank Drs. Goldstein and Mascitelli for their comments regarding fluoroquinolones and thoracic aortic aneurysms. We acknowledge that fluoroquinolones (particularly ciprofloxacin) have been associated with a risk of aortic aneurysm and dissection based on large observational studies from Taiwan, Canada, and Sweden. Although all of the studies have shown an association between ciprofloxacin and aortic aneurysm, the causative role is not well established. In addition, the numbers of events were very small in these large cohorts of patients. In our large tertiary care practice at Cleveland Clinic, we have very few patients with aortic aneurysm or dissection who have used fluoroquinolones.

We recognize the association; however, our paper was intended to emphasize the more common causes and treatment options that primary care physicians are likely to encounter in routine practice.

We also thank Drs. Ayoubieh and MacCarrick for their comments about genetic counseling. We agree that genetic counseling is important, as is a detailed physical examination for subtle features of genetically mediated aortic aneurysm. In fact, we incorporate the physical examination when patients are seen at our aortic center so as to recognize the physical features. We do routinely recommend screening of first-degree relatives even without significant family history on an individual basis and make appropriate referrals for other conditions that can be seen in these patients. Our article, however, is primarily intended to emphasize the importance of referring these patients for more-focused care at a specialized center, where we incorporate all of the suggestions that were made.

In Reply: We thank Drs. Goldstein and Mascitelli for their comments regarding fluoroquinolones and thoracic aortic aneurysms. We acknowledge that fluoroquinolones (particularly ciprofloxacin) have been associated with a risk of aortic aneurysm and dissection based on large observational studies from Taiwan, Canada, and Sweden. Although all of the studies have shown an association between ciprofloxacin and aortic aneurysm, the causative role is not well established. In addition, the numbers of events were very small in these large cohorts of patients. In our large tertiary care practice at Cleveland Clinic, we have very few patients with aortic aneurysm or dissection who have used fluoroquinolones.

We recognize the association; however, our paper was intended to emphasize the more common causes and treatment options that primary care physicians are likely to encounter in routine practice.

We also thank Drs. Ayoubieh and MacCarrick for their comments about genetic counseling. We agree that genetic counseling is important, as is a detailed physical examination for subtle features of genetically mediated aortic aneurysm. In fact, we incorporate the physical examination when patients are seen at our aortic center so as to recognize the physical features. We do routinely recommend screening of first-degree relatives even without significant family history on an individual basis and make appropriate referrals for other conditions that can be seen in these patients. Our article, however, is primarily intended to emphasize the importance of referring these patients for more-focused care at a specialized center, where we incorporate all of the suggestions that were made.

In Reply: We thank Drs. Goldstein and Mascitelli for their comments regarding fluoroquinolones and thoracic aortic aneurysms. We acknowledge that fluoroquinolones (particularly ciprofloxacin) have been associated with a risk of aortic aneurysm and dissection based on large observational studies from Taiwan, Canada, and Sweden. Although all of the studies have shown an association between ciprofloxacin and aortic aneurysm, the causative role is not well established. In addition, the numbers of events were very small in these large cohorts of patients. In our large tertiary care practice at Cleveland Clinic, we have very few patients with aortic aneurysm or dissection who have used fluoroquinolones.

We recognize the association; however, our paper was intended to emphasize the more common causes and treatment options that primary care physicians are likely to encounter in routine practice.

We also thank Drs. Ayoubieh and MacCarrick for their comments about genetic counseling. We agree that genetic counseling is important, as is a detailed physical examination for subtle features of genetically mediated aortic aneurysm. In fact, we incorporate the physical examination when patients are seen at our aortic center so as to recognize the physical features. We do routinely recommend screening of first-degree relatives even without significant family history on an individual basis and make appropriate referrals for other conditions that can be seen in these patients. Our article, however, is primarily intended to emphasize the importance of referring these patients for more-focused care at a specialized center, where we incorporate all of the suggestions that were made.

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.

In the current sociopolitical environment in the United States, the slogan “words matter” has become a battle cry for several groups and causes, emphasizing that our choice of words can influence the way we assess a specific person or situation. We are not immune to the subliminal bias of words, even as we evaluate such seemingly objective components of clinical management as laboratory test results.

Several years ago, I was supervising teaching rounds on a general medicine service. It was the first rounds of the month, and the patients were relatively new to the residents and totally unknown to me. One patient was an elderly man with weight loss, fatigue, weakness, and a history of excessive alcohol ingestion. His family had corroborated the last detail, but he had stopped drinking a long time before his admission. He had normal creatinine, minimal anemia, and markedly elevated and unexplained “liver function tests.” Liver biopsy was planned.

As we entered his room, we saw a gaunt man struggle to rise from the bedside chair to get back into bed. He rocked several times and then pushed himself up from the chair using his arms. Then, after a few short steps, he plopped back into bed and greeted us. His breakfast tray was untouched at the bedside. I introduced myself, we chatted for a short while as I examined him in front of our team, and we left.

In the hallway I asked, “Who would like to get an additional blood test before we do a liver biopsy?” Without waiting for a response I asked a second question, “What exactly are liver function tests?”

Words do matter, and they influence the way we analyze clinical scenarios. It could be argued that a complete and careful history would have established that our patient’s fatigue and weakness were due to proximal muscle weakness and not general asthenia, and that detailed questioning would have revealed that his weight loss was mainly from difficulty in swallowing without a sense of choking and coughing. But faced with an elderly man, a likely explanation for liver disease, and markedly elevated aspartate and alanine aminotransferase (AST and ALT) levels, there was premature closure of the diagnosis, and the decision was made to obtain a liver biopsy—which our hepatology consultants surely would not have done. I believe that a major contributor to the premature diagnosis was the choice of the words “liver function tests” and the default assumption that elevated serum levels of these enzymes always reflect liver disease.

Aminotransferases are fairly ubiquitous, likely present in various concentrations in all cells in our body. AST exists in mitochondrial and cytosolic forms, and ALT in the cytosol. The concentration of ALT is higher in the liver than in other organs, and its enzymatic activity is suppressed by hepatic exposure to alcohol. Both enzymes are present in muscle, and although AST is more abundant in cells other than hepatocytes, the longer serum half-life of ALT may result in roughly equal serum levels in the setting of chronic muscle injury such as myositis (the true diagnosis in our weak patient).

While a meticulous history and examination would indeed have led to the diagnosis of muscle disease in this man, they alone could not have determined whether he had coexistent liver and muscle disease. And this is a real challenge when acute muscle toxicity and liver toxicity are equally possible (eg, statin or immune checkpoint autoimmune tissue damage, or after significant trauma).

There are many nuances in the interpretation of even the most common laboratory tests. In this issue of the Journal, Agganis et al discuss liver enzymes (a term slightly more acceptable to me than liver function tests). In future issues, we will address the interpretation of other laboratory tests.

In the current sociopolitical environment in the United States, the slogan “words matter” has become a battle cry for several groups and causes, emphasizing that our choice of words can influence the way we assess a specific person or situation. We are not immune to the subliminal bias of words, even as we evaluate such seemingly objective components of clinical management as laboratory test results.

Several years ago, I was supervising teaching rounds on a general medicine service. It was the first rounds of the month, and the patients were relatively new to the residents and totally unknown to me. One patient was an elderly man with weight loss, fatigue, weakness, and a history of excessive alcohol ingestion. His family had corroborated the last detail, but he had stopped drinking a long time before his admission. He had normal creatinine, minimal anemia, and markedly elevated and unexplained “liver function tests.” Liver biopsy was planned.

As we entered his room, we saw a gaunt man struggle to rise from the bedside chair to get back into bed. He rocked several times and then pushed himself up from the chair using his arms. Then, after a few short steps, he plopped back into bed and greeted us. His breakfast tray was untouched at the bedside. I introduced myself, we chatted for a short while as I examined him in front of our team, and we left.

In the hallway I asked, “Who would like to get an additional blood test before we do a liver biopsy?” Without waiting for a response I asked a second question, “What exactly are liver function tests?”

Words do matter, and they influence the way we analyze clinical scenarios. It could be argued that a complete and careful history would have established that our patient’s fatigue and weakness were due to proximal muscle weakness and not general asthenia, and that detailed questioning would have revealed that his weight loss was mainly from difficulty in swallowing without a sense of choking and coughing. But faced with an elderly man, a likely explanation for liver disease, and markedly elevated aspartate and alanine aminotransferase (AST and ALT) levels, there was premature closure of the diagnosis, and the decision was made to obtain a liver biopsy—which our hepatology consultants surely would not have done. I believe that a major contributor to the premature diagnosis was the choice of the words “liver function tests” and the default assumption that elevated serum levels of these enzymes always reflect liver disease.

Aminotransferases are fairly ubiquitous, likely present in various concentrations in all cells in our body. AST exists in mitochondrial and cytosolic forms, and ALT in the cytosol. The concentration of ALT is higher in the liver than in other organs, and its enzymatic activity is suppressed by hepatic exposure to alcohol. Both enzymes are present in muscle, and although AST is more abundant in cells other than hepatocytes, the longer serum half-life of ALT may result in roughly equal serum levels in the setting of chronic muscle injury such as myositis (the true diagnosis in our weak patient).

While a meticulous history and examination would indeed have led to the diagnosis of muscle disease in this man, they alone could not have determined whether he had coexistent liver and muscle disease. And this is a real challenge when acute muscle toxicity and liver toxicity are equally possible (eg, statin or immune checkpoint autoimmune tissue damage, or after significant trauma).

There are many nuances in the interpretation of even the most common laboratory tests. In this issue of the Journal, Agganis et al discuss liver enzymes (a term slightly more acceptable to me than liver function tests). In future issues, we will address the interpretation of other laboratory tests.

In the current sociopolitical environment in the United States, the slogan “words matter” has become a battle cry for several groups and causes, emphasizing that our choice of words can influence the way we assess a specific person or situation. We are not immune to the subliminal bias of words, even as we evaluate such seemingly objective components of clinical management as laboratory test results.

Several years ago, I was supervising teaching rounds on a general medicine service. It was the first rounds of the month, and the patients were relatively new to the residents and totally unknown to me. One patient was an elderly man with weight loss, fatigue, weakness, and a history of excessive alcohol ingestion. His family had corroborated the last detail, but he had stopped drinking a long time before his admission. He had normal creatinine, minimal anemia, and markedly elevated and unexplained “liver function tests.” Liver biopsy was planned.

As we entered his room, we saw a gaunt man struggle to rise from the bedside chair to get back into bed. He rocked several times and then pushed himself up from the chair using his arms. Then, after a few short steps, he plopped back into bed and greeted us. His breakfast tray was untouched at the bedside. I introduced myself, we chatted for a short while as I examined him in front of our team, and we left.

In the hallway I asked, “Who would like to get an additional blood test before we do a liver biopsy?” Without waiting for a response I asked a second question, “What exactly are liver function tests?”

Words do matter, and they influence the way we analyze clinical scenarios. It could be argued that a complete and careful history would have established that our patient’s fatigue and weakness were due to proximal muscle weakness and not general asthenia, and that detailed questioning would have revealed that his weight loss was mainly from difficulty in swallowing without a sense of choking and coughing. But faced with an elderly man, a likely explanation for liver disease, and markedly elevated aspartate and alanine aminotransferase (AST and ALT) levels, there was premature closure of the diagnosis, and the decision was made to obtain a liver biopsy—which our hepatology consultants surely would not have done. I believe that a major contributor to the premature diagnosis was the choice of the words “liver function tests” and the default assumption that elevated serum levels of these enzymes always reflect liver disease.

Aminotransferases are fairly ubiquitous, likely present in various concentrations in all cells in our body. AST exists in mitochondrial and cytosolic forms, and ALT in the cytosol. The concentration of ALT is higher in the liver than in other organs, and its enzymatic activity is suppressed by hepatic exposure to alcohol. Both enzymes are present in muscle, and although AST is more abundant in cells other than hepatocytes, the longer serum half-life of ALT may result in roughly equal serum levels in the setting of chronic muscle injury such as myositis (the true diagnosis in our weak patient).

While a meticulous history and examination would indeed have led to the diagnosis of muscle disease in this man, they alone could not have determined whether he had coexistent liver and muscle disease. And this is a real challenge when acute muscle toxicity and liver toxicity are equally possible (eg, statin or immune checkpoint autoimmune tissue damage, or after significant trauma).

There are many nuances in the interpretation of even the most common laboratory tests. In this issue of the Journal, Agganis et al discuss liver enzymes (a term slightly more acceptable to me than liver function tests). In future issues, we will address the interpretation of other laboratory tests.

The balance between dietary intake and excretion of phosphorus can be impaired in patients with decreased renal function, leading to hyperphosphatemia. Many patients with end-stage renal disease on dialysis require phosphorus-binding drugs to control their serum phosphorus levels.

See related editorial and article

In this review, we discuss the pathophysiology of hyperphosphatemia in kidney disease, its consequences, and how to control it, focusing on the different classes of phosphorus binders.

ROLE OF THE INTERNIST

With kidney disease common and on the increase,¹ nephrologists and internists need to work together to provide optimal care.

Further, many internists in managed care plans and accountable care organizations now handle many tasks previously left to specialists—including prescribing and managing phosphorus binders in patients with kidney disease.

PATHOPHYSIOLOGY OF HYPERPHOSPHATEMIA

The pathophysiology of bone mineral disorders in kidney disease is complex. To simplify the discussion, we will address it in 3 parts:

• Phosphorus balance
• The interplay of hormones, including fibro­blast growth factor 23 (FGF23)
• The mechanism of hyperphosphatemia in kidney disease.

Phosphorus balance

Phosphorus is a macronutrient essential for a range of cellular functions that include structure, energy production, metabolism, and cell signaling. It exists primarily in the form of inorganic phosphate.

An average Western diet provides 20 mg of phosphorus per kilogram of body weight per day. Of this, 13 mg/kg is absorbed, and the rest is excreted in the feces.²

Absorption of dietary phosphorus occurs mainly in the jejunum. It is mediated by both a paracellular sodium-independent pathway (driven by high intraluminal phosphorus content) and by active sodium-dependent cotransporters. It is also influenced by diet and promoted by active vitamin D (1,25 dihydroxyvitamin D₃, also called calcitriol).³

Absorbed phosphorus enters the extracellular fluid and shifts in and out of the skeleton under the influence of parathyroid hormone.

Phosphorus excretion is handled almost entirely by the kidneys. Phosphorus is freely filtered at the glomerulus and reabsorbed mainly in the proximal tubule by sodium-phosphate cotransporters.

Normally, when phosphorus intake is adequate, most of the filtered phosphorus is reabsorbed and only 10% to 20% is excreted in the urine. However, the threshold for phosphorus reabsorption in the proximal tubule is influenced by parathyroid hormone, FGF23, and dietary phosphorus intake: low serum phosphate levels lead to an increase in the synthesis of sodium-phosphorus cotransporters, resulting in increased (nearly complete) proximal reabsorption and an increase in the serum phosphorus concentration.⁴ Conversely, both parathyroid hormone and FGF23 are phosphaturic and decrease the number of phosphorus transporters, which in turn leads to increased phosphorus excretion and a decrease in serum phosphorus concentration.⁵

Interplay of hormones

FGF23 is a phosphaturic glycoprotein secreted by osteoblasts and osteocytes. It acts by binding to fibroblastic growth receptor 1 in the presence of its coreceptor, the Klotho protein.⁶

FGF23 is regulated by serum phosphorus levels and plays a major role in the response to elevated serum phosphorus. It causes a direct increase in urinary phosphorus excretion, a decrease in intestinal phosphorus absorption (indirectly via inhibition of calcitriol), and decreased bone resorption via a decrease in parathyroid hormone production.⁷

Mechanism of hyperphosphatemia in kidney disease

In chronic kidney disease, phosphorus retention can trigger secondary hyperparathyroidism, as rising phosphorus levels stimulate FGF23. In the early stages of chronic kidney disease, this response can correct the phosphorus levels, but with several consequences:

• Decreased calcitriol due to its inhibition by FGF23⁹
• Hypocalcemia due to decreased calcitriol (leading to decreased intestinal calcium absorption) and calcium binding of retained phosphorus
• Elevated parathyroid hormone due to low calcitriol levels (lack of inhibitory feedback by calcitriol), hyperphosphatemia, and hypocalcemia (direct parathyroid hormone stimulation).

As the elevated phosphorus level is likely to be the triggering event behind secondary renal hyperparathyroidism, it needs to be controlled. This is accomplished by restricting dietary phosphorus and using phosphorus binders.

HYPERPHOSPHATEMIA MAY LEAD TO VASCULAR CALCIFICATION

Elevated serum phosphorus levels (normal range 2.48–4.65 mg/dL in adults¹¹) are associated with cardiovascular calcification and subsequent increases in mortality and morbidity rates. Elevations in serum phosphorus and calcium levels are associated with progression in vascular calcification¹² and likely account for the accelerated vascular calcification that is seen in kidney disease.¹³

Hyperphosphatemia has been identified as an independent risk factor for death in patients with end-stage renal disease,¹⁴ but that relationship is less clear in patients with chronic kidney disease. A study in patients with chronic kidney disease and not on dialysis found a lower mortality rate in those who were prescribed phosphorus binders,¹⁵ but the study was criticized for limitations in its design.

Hyperphosphatemia can also lead to adverse effects on bone health due to complications such as renal osteodystrophy.

However, in its 2017 update, the Kidney Disease: Improving Global Outcomes (KDIGO) program only “suggests” lowering elevated phosphorus levels “toward” the normal range in patients with chronic kidney disease stages G3a through G5D, ie, those with glomerular filtration rates less than 60 mL/min/1.73 m², including those on dialysis. The recommendation is graded 2C, ie, weak, based on low-quality evidence (https://kdigo.org/guidelines/ckd-mbd).

DIETARY RESTRICTION OF PHOSPHORUS

Diet is the major source of phosphorus intake. The average daily phosphorus consumption is  20 mg/kg, or 1,400 mg, and protein is the major source of dietary phosphorus.

In patients with stage 4 or 5 chronic kidney disease, the Kidney Disease Outcomes Quality Initiative recommends limiting protein intake to 0.6 mg/kg/day.¹⁶ However, in patients on hemodialysis, they recommend increasing protein intake to 1.1 mg/kg/day while limiting phosphorus intake to about 800 to 1,000 mg/day. This poses a challenge, as limiting phosphorus intake can reduce protein intake.

Sources of protein can be broadly classified as plant-based or animal-based. Animal protein contains organic phosphorus, which is easily absorbed.¹⁸ Plant protein may not be absorbed as easily.

Moe et al¹⁹ studied the importance of the protein source of phosphorus after 7 days of controlled diets. Despite equivalent protein and phosphorus concentrations in the vegetarian and meat-based diets, participants on the vegetarian diet had lower serum phosphorus levels, a trend toward lower 24-hour urinary phosphorus excretion, and significantly lower FGF23 levels than those on the meat-based diet. This suggests that a vegetarian diet may have advantages in terms of preventing hyperphosphatemia.

Another measure to reduce phosphorus absorption from meat is to boil it, which reduces the phosphorus content by 50%.²⁰

Processed foods containing additives and preservatives are very high in phosphorus²¹ and should be avoided, particularly as there is no mandate to label phosphorus content in food.

PHOSPHORUS AND DIALYSIS

Although hemodialysis removes phosphorus, it does not remove enough to keep levels within normal limits. Indeed, even when patients adhere to a daily phosphorus limit of 1,000 mg, phosphorus accumulates. If 70% of the phosphorus in the diet is absorbed, this is 4,500 to 5,000 mg in a week. A 4-hour hemodialysis session will remove only 1,000 mg of phosphorus, which equals about 3,000 mg for patients undergoing dialysis 3 times a week,²² far less than phosphorus absorption.

In patients on continuous ambulatory peritoneal dialysis, a daily regimen of 4 exchanges of 2 L per exchange removes about 200 mg of phosphorus per day. In a 2012 study, patients on nocturnal dialysis or home dialysis involving longer session length had greater lowering of phosphorus levels than patients undergoing routine hemodialysis.²³

Hence, phosphorus binders are often necessary in patients on routine hemodialysis or peritoneal dialysis.

PHOSPHORUS BINDERS

Phosphorus binders reduce serum phosphorus levels by binding with ingested phosphorus in the gastrointestinal tract and forming insoluble complexes that are not absorbed. For this reason they are much more effective when taken with meals. Phosphorus binders come in different formulations: pills, capsules, chewable tablets, liquids, and even powders that can be sprinkled on food.

The potency of each binder is quantified by its “phosphorus binder equivalent dose,” ie, its binding capacity compared with that of calcium carbonate as a reference.²⁴

Phosphorus binders are broadly divided into those that contain calcium and those that do not.

Calcium-containing binders

The 2 most commonly used preparations are calcium carbonate (eg, Tums) and calcium acetate (eg, Phoslo). While these are relatively safe, some studies suggest that their use can lead to accelerated vascular calcification.²⁵

According to KDIGO,²⁶ calcium-containing binders should be avoided in hypercalcemia and adynamic bone disease. Additionally, the daily elemental calcium intake from binders should be limited to 1,500 mg, with a total daily intake that does not exceed 2,000 mg.

The elemental calcium content of calcium carbonate is about 40% of its weight (eg, 200 mg of elemental calcium in a 500-mg tablet of Tums), while the elemental calcium content of calcium acetate is about 25%. Therefore, a patient who needs 6 g of calcium carbonate for efficacy will be ingesting 2.4 g of elemental calcium per day, and that exceeds the recommended daily maximum. The main advantage of calcium carbonate is its low cost and easy availability. Commonly reported side effects include nausea and constipation.

A less commonly used calcium-based binder is calcium citrate (eg, Calcitrate). It should, however, be avoided in chronic kidney disease because of the risk of aluminum accumulation. Calcium citrate can enhance intestinal absorption of aluminum from dietary sources, as aluminum can form complexes with citrate.²⁷

Calcium-free binders

There are several calcium-free binders. Some are based on metals such as aluminum, magnesium, iron, and lanthanum; others, such as sevelamer, are resin-based.

Aluminum- and magnesium-based binders are generally not used long-term in kidney disease because of the toxicity associated with aluminum and magnesium accumulation. However, aluminum hydroxide has an off-label use as a phosphorus binder in the acute setting, particularly when serum phosphorus levels are above 7 mg/dL.²⁸ The dose is 300 to 600 mg 3 times daily with meals for a maximum of 4 weeks.

Sevelamer. Approved by the US Food and Drug Administration (FDA) in 1998, sevelamer acts by trapping phosphorus through ion exchange and hydrogen binding. It has the advantage of being calcium-free, which makes it particularly desirable in patients with hypercalcemia.

The Renagel in New Dialysis²⁵ and Treat-To-Goal²⁹ studies were randomized controlled trials that looked at the effects of sevelamer vs calcium-based binders on the risk of vascular calcification. The primary end points were serum phosphorus and calcium levels, while the secondary end points were coronary artery calcification on computed tomography and thoracic vertebral bone density. Both studies demonstrated a higher risk of vascular calcification with the calcium-based binders.

Another possible benefit of sevelamer is an improvement in lipid profile. Sevelamer lowers total cholesterol and low-density lipoprotein cholesterol levels without affecting high-density lipoprotein cholesterol or triglyceride levels.³⁰ This is likely due to its bile acid-binding effect.³¹ Sevelamer has also been shown to lower C-reactive protein levels.³² While the cardiovascular profile appears to be improved with the treatment, there are no convincing data to confirm that those properties translate to a proven independent survival benefit.

The Calcium Acetate Renagel Evaluation³³ was a randomized controlled study comparing sevelamer and calcium acetate. The authors attempted to control for the lipid-lowering effects of sevelamer by giving atorvastatin to all patients in both groups who had a low-density lipoprotein level greater than 70 mg/dL. The study found sevelamer to be not inferior to calcium acetate in terms of mortality and coronary calcification.

Further studies such as the Brazilian Renagel and Calcium trial³⁴ and the Dialysis Clinical Outcomes Revisited trial failed to show a significant long-term benefit of sevelamer over calcium-based binders. However, a secondary statistical analysis of the latter study showed possible benefit of sevelamer over calcium acetate among those age 65 and older.³⁵

To understand how sevelamer could affect vascular calcification, Yilmaz et al³⁶ compared the effects of sevelamer vs calcium acetate on FGF23 and fetuin A levels. Fetuin A is an important inhibitor of vascular calcification and is progressively diminished in kidney disease, leading to accelerated calcification.³⁷ Patients on sevelamer had higher levels of fetuin A than their counterparts on calcium acetate.³⁷ The authors proposed increased fetuin A levels as a mechanism for decreased vascular calcification.

In summary, some studies suggest that sevelamer may offer the advantage of decreasing vascular calcification, but the data are mixed and do not provide a solid answer. The main disadvantages of sevelamer are a high pill burden and side effects of nausea and dyspepsia.

Lanthanum, a metallic element, was approved as a phosphorus binder by the FDA in 2008. It comes as a chewable tablet and offers the advantage of requiring the patient to take fewer pills than sevelamer and calcium-based binders.

Sucroferric oxyhydroxide comes as a chewable tablet. It was approved by the FDA in 2013. Although each tablet contains 500 mg of iron, it has not been shown to improve iron markers. In terms of phosphorus-lowering ability, it has been shown to be noninferior to sevelamer.³⁹ Advantages include a significantly lower pill burden. Disadvantages include gastrointestinal side effects such as diarrhea and nausea and the drug’s high cost.

Ferric citrate was approved by the FDA in 2014, and 1 g delivers 210 mg of elemental iron. The main advantage of ferric citrate is its ability to increase iron markers. The phase 3 trial that demonstrated its efficacy as a binder showed an increase in ferritin compared with the active control.⁴⁰ The study also showed a decrease in the need to use intravenous iron and erythropoesis-stimulating agents. This was thought to be due to improved iron stores, leading to decreased erythropoietin resistance.⁴¹

The mean number of ferric citrate tablets needed to achieve the desired phosphorus-lowering effect was 8 per day, containing 1,680 mg of iron. In comparison, oral ferrous sulfate typically provides 210 mg of iron per day.⁴²

Disadvantages of ferric citrate include high pill burden, high cost, and gastrointestinal side effects such as nausea and constipation.

Chitosan binds salivary phosphorus. It can potentially be used, but it is not approved, and its efficacy in lowering serum phosphorus remains unclear.⁴³

CHOOSING THE APPROPRIATE PHOSPHORUS BINDER

The choice of phosphorus binder is based on the patient’s serum calcium level and iron stores and on the drug’s side effect profile, iron pill burden, and cost. Involving patients in the choice after discussing potential side effects, pill burden, and cost is important for shared decision-making and could play a role in improving adherence.

Phosphorus binders are a major portion of the pill burden in patients with end-stage renal disease, possibly affecting patient adherence. The cost of phosphorus binders is estimated at half a billion dollars annually, underlining the significant economic impact of phosphorus control.¹¹

Calcium-based binders should be the first choice when there is secondary hyperparathyroidism without hypercalcemia. There is no clear evidence regarding the benefit of correcting hypocalcemia, but KDIGO recommends keeping the serum calcium level within the reference range. KDIGO also recommends restricting calcium-based binders in persistent hypercalcemia, arterial calcification, and adynamic bone disease. This recommendation is largely based on expert opinion.

Noncalcium-based binders, which in theory might prevent vascular calcification, should be considered for patients with at least 1 of the following⁴⁴:

• Complicated diabetes mellitus
• Vascular or valvular calcification
• Persistent inflammation.

Noncalcium-based binders are also preferred in low bone-turnover states such as adynamic bone disease, as elevated calcium can inhibit parathyroid hormone.

However, the advantage of noncalcium-based binders regarding vascular calcification is largely theoretical and has not been proven clinically. Indeed, there are data comparing long-term outcomes of the different classes of phosphorus binders, but studies were limited by short follow-up, and individual studies have lacked power to detect statistical significance between two classes of binders on long-term outcomes. Meta-analyses have provided conflicting data, with some suggesting better outcomes with sevelamer than with calcium-based binders, and with others failing to show any difference.⁴⁵

Because iron deficiency is common in kidney disease, ferric citrate, which can improve iron markers, may be a suitable option, provided its cost is covered by insurance.

SPECIAL CIRCUMSTANCES FOR THE USE OF PHOSPHORUS BINDERS

Tumor lysis syndrome

Tumor lysis syndrome occurs when tumor cells release their contents into the bloodstream, either spontaneously or in response to therapy, leading to the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.⁴⁶ Phosphorus binders in conjunction with intravenous hydration are used to treat hyperphosphatemia, but evidence about their efficacy in this setting is limited.

Hypocalcemia in tumor lysis syndrome is usually not treated unless symptomatic, as the calcium-phosphorus product can increase, leading to calcium phosphate crystallization. When the calcium-phosphorus product is greater than 60, there is a higher risk of calcium phosphate deposition in the renal tubules that can lead to acute renal failure in tumor lysis syndrome.⁴⁷ To lower the risk of calcium phosphate crystallization, calcium-based binders should be avoided in tumor lysis syndrome.

Total parenteral nutrition

Since patients on total parenteral nutrition do not eat, phosphorus binders are considered ineffective; there are no concrete data showing that phosphorus binders are effective in these patients.⁴⁸ In patients with kidney disease, the phosphorus content in the parenteral nutrition formulation must be reduced.

Pregnancy

Data on phosphorus binders in pregnancy are limited. Calcium can cross the placenta. Calcium carbonate can be used in pregnancy, and fetal harm is not expected if calcium concentrations are within normal limits.⁴⁹ Calcium acetate, sevelamer, and lanthanum are considered pregnancy category C drugs. Patients with advanced chronic kidney disease and end-stage renal disease who become pregnant must receive specialized obstetric care for high-risk pregnancy.

FUTURE DIRECTIONS

Future therapies may target FGF23 and other inflammatory markers that are up-regulated in renal hyperparathyroidism. However, trials studying these markers are needed to provide a better understanding of their role in bone mineral and cardiovascular health and in overall long-term outcomes. Additionally, randomized controlled trials are needed to study long-term nonsurrogate outcomes such as reduction in cardiovascular disease and rates of overall mortality.

The balance between dietary intake and excretion of phosphorus can be impaired in patients with decreased renal function, leading to hyperphosphatemia. Many patients with end-stage renal disease on dialysis require phosphorus-binding drugs to control their serum phosphorus levels.

See related editorial and article

In this review, we discuss the pathophysiology of hyperphosphatemia in kidney disease, its consequences, and how to control it, focusing on the different classes of phosphorus binders.

ROLE OF THE INTERNIST

With kidney disease common and on the increase,¹ nephrologists and internists need to work together to provide optimal care.

Further, many internists in managed care plans and accountable care organizations now handle many tasks previously left to specialists—including prescribing and managing phosphorus binders in patients with kidney disease.

PATHOPHYSIOLOGY OF HYPERPHOSPHATEMIA

The pathophysiology of bone mineral disorders in kidney disease is complex. To simplify the discussion, we will address it in 3 parts:

• Phosphorus balance
• The interplay of hormones, including fibro­blast growth factor 23 (FGF23)
• The mechanism of hyperphosphatemia in kidney disease.

Phosphorus balance

Phosphorus is a macronutrient essential for a range of cellular functions that include structure, energy production, metabolism, and cell signaling. It exists primarily in the form of inorganic phosphate.

An average Western diet provides 20 mg of phosphorus per kilogram of body weight per day. Of this, 13 mg/kg is absorbed, and the rest is excreted in the feces.²

Absorption of dietary phosphorus occurs mainly in the jejunum. It is mediated by both a paracellular sodium-independent pathway (driven by high intraluminal phosphorus content) and by active sodium-dependent cotransporters. It is also influenced by diet and promoted by active vitamin D (1,25 dihydroxyvitamin D₃, also called calcitriol).³

Absorbed phosphorus enters the extracellular fluid and shifts in and out of the skeleton under the influence of parathyroid hormone.

Phosphorus excretion is handled almost entirely by the kidneys. Phosphorus is freely filtered at the glomerulus and reabsorbed mainly in the proximal tubule by sodium-phosphate cotransporters.

Normally, when phosphorus intake is adequate, most of the filtered phosphorus is reabsorbed and only 10% to 20% is excreted in the urine. However, the threshold for phosphorus reabsorption in the proximal tubule is influenced by parathyroid hormone, FGF23, and dietary phosphorus intake: low serum phosphate levels lead to an increase in the synthesis of sodium-phosphorus cotransporters, resulting in increased (nearly complete) proximal reabsorption and an increase in the serum phosphorus concentration.⁴ Conversely, both parathyroid hormone and FGF23 are phosphaturic and decrease the number of phosphorus transporters, which in turn leads to increased phosphorus excretion and a decrease in serum phosphorus concentration.⁵

Interplay of hormones

FGF23 is a phosphaturic glycoprotein secreted by osteoblasts and osteocytes. It acts by binding to fibroblastic growth receptor 1 in the presence of its coreceptor, the Klotho protein.⁶

FGF23 is regulated by serum phosphorus levels and plays a major role in the response to elevated serum phosphorus. It causes a direct increase in urinary phosphorus excretion, a decrease in intestinal phosphorus absorption (indirectly via inhibition of calcitriol), and decreased bone resorption via a decrease in parathyroid hormone production.⁷

Mechanism of hyperphosphatemia in kidney disease

In chronic kidney disease, phosphorus retention can trigger secondary hyperparathyroidism, as rising phosphorus levels stimulate FGF23. In the early stages of chronic kidney disease, this response can correct the phosphorus levels, but with several consequences:

• Decreased calcitriol due to its inhibition by FGF23⁹
• Hypocalcemia due to decreased calcitriol (leading to decreased intestinal calcium absorption) and calcium binding of retained phosphorus
• Elevated parathyroid hormone due to low calcitriol levels (lack of inhibitory feedback by calcitriol), hyperphosphatemia, and hypocalcemia (direct parathyroid hormone stimulation).

As the elevated phosphorus level is likely to be the triggering event behind secondary renal hyperparathyroidism, it needs to be controlled. This is accomplished by restricting dietary phosphorus and using phosphorus binders.

HYPERPHOSPHATEMIA MAY LEAD TO VASCULAR CALCIFICATION

Elevated serum phosphorus levels (normal range 2.48–4.65 mg/dL in adults¹¹) are associated with cardiovascular calcification and subsequent increases in mortality and morbidity rates. Elevations in serum phosphorus and calcium levels are associated with progression in vascular calcification¹² and likely account for the accelerated vascular calcification that is seen in kidney disease.¹³

Hyperphosphatemia has been identified as an independent risk factor for death in patients with end-stage renal disease,¹⁴ but that relationship is less clear in patients with chronic kidney disease. A study in patients with chronic kidney disease and not on dialysis found a lower mortality rate in those who were prescribed phosphorus binders,¹⁵ but the study was criticized for limitations in its design.

Hyperphosphatemia can also lead to adverse effects on bone health due to complications such as renal osteodystrophy.

However, in its 2017 update, the Kidney Disease: Improving Global Outcomes (KDIGO) program only “suggests” lowering elevated phosphorus levels “toward” the normal range in patients with chronic kidney disease stages G3a through G5D, ie, those with glomerular filtration rates less than 60 mL/min/1.73 m², including those on dialysis. The recommendation is graded 2C, ie, weak, based on low-quality evidence (https://kdigo.org/guidelines/ckd-mbd).

DIETARY RESTRICTION OF PHOSPHORUS

Diet is the major source of phosphorus intake. The average daily phosphorus consumption is  20 mg/kg, or 1,400 mg, and protein is the major source of dietary phosphorus.

In patients with stage 4 or 5 chronic kidney disease, the Kidney Disease Outcomes Quality Initiative recommends limiting protein intake to 0.6 mg/kg/day.¹⁶ However, in patients on hemodialysis, they recommend increasing protein intake to 1.1 mg/kg/day while limiting phosphorus intake to about 800 to 1,000 mg/day. This poses a challenge, as limiting phosphorus intake can reduce protein intake.

Sources of protein can be broadly classified as plant-based or animal-based. Animal protein contains organic phosphorus, which is easily absorbed.¹⁸ Plant protein may not be absorbed as easily.

Moe et al¹⁹ studied the importance of the protein source of phosphorus after 7 days of controlled diets. Despite equivalent protein and phosphorus concentrations in the vegetarian and meat-based diets, participants on the vegetarian diet had lower serum phosphorus levels, a trend toward lower 24-hour urinary phosphorus excretion, and significantly lower FGF23 levels than those on the meat-based diet. This suggests that a vegetarian diet may have advantages in terms of preventing hyperphosphatemia.

Another measure to reduce phosphorus absorption from meat is to boil it, which reduces the phosphorus content by 50%.²⁰

Processed foods containing additives and preservatives are very high in phosphorus²¹ and should be avoided, particularly as there is no mandate to label phosphorus content in food.

PHOSPHORUS AND DIALYSIS

Although hemodialysis removes phosphorus, it does not remove enough to keep levels within normal limits. Indeed, even when patients adhere to a daily phosphorus limit of 1,000 mg, phosphorus accumulates. If 70% of the phosphorus in the diet is absorbed, this is 4,500 to 5,000 mg in a week. A 4-hour hemodialysis session will remove only 1,000 mg of phosphorus, which equals about 3,000 mg for patients undergoing dialysis 3 times a week,²² far less than phosphorus absorption.

In patients on continuous ambulatory peritoneal dialysis, a daily regimen of 4 exchanges of 2 L per exchange removes about 200 mg of phosphorus per day. In a 2012 study, patients on nocturnal dialysis or home dialysis involving longer session length had greater lowering of phosphorus levels than patients undergoing routine hemodialysis.²³

Hence, phosphorus binders are often necessary in patients on routine hemodialysis or peritoneal dialysis.

PHOSPHORUS BINDERS

Phosphorus binders reduce serum phosphorus levels by binding with ingested phosphorus in the gastrointestinal tract and forming insoluble complexes that are not absorbed. For this reason they are much more effective when taken with meals. Phosphorus binders come in different formulations: pills, capsules, chewable tablets, liquids, and even powders that can be sprinkled on food.

The potency of each binder is quantified by its “phosphorus binder equivalent dose,” ie, its binding capacity compared with that of calcium carbonate as a reference.²⁴

Phosphorus binders are broadly divided into those that contain calcium and those that do not.

Calcium-containing binders

The 2 most commonly used preparations are calcium carbonate (eg, Tums) and calcium acetate (eg, Phoslo). While these are relatively safe, some studies suggest that their use can lead to accelerated vascular calcification.²⁵

According to KDIGO,²⁶ calcium-containing binders should be avoided in hypercalcemia and adynamic bone disease. Additionally, the daily elemental calcium intake from binders should be limited to 1,500 mg, with a total daily intake that does not exceed 2,000 mg.

The elemental calcium content of calcium carbonate is about 40% of its weight (eg, 200 mg of elemental calcium in a 500-mg tablet of Tums), while the elemental calcium content of calcium acetate is about 25%. Therefore, a patient who needs 6 g of calcium carbonate for efficacy will be ingesting 2.4 g of elemental calcium per day, and that exceeds the recommended daily maximum. The main advantage of calcium carbonate is its low cost and easy availability. Commonly reported side effects include nausea and constipation.

A less commonly used calcium-based binder is calcium citrate (eg, Calcitrate). It should, however, be avoided in chronic kidney disease because of the risk of aluminum accumulation. Calcium citrate can enhance intestinal absorption of aluminum from dietary sources, as aluminum can form complexes with citrate.²⁷

Calcium-free binders

There are several calcium-free binders. Some are based on metals such as aluminum, magnesium, iron, and lanthanum; others, such as sevelamer, are resin-based.

Aluminum- and magnesium-based binders are generally not used long-term in kidney disease because of the toxicity associated with aluminum and magnesium accumulation. However, aluminum hydroxide has an off-label use as a phosphorus binder in the acute setting, particularly when serum phosphorus levels are above 7 mg/dL.²⁸ The dose is 300 to 600 mg 3 times daily with meals for a maximum of 4 weeks.

Sevelamer. Approved by the US Food and Drug Administration (FDA) in 1998, sevelamer acts by trapping phosphorus through ion exchange and hydrogen binding. It has the advantage of being calcium-free, which makes it particularly desirable in patients with hypercalcemia.

The Renagel in New Dialysis²⁵ and Treat-To-Goal²⁹ studies were randomized controlled trials that looked at the effects of sevelamer vs calcium-based binders on the risk of vascular calcification. The primary end points were serum phosphorus and calcium levels, while the secondary end points were coronary artery calcification on computed tomography and thoracic vertebral bone density. Both studies demonstrated a higher risk of vascular calcification with the calcium-based binders.

Another possible benefit of sevelamer is an improvement in lipid profile. Sevelamer lowers total cholesterol and low-density lipoprotein cholesterol levels without affecting high-density lipoprotein cholesterol or triglyceride levels.³⁰ This is likely due to its bile acid-binding effect.³¹ Sevelamer has also been shown to lower C-reactive protein levels.³² While the cardiovascular profile appears to be improved with the treatment, there are no convincing data to confirm that those properties translate to a proven independent survival benefit.

The Calcium Acetate Renagel Evaluation³³ was a randomized controlled study comparing sevelamer and calcium acetate. The authors attempted to control for the lipid-lowering effects of sevelamer by giving atorvastatin to all patients in both groups who had a low-density lipoprotein level greater than 70 mg/dL. The study found sevelamer to be not inferior to calcium acetate in terms of mortality and coronary calcification.

Further studies such as the Brazilian Renagel and Calcium trial³⁴ and the Dialysis Clinical Outcomes Revisited trial failed to show a significant long-term benefit of sevelamer over calcium-based binders. However, a secondary statistical analysis of the latter study showed possible benefit of sevelamer over calcium acetate among those age 65 and older.³⁵

To understand how sevelamer could affect vascular calcification, Yilmaz et al³⁶ compared the effects of sevelamer vs calcium acetate on FGF23 and fetuin A levels. Fetuin A is an important inhibitor of vascular calcification and is progressively diminished in kidney disease, leading to accelerated calcification.³⁷ Patients on sevelamer had higher levels of fetuin A than their counterparts on calcium acetate.³⁷ The authors proposed increased fetuin A levels as a mechanism for decreased vascular calcification.

In summary, some studies suggest that sevelamer may offer the advantage of decreasing vascular calcification, but the data are mixed and do not provide a solid answer. The main disadvantages of sevelamer are a high pill burden and side effects of nausea and dyspepsia.

Lanthanum, a metallic element, was approved as a phosphorus binder by the FDA in 2008. It comes as a chewable tablet and offers the advantage of requiring the patient to take fewer pills than sevelamer and calcium-based binders.

Sucroferric oxyhydroxide comes as a chewable tablet. It was approved by the FDA in 2013. Although each tablet contains 500 mg of iron, it has not been shown to improve iron markers. In terms of phosphorus-lowering ability, it has been shown to be noninferior to sevelamer.³⁹ Advantages include a significantly lower pill burden. Disadvantages include gastrointestinal side effects such as diarrhea and nausea and the drug’s high cost.

Ferric citrate was approved by the FDA in 2014, and 1 g delivers 210 mg of elemental iron. The main advantage of ferric citrate is its ability to increase iron markers. The phase 3 trial that demonstrated its efficacy as a binder showed an increase in ferritin compared with the active control.⁴⁰ The study also showed a decrease in the need to use intravenous iron and erythropoesis-stimulating agents. This was thought to be due to improved iron stores, leading to decreased erythropoietin resistance.⁴¹

The mean number of ferric citrate tablets needed to achieve the desired phosphorus-lowering effect was 8 per day, containing 1,680 mg of iron. In comparison, oral ferrous sulfate typically provides 210 mg of iron per day.⁴²

Disadvantages of ferric citrate include high pill burden, high cost, and gastrointestinal side effects such as nausea and constipation.

Chitosan binds salivary phosphorus. It can potentially be used, but it is not approved, and its efficacy in lowering serum phosphorus remains unclear.⁴³

CHOOSING THE APPROPRIATE PHOSPHORUS BINDER

The choice of phosphorus binder is based on the patient’s serum calcium level and iron stores and on the drug’s side effect profile, iron pill burden, and cost. Involving patients in the choice after discussing potential side effects, pill burden, and cost is important for shared decision-making and could play a role in improving adherence.

Phosphorus binders are a major portion of the pill burden in patients with end-stage renal disease, possibly affecting patient adherence. The cost of phosphorus binders is estimated at half a billion dollars annually, underlining the significant economic impact of phosphorus control.¹¹

Calcium-based binders should be the first choice when there is secondary hyperparathyroidism without hypercalcemia. There is no clear evidence regarding the benefit of correcting hypocalcemia, but KDIGO recommends keeping the serum calcium level within the reference range. KDIGO also recommends restricting calcium-based binders in persistent hypercalcemia, arterial calcification, and adynamic bone disease. This recommendation is largely based on expert opinion.

Noncalcium-based binders, which in theory might prevent vascular calcification, should be considered for patients with at least 1 of the following⁴⁴:

• Complicated diabetes mellitus
• Vascular or valvular calcification
• Persistent inflammation.

Noncalcium-based binders are also preferred in low bone-turnover states such as adynamic bone disease, as elevated calcium can inhibit parathyroid hormone.

However, the advantage of noncalcium-based binders regarding vascular calcification is largely theoretical and has not been proven clinically. Indeed, there are data comparing long-term outcomes of the different classes of phosphorus binders, but studies were limited by short follow-up, and individual studies have lacked power to detect statistical significance between two classes of binders on long-term outcomes. Meta-analyses have provided conflicting data, with some suggesting better outcomes with sevelamer than with calcium-based binders, and with others failing to show any difference.⁴⁵

Because iron deficiency is common in kidney disease, ferric citrate, which can improve iron markers, may be a suitable option, provided its cost is covered by insurance.

SPECIAL CIRCUMSTANCES FOR THE USE OF PHOSPHORUS BINDERS

Tumor lysis syndrome

Tumor lysis syndrome occurs when tumor cells release their contents into the bloodstream, either spontaneously or in response to therapy, leading to the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.⁴⁶ Phosphorus binders in conjunction with intravenous hydration are used to treat hyperphosphatemia, but evidence about their efficacy in this setting is limited.

Hypocalcemia in tumor lysis syndrome is usually not treated unless symptomatic, as the calcium-phosphorus product can increase, leading to calcium phosphate crystallization. When the calcium-phosphorus product is greater than 60, there is a higher risk of calcium phosphate deposition in the renal tubules that can lead to acute renal failure in tumor lysis syndrome.⁴⁷ To lower the risk of calcium phosphate crystallization, calcium-based binders should be avoided in tumor lysis syndrome.

Total parenteral nutrition

Since patients on total parenteral nutrition do not eat, phosphorus binders are considered ineffective; there are no concrete data showing that phosphorus binders are effective in these patients.⁴⁸ In patients with kidney disease, the phosphorus content in the parenteral nutrition formulation must be reduced.

Pregnancy

Data on phosphorus binders in pregnancy are limited. Calcium can cross the placenta. Calcium carbonate can be used in pregnancy, and fetal harm is not expected if calcium concentrations are within normal limits.⁴⁹ Calcium acetate, sevelamer, and lanthanum are considered pregnancy category C drugs. Patients with advanced chronic kidney disease and end-stage renal disease who become pregnant must receive specialized obstetric care for high-risk pregnancy.

FUTURE DIRECTIONS

Future therapies may target FGF23 and other inflammatory markers that are up-regulated in renal hyperparathyroidism. However, trials studying these markers are needed to provide a better understanding of their role in bone mineral and cardiovascular health and in overall long-term outcomes. Additionally, randomized controlled trials are needed to study long-term nonsurrogate outcomes such as reduction in cardiovascular disease and rates of overall mortality.

The balance between dietary intake and excretion of phosphorus can be impaired in patients with decreased renal function, leading to hyperphosphatemia. Many patients with end-stage renal disease on dialysis require phosphorus-binding drugs to control their serum phosphorus levels.

See related editorial and article

In this review, we discuss the pathophysiology of hyperphosphatemia in kidney disease, its consequences, and how to control it, focusing on the different classes of phosphorus binders.

ROLE OF THE INTERNIST

With kidney disease common and on the increase,¹ nephrologists and internists need to work together to provide optimal care.

Further, many internists in managed care plans and accountable care organizations now handle many tasks previously left to specialists—including prescribing and managing phosphorus binders in patients with kidney disease.

PATHOPHYSIOLOGY OF HYPERPHOSPHATEMIA

The pathophysiology of bone mineral disorders in kidney disease is complex. To simplify the discussion, we will address it in 3 parts:

• Phosphorus balance
• The interplay of hormones, including fibro­blast growth factor 23 (FGF23)
• The mechanism of hyperphosphatemia in kidney disease.

Phosphorus balance

Phosphorus is a macronutrient essential for a range of cellular functions that include structure, energy production, metabolism, and cell signaling. It exists primarily in the form of inorganic phosphate.

An average Western diet provides 20 mg of phosphorus per kilogram of body weight per day. Of this, 13 mg/kg is absorbed, and the rest is excreted in the feces.²

Absorption of dietary phosphorus occurs mainly in the jejunum. It is mediated by both a paracellular sodium-independent pathway (driven by high intraluminal phosphorus content) and by active sodium-dependent cotransporters. It is also influenced by diet and promoted by active vitamin D (1,25 dihydroxyvitamin D₃, also called calcitriol).³

Absorbed phosphorus enters the extracellular fluid and shifts in and out of the skeleton under the influence of parathyroid hormone.

Phosphorus excretion is handled almost entirely by the kidneys. Phosphorus is freely filtered at the glomerulus and reabsorbed mainly in the proximal tubule by sodium-phosphate cotransporters.

Normally, when phosphorus intake is adequate, most of the filtered phosphorus is reabsorbed and only 10% to 20% is excreted in the urine. However, the threshold for phosphorus reabsorption in the proximal tubule is influenced by parathyroid hormone, FGF23, and dietary phosphorus intake: low serum phosphate levels lead to an increase in the synthesis of sodium-phosphorus cotransporters, resulting in increased (nearly complete) proximal reabsorption and an increase in the serum phosphorus concentration.⁴ Conversely, both parathyroid hormone and FGF23 are phosphaturic and decrease the number of phosphorus transporters, which in turn leads to increased phosphorus excretion and a decrease in serum phosphorus concentration.⁵

Interplay of hormones

FGF23 is a phosphaturic glycoprotein secreted by osteoblasts and osteocytes. It acts by binding to fibroblastic growth receptor 1 in the presence of its coreceptor, the Klotho protein.⁶

FGF23 is regulated by serum phosphorus levels and plays a major role in the response to elevated serum phosphorus. It causes a direct increase in urinary phosphorus excretion, a decrease in intestinal phosphorus absorption (indirectly via inhibition of calcitriol), and decreased bone resorption via a decrease in parathyroid hormone production.⁷

Mechanism of hyperphosphatemia in kidney disease

In chronic kidney disease, phosphorus retention can trigger secondary hyperparathyroidism, as rising phosphorus levels stimulate FGF23. In the early stages of chronic kidney disease, this response can correct the phosphorus levels, but with several consequences:

• Decreased calcitriol due to its inhibition by FGF23⁹
• Hypocalcemia due to decreased calcitriol (leading to decreased intestinal calcium absorption) and calcium binding of retained phosphorus
• Elevated parathyroid hormone due to low calcitriol levels (lack of inhibitory feedback by calcitriol), hyperphosphatemia, and hypocalcemia (direct parathyroid hormone stimulation).

As the elevated phosphorus level is likely to be the triggering event behind secondary renal hyperparathyroidism, it needs to be controlled. This is accomplished by restricting dietary phosphorus and using phosphorus binders.

HYPERPHOSPHATEMIA MAY LEAD TO VASCULAR CALCIFICATION

Elevated serum phosphorus levels (normal range 2.48–4.65 mg/dL in adults¹¹) are associated with cardiovascular calcification and subsequent increases in mortality and morbidity rates. Elevations in serum phosphorus and calcium levels are associated with progression in vascular calcification¹² and likely account for the accelerated vascular calcification that is seen in kidney disease.¹³

Hyperphosphatemia has been identified as an independent risk factor for death in patients with end-stage renal disease,¹⁴ but that relationship is less clear in patients with chronic kidney disease. A study in patients with chronic kidney disease and not on dialysis found a lower mortality rate in those who were prescribed phosphorus binders,¹⁵ but the study was criticized for limitations in its design.

Hyperphosphatemia can also lead to adverse effects on bone health due to complications such as renal osteodystrophy.

However, in its 2017 update, the Kidney Disease: Improving Global Outcomes (KDIGO) program only “suggests” lowering elevated phosphorus levels “toward” the normal range in patients with chronic kidney disease stages G3a through G5D, ie, those with glomerular filtration rates less than 60 mL/min/1.73 m², including those on dialysis. The recommendation is graded 2C, ie, weak, based on low-quality evidence (https://kdigo.org/guidelines/ckd-mbd).

DIETARY RESTRICTION OF PHOSPHORUS

Diet is the major source of phosphorus intake. The average daily phosphorus consumption is  20 mg/kg, or 1,400 mg, and protein is the major source of dietary phosphorus.

In patients with stage 4 or 5 chronic kidney disease, the Kidney Disease Outcomes Quality Initiative recommends limiting protein intake to 0.6 mg/kg/day.¹⁶ However, in patients on hemodialysis, they recommend increasing protein intake to 1.1 mg/kg/day while limiting phosphorus intake to about 800 to 1,000 mg/day. This poses a challenge, as limiting phosphorus intake can reduce protein intake.

Sources of protein can be broadly classified as plant-based or animal-based. Animal protein contains organic phosphorus, which is easily absorbed.¹⁸ Plant protein may not be absorbed as easily.

Moe et al¹⁹ studied the importance of the protein source of phosphorus after 7 days of controlled diets. Despite equivalent protein and phosphorus concentrations in the vegetarian and meat-based diets, participants on the vegetarian diet had lower serum phosphorus levels, a trend toward lower 24-hour urinary phosphorus excretion, and significantly lower FGF23 levels than those on the meat-based diet. This suggests that a vegetarian diet may have advantages in terms of preventing hyperphosphatemia.

Another measure to reduce phosphorus absorption from meat is to boil it, which reduces the phosphorus content by 50%.²⁰

Processed foods containing additives and preservatives are very high in phosphorus²¹ and should be avoided, particularly as there is no mandate to label phosphorus content in food.

PHOSPHORUS AND DIALYSIS

Although hemodialysis removes phosphorus, it does not remove enough to keep levels within normal limits. Indeed, even when patients adhere to a daily phosphorus limit of 1,000 mg, phosphorus accumulates. If 70% of the phosphorus in the diet is absorbed, this is 4,500 to 5,000 mg in a week. A 4-hour hemodialysis session will remove only 1,000 mg of phosphorus, which equals about 3,000 mg for patients undergoing dialysis 3 times a week,²² far less than phosphorus absorption.

In patients on continuous ambulatory peritoneal dialysis, a daily regimen of 4 exchanges of 2 L per exchange removes about 200 mg of phosphorus per day. In a 2012 study, patients on nocturnal dialysis or home dialysis involving longer session length had greater lowering of phosphorus levels than patients undergoing routine hemodialysis.²³

Hence, phosphorus binders are often necessary in patients on routine hemodialysis or peritoneal dialysis.

PHOSPHORUS BINDERS

Phosphorus binders reduce serum phosphorus levels by binding with ingested phosphorus in the gastrointestinal tract and forming insoluble complexes that are not absorbed. For this reason they are much more effective when taken with meals. Phosphorus binders come in different formulations: pills, capsules, chewable tablets, liquids, and even powders that can be sprinkled on food.

The potency of each binder is quantified by its “phosphorus binder equivalent dose,” ie, its binding capacity compared with that of calcium carbonate as a reference.²⁴

Phosphorus binders are broadly divided into those that contain calcium and those that do not.

Calcium-containing binders

The 2 most commonly used preparations are calcium carbonate (eg, Tums) and calcium acetate (eg, Phoslo). While these are relatively safe, some studies suggest that their use can lead to accelerated vascular calcification.²⁵

According to KDIGO,²⁶ calcium-containing binders should be avoided in hypercalcemia and adynamic bone disease. Additionally, the daily elemental calcium intake from binders should be limited to 1,500 mg, with a total daily intake that does not exceed 2,000 mg.

The elemental calcium content of calcium carbonate is about 40% of its weight (eg, 200 mg of elemental calcium in a 500-mg tablet of Tums), while the elemental calcium content of calcium acetate is about 25%. Therefore, a patient who needs 6 g of calcium carbonate for efficacy will be ingesting 2.4 g of elemental calcium per day, and that exceeds the recommended daily maximum. The main advantage of calcium carbonate is its low cost and easy availability. Commonly reported side effects include nausea and constipation.

A less commonly used calcium-based binder is calcium citrate (eg, Calcitrate). It should, however, be avoided in chronic kidney disease because of the risk of aluminum accumulation. Calcium citrate can enhance intestinal absorption of aluminum from dietary sources, as aluminum can form complexes with citrate.²⁷

Calcium-free binders

There are several calcium-free binders. Some are based on metals such as aluminum, magnesium, iron, and lanthanum; others, such as sevelamer, are resin-based.

Aluminum- and magnesium-based binders are generally not used long-term in kidney disease because of the toxicity associated with aluminum and magnesium accumulation. However, aluminum hydroxide has an off-label use as a phosphorus binder in the acute setting, particularly when serum phosphorus levels are above 7 mg/dL.²⁸ The dose is 300 to 600 mg 3 times daily with meals for a maximum of 4 weeks.

Sevelamer. Approved by the US Food and Drug Administration (FDA) in 1998, sevelamer acts by trapping phosphorus through ion exchange and hydrogen binding. It has the advantage of being calcium-free, which makes it particularly desirable in patients with hypercalcemia.

The Renagel in New Dialysis²⁵ and Treat-To-Goal²⁹ studies were randomized controlled trials that looked at the effects of sevelamer vs calcium-based binders on the risk of vascular calcification. The primary end points were serum phosphorus and calcium levels, while the secondary end points were coronary artery calcification on computed tomography and thoracic vertebral bone density. Both studies demonstrated a higher risk of vascular calcification with the calcium-based binders.

Another possible benefit of sevelamer is an improvement in lipid profile. Sevelamer lowers total cholesterol and low-density lipoprotein cholesterol levels without affecting high-density lipoprotein cholesterol or triglyceride levels.³⁰ This is likely due to its bile acid-binding effect.³¹ Sevelamer has also been shown to lower C-reactive protein levels.³² While the cardiovascular profile appears to be improved with the treatment, there are no convincing data to confirm that those properties translate to a proven independent survival benefit.

The Calcium Acetate Renagel Evaluation³³ was a randomized controlled study comparing sevelamer and calcium acetate. The authors attempted to control for the lipid-lowering effects of sevelamer by giving atorvastatin to all patients in both groups who had a low-density lipoprotein level greater than 70 mg/dL. The study found sevelamer to be not inferior to calcium acetate in terms of mortality and coronary calcification.

Further studies such as the Brazilian Renagel and Calcium trial³⁴ and the Dialysis Clinical Outcomes Revisited trial failed to show a significant long-term benefit of sevelamer over calcium-based binders. However, a secondary statistical analysis of the latter study showed possible benefit of sevelamer over calcium acetate among those age 65 and older.³⁵

To understand how sevelamer could affect vascular calcification, Yilmaz et al³⁶ compared the effects of sevelamer vs calcium acetate on FGF23 and fetuin A levels. Fetuin A is an important inhibitor of vascular calcification and is progressively diminished in kidney disease, leading to accelerated calcification.³⁷ Patients on sevelamer had higher levels of fetuin A than their counterparts on calcium acetate.³⁷ The authors proposed increased fetuin A levels as a mechanism for decreased vascular calcification.

In summary, some studies suggest that sevelamer may offer the advantage of decreasing vascular calcification, but the data are mixed and do not provide a solid answer. The main disadvantages of sevelamer are a high pill burden and side effects of nausea and dyspepsia.

Lanthanum, a metallic element, was approved as a phosphorus binder by the FDA in 2008. It comes as a chewable tablet and offers the advantage of requiring the patient to take fewer pills than sevelamer and calcium-based binders.

Sucroferric oxyhydroxide comes as a chewable tablet. It was approved by the FDA in 2013. Although each tablet contains 500 mg of iron, it has not been shown to improve iron markers. In terms of phosphorus-lowering ability, it has been shown to be noninferior to sevelamer.³⁹ Advantages include a significantly lower pill burden. Disadvantages include gastrointestinal side effects such as diarrhea and nausea and the drug’s high cost.

Ferric citrate was approved by the FDA in 2014, and 1 g delivers 210 mg of elemental iron. The main advantage of ferric citrate is its ability to increase iron markers. The phase 3 trial that demonstrated its efficacy as a binder showed an increase in ferritin compared with the active control.⁴⁰ The study also showed a decrease in the need to use intravenous iron and erythropoesis-stimulating agents. This was thought to be due to improved iron stores, leading to decreased erythropoietin resistance.⁴¹

The mean number of ferric citrate tablets needed to achieve the desired phosphorus-lowering effect was 8 per day, containing 1,680 mg of iron. In comparison, oral ferrous sulfate typically provides 210 mg of iron per day.⁴²

Disadvantages of ferric citrate include high pill burden, high cost, and gastrointestinal side effects such as nausea and constipation.

Chitosan binds salivary phosphorus. It can potentially be used, but it is not approved, and its efficacy in lowering serum phosphorus remains unclear.⁴³

CHOOSING THE APPROPRIATE PHOSPHORUS BINDER

The choice of phosphorus binder is based on the patient’s serum calcium level and iron stores and on the drug’s side effect profile, iron pill burden, and cost. Involving patients in the choice after discussing potential side effects, pill burden, and cost is important for shared decision-making and could play a role in improving adherence.

Phosphorus binders are a major portion of the pill burden in patients with end-stage renal disease, possibly affecting patient adherence. The cost of phosphorus binders is estimated at half a billion dollars annually, underlining the significant economic impact of phosphorus control.¹¹

Calcium-based binders should be the first choice when there is secondary hyperparathyroidism without hypercalcemia. There is no clear evidence regarding the benefit of correcting hypocalcemia, but KDIGO recommends keeping the serum calcium level within the reference range. KDIGO also recommends restricting calcium-based binders in persistent hypercalcemia, arterial calcification, and adynamic bone disease. This recommendation is largely based on expert opinion.

Noncalcium-based binders, which in theory might prevent vascular calcification, should be considered for patients with at least 1 of the following⁴⁴:

• Complicated diabetes mellitus
• Vascular or valvular calcification
• Persistent inflammation.

Noncalcium-based binders are also preferred in low bone-turnover states such as adynamic bone disease, as elevated calcium can inhibit parathyroid hormone.

However, the advantage of noncalcium-based binders regarding vascular calcification is largely theoretical and has not been proven clinically. Indeed, there are data comparing long-term outcomes of the different classes of phosphorus binders, but studies were limited by short follow-up, and individual studies have lacked power to detect statistical significance between two classes of binders on long-term outcomes. Meta-analyses have provided conflicting data, with some suggesting better outcomes with sevelamer than with calcium-based binders, and with others failing to show any difference.⁴⁵

Because iron deficiency is common in kidney disease, ferric citrate, which can improve iron markers, may be a suitable option, provided its cost is covered by insurance.

SPECIAL CIRCUMSTANCES FOR THE USE OF PHOSPHORUS BINDERS

Tumor lysis syndrome

Tumor lysis syndrome occurs when tumor cells release their contents into the bloodstream, either spontaneously or in response to therapy, leading to the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.⁴⁶ Phosphorus binders in conjunction with intravenous hydration are used to treat hyperphosphatemia, but evidence about their efficacy in this setting is limited.

Hypocalcemia in tumor lysis syndrome is usually not treated unless symptomatic, as the calcium-phosphorus product can increase, leading to calcium phosphate crystallization. When the calcium-phosphorus product is greater than 60, there is a higher risk of calcium phosphate deposition in the renal tubules that can lead to acute renal failure in tumor lysis syndrome.⁴⁷ To lower the risk of calcium phosphate crystallization, calcium-based binders should be avoided in tumor lysis syndrome.

Total parenteral nutrition

Since patients on total parenteral nutrition do not eat, phosphorus binders are considered ineffective; there are no concrete data showing that phosphorus binders are effective in these patients.⁴⁸ In patients with kidney disease, the phosphorus content in the parenteral nutrition formulation must be reduced.

Pregnancy

Data on phosphorus binders in pregnancy are limited. Calcium can cross the placenta. Calcium carbonate can be used in pregnancy, and fetal harm is not expected if calcium concentrations are within normal limits.⁴⁹ Calcium acetate, sevelamer, and lanthanum are considered pregnancy category C drugs. Patients with advanced chronic kidney disease and end-stage renal disease who become pregnant must receive specialized obstetric care for high-risk pregnancy.

FUTURE DIRECTIONS

Future therapies may target FGF23 and other inflammatory markers that are up-regulated in renal hyperparathyroidism. However, trials studying these markers are needed to provide a better understanding of their role in bone mineral and cardiovascular health and in overall long-term outcomes. Additionally, randomized controlled trials are needed to study long-term nonsurrogate outcomes such as reduction in cardiovascular disease and rates of overall mortality.

Phosphorus is essential for life. However, both low and high levels of phosphorus in the body have consequences, and its concentration in the blood is tightly regulated through dietary absorption, bone flux, and renal excretion and is influenced by calcitriol (1,25 hydroxyvitamin D₃), parathyroid hormone, and fibroblast growth factor 23 (FGF23).

See related articles by M. Shetty and A. Sekar

Sekar et al,¹ in this issue of the Journal, provide an extensive review of the pathophysiology of phosphorus metabolism and strategies to control phosphorus levels in patients with hyperphosphatemia and end-stage kidney disease.

PHOSPHORUS OR PHOSPHATE?

What's in a name? That which we call a rose
By any other word would smell as sweet.
—Shakespeare, Romeo and Juliet

The terms phosphate and phosphorus are often used interchangeably, though most writers still prefer phosphate over phosphorus.

The serum concentrations of phosphate and phosphorus are the same when expressed in millimoles per liter, as every mole of phosphate contains 1 mole of phosphorus, but not the same when expressed in milligrams per deciliter.² The molecular weight of phosphorus is 30.97, whereas the molecular weight of the phosphate ion (PO₄^3–) is 94.97—more than 3 times higher. Therefore, using these terms interchangeably in this context can lead to numerical error.³

Phosphorus, being highly reactive, does not exist by itself in nature and is typically present as phosphates in biologic systems. When describing phosphorus metabolism, the term phosphates should ideally be used because phosphates are the actual participants in the bodily processes. But in the clinical laboratory, all methods that measure serum phosphorus in fact measure inorganic phosphate and are expressed in terms of milligrams of phosphorus per deciliter rather than milligrams of phosphate per deciliter, and using these 2 terms interchangeably in clinical practice should not be of concern.⁴

THE PROBLEM

US adults typically ingest 1,200 mg of phosphorus each day, and about 60% to 70% of the ingested phosphorus is absorbed both by passive paracellular diffusion via tight junctions and by active transcellular transport via sodium-phosphate cotransport. The kidneys must excrete the same amount daily to maintain a steady state. As kidney function declines, phosphorus accumulates in the blood, leading to hyperphosphatemia.

Hyperphosphatemia is often asymptomatic, but it can cause generalized itching, red eyes, and adverse effects on the bone and parathyroid glands. Higher serum phosphorus levels have been shown to be associated with vascular calcification,⁵ cardiovascular events, and higher all-cause mortality rates in the general population,⁶ in patients with diabetes,⁷ and in those with chronic kidney disease.⁸ This association between higher serum phosphorus levels and the all-cause mortality rate led to the assumption that lowering serum phosphorus levels in these patients could reduce the rates of cardiovascular events and death, and to efforts to correct hyperphosphatemia.

Research into FGF23 continues, especially its role in cardiovascular complications of chronic kidney disease, as both phosphorus and FGF23 levels are elevated in chronic kidney disease and are implicated in poor clinical outcomes in these patients. However, both FGF23 and parathyroid hormone levels rise early in the course of kidney disease, long before overt hyperphosphatemia develops. Further, FGF23 rises earlier than parathyroid hormone and has been found to be an independent risk factor for cardiovascular events and death from any cause in end-stage kidney disease.⁹

Whether hyperphosphatemia is the culprit or merely an epiphenomenon of metabolic complications of chronic kidney disease is still unclear, as more molecules are being identified in the complex process of cardiovascular calcification.¹⁰

However, one thing is clear: vascular calcification is not just a simple precipitation of calcium and phosphorus. Instead, it is an active process that involves many regulators of mineral metabolism.¹⁰ The complex nature of this process is likely one of the reasons that evidence is conflicting¹¹ about the benefits of phosphorus binders in terms of cardiovascular events or all-cause mortality in these patients.

Reducing intake

Dietary phosphorus restriction is the first step in controlling serum phosphorus. But reducing phosphorus intake while otherwise trying to optimize the nutritional status can be challenging.

The recommended daily protein intake is 1.0 to 1.2 g/kg. But phosphorus is typically found in foods rich in proteins, and restricting protein severely can compromise nutritional status and may be as bad as elevated phosphate levels in terms of outcomes.

Although plant-based foods contain more phosphate per gram of protein (ie, they have a higher ratio of phosphorus to protein) than animal-based foods, the bioavailability of phosphorus from plant foods is lower. Phosphorus in plant-based foods is mainly in the form of phytate. Humans cannot hydrolyze phytate because we lack the phytase enzyme; hence, the phosphorus in plant-based foods is not well absorbed. Therefore, a vegetarian diet may be preferable and beneficial in patients with chronic kidney disease. A small study in humans showed that a vegetarian diet resulted in lower serum phosphorus and FGF23 levels, but the study was limited by its small sample size.¹²

Patients should be advised to avoid foods that have a high phosphate content, such as processed foods, fast foods, and cola beverages, which often have phosphate-based food additives.

Further, one should be cautious about using supplements with healthy-sounding names. A case in point is “vitamin water”: 12 oz of this fruit punch-flavored beverage contains 392 mg of phosphorus,¹³ and this alone would require 12 to 15 phosphate binder tablets to bind its phosphorus content.

In addition, many prescription drugs have significant amounts of phosphorus, and this is often unrecognized.

Sherman et al¹⁴ reviewed 200 of the most commonly prescribed drugs in dialysis patients and found that 23 (11.5%) of the drug labels listed phosphorus-containing ingredients, but the actual amount of phosphorus was not listed. The phosphorus content ranged from 1.4 mg (clonidine 0.2 mg, Blue Point Laboratories, Dublin, Ireland) to 111.5 mg (paroxetine 40 mg, GlaxoSmith Kline, Philadelphia, PA). The phosphorus content was inconsistent and varied with the dose of the agent, type of formulation (tablet or syrup), branded or generic formulation, and manufacturer.

Branded lisinopril (Merck, Kenilworth, NJ) had 21.4 mg of phosphorus per 10-mg dose, while a generic product (Blue Point Laboratories, Dublin, Ireland) had 32.6 mg. Different brands of generic amlodipine 10 mg varied in their phosphorus content from 8.6 mg (Lupin Pharmaceuticals, Mumbai, India) to 27.8 mg (Greenstone LLC, Peapack, NJ) to 40.1 mg (Qualitest Pharmaceuticals, Huntsville, AL. Rena-Vite (Cypress Pharmaceuticals, Madison, MS), a multivitamin marketed to patients with kidney disease, had 37.7 mg of phosphorus per tablet. Thus, just to bind the phosphorus content of these 3 tablets (lisinopril, amlodipine, and Rena-Vite), a patient could need at least 3 to 4 extra doses of phosphate binder.

The phosphate content of medications should be considered when prescribing. For example, Reno Caps (Nnodum Pharmaceuticals, Cincinnati, OH), another vitamin supplement, has only 1.7 mg of phosphorus per tablet and should be considered, especially in patients with poorly controlled serum phosphorus levels. However, the challenge is that medication labels do not provide the phosphorus content.

Reducing phosphorus absorption

Although these agents reduce serum phosphorus and help reduce symptoms, an important quality-of-life measure, it is uncertain whether they improve clinical outcomes.¹¹ To date, no specific phosphorus binder offers a survival benefit over placebo.¹¹

Based on the limited and conflicting evidence, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, recently updated, suggest that oral phosphorus binders should be used in patients with hyperphosphatemia to lower serum phosphorus levels toward the normal range.¹⁵ They further recommend not exceeding 1,500 mg of elemental calcium per day if a calcium-based binder is used, and they recommend avoiding calcium-based binders in patients with hypercalcemia, adynamic bone disease, or vascular calcification.

Phosphorus binders may account for up to 50% of the daily pill burden and may contribute to poor medication adherence.¹⁶ Dialysis patients need to take a lot of these drugs: by weight, 5 to 6 pounds per year.

These drugs can bind and interfere with the absorption of other vital medications and so should be taken with meals and separately from other medications.

Removing phosphorus

Removal of phosphorus by adequate dialysis or kidney transplant is the final strategy.

New agents under study

To improve phosphorus control, other agents that inhibit absorption of phosphate are being investigated.

Nicotinamide reduces expression of the sodium-phosphorus cotransporter NTP2b. Its use in combination with a low-phosphorus diet and phosphorus binders may maximize reductions in phosphorus absorption and is being studied in the CKD Optimal Management With Binders and Nicotinamide (COMBINE) study.

Tenapanor, an inhibitor of the sodium-hydrogen transporter NHE3, has been shown in animal studies to increase fecal phosphate excretion and decrease urinary phosphate excretion17 but requires further evaluation.

Phosphorus is essential for life. However, both low and high levels of phosphorus in the body have consequences, and its concentration in the blood is tightly regulated through dietary absorption, bone flux, and renal excretion and is influenced by calcitriol (1,25 hydroxyvitamin D₃), parathyroid hormone, and fibroblast growth factor 23 (FGF23).

See related articles by M. Shetty and A. Sekar

Sekar et al,¹ in this issue of the Journal, provide an extensive review of the pathophysiology of phosphorus metabolism and strategies to control phosphorus levels in patients with hyperphosphatemia and end-stage kidney disease.

PHOSPHORUS OR PHOSPHATE?

What's in a name? That which we call a rose
By any other word would smell as sweet.
—Shakespeare, Romeo and Juliet

The terms phosphate and phosphorus are often used interchangeably, though most writers still prefer phosphate over phosphorus.

The serum concentrations of phosphate and phosphorus are the same when expressed in millimoles per liter, as every mole of phosphate contains 1 mole of phosphorus, but not the same when expressed in milligrams per deciliter.² The molecular weight of phosphorus is 30.97, whereas the molecular weight of the phosphate ion (PO₄^3–) is 94.97—more than 3 times higher. Therefore, using these terms interchangeably in this context can lead to numerical error.³

Phosphorus, being highly reactive, does not exist by itself in nature and is typically present as phosphates in biologic systems. When describing phosphorus metabolism, the term phosphates should ideally be used because phosphates are the actual participants in the bodily processes. But in the clinical laboratory, all methods that measure serum phosphorus in fact measure inorganic phosphate and are expressed in terms of milligrams of phosphorus per deciliter rather than milligrams of phosphate per deciliter, and using these 2 terms interchangeably in clinical practice should not be of concern.⁴

THE PROBLEM

US adults typically ingest 1,200 mg of phosphorus each day, and about 60% to 70% of the ingested phosphorus is absorbed both by passive paracellular diffusion via tight junctions and by active transcellular transport via sodium-phosphate cotransport. The kidneys must excrete the same amount daily to maintain a steady state. As kidney function declines, phosphorus accumulates in the blood, leading to hyperphosphatemia.

Hyperphosphatemia is often asymptomatic, but it can cause generalized itching, red eyes, and adverse effects on the bone and parathyroid glands. Higher serum phosphorus levels have been shown to be associated with vascular calcification,⁵ cardiovascular events, and higher all-cause mortality rates in the general population,⁶ in patients with diabetes,⁷ and in those with chronic kidney disease.⁸ This association between higher serum phosphorus levels and the all-cause mortality rate led to the assumption that lowering serum phosphorus levels in these patients could reduce the rates of cardiovascular events and death, and to efforts to correct hyperphosphatemia.

Research into FGF23 continues, especially its role in cardiovascular complications of chronic kidney disease, as both phosphorus and FGF23 levels are elevated in chronic kidney disease and are implicated in poor clinical outcomes in these patients. However, both FGF23 and parathyroid hormone levels rise early in the course of kidney disease, long before overt hyperphosphatemia develops. Further, FGF23 rises earlier than parathyroid hormone and has been found to be an independent risk factor for cardiovascular events and death from any cause in end-stage kidney disease.⁹

Whether hyperphosphatemia is the culprit or merely an epiphenomenon of metabolic complications of chronic kidney disease is still unclear, as more molecules are being identified in the complex process of cardiovascular calcification.¹⁰

However, one thing is clear: vascular calcification is not just a simple precipitation of calcium and phosphorus. Instead, it is an active process that involves many regulators of mineral metabolism.¹⁰ The complex nature of this process is likely one of the reasons that evidence is conflicting¹¹ about the benefits of phosphorus binders in terms of cardiovascular events or all-cause mortality in these patients.

Reducing intake

Dietary phosphorus restriction is the first step in controlling serum phosphorus. But reducing phosphorus intake while otherwise trying to optimize the nutritional status can be challenging.

The recommended daily protein intake is 1.0 to 1.2 g/kg. But phosphorus is typically found in foods rich in proteins, and restricting protein severely can compromise nutritional status and may be as bad as elevated phosphate levels in terms of outcomes.

Although plant-based foods contain more phosphate per gram of protein (ie, they have a higher ratio of phosphorus to protein) than animal-based foods, the bioavailability of phosphorus from plant foods is lower. Phosphorus in plant-based foods is mainly in the form of phytate. Humans cannot hydrolyze phytate because we lack the phytase enzyme; hence, the phosphorus in plant-based foods is not well absorbed. Therefore, a vegetarian diet may be preferable and beneficial in patients with chronic kidney disease. A small study in humans showed that a vegetarian diet resulted in lower serum phosphorus and FGF23 levels, but the study was limited by its small sample size.¹²

Patients should be advised to avoid foods that have a high phosphate content, such as processed foods, fast foods, and cola beverages, which often have phosphate-based food additives.

Further, one should be cautious about using supplements with healthy-sounding names. A case in point is “vitamin water”: 12 oz of this fruit punch-flavored beverage contains 392 mg of phosphorus,¹³ and this alone would require 12 to 15 phosphate binder tablets to bind its phosphorus content.

In addition, many prescription drugs have significant amounts of phosphorus, and this is often unrecognized.

Sherman et al¹⁴ reviewed 200 of the most commonly prescribed drugs in dialysis patients and found that 23 (11.5%) of the drug labels listed phosphorus-containing ingredients, but the actual amount of phosphorus was not listed. The phosphorus content ranged from 1.4 mg (clonidine 0.2 mg, Blue Point Laboratories, Dublin, Ireland) to 111.5 mg (paroxetine 40 mg, GlaxoSmith Kline, Philadelphia, PA). The phosphorus content was inconsistent and varied with the dose of the agent, type of formulation (tablet or syrup), branded or generic formulation, and manufacturer.

Branded lisinopril (Merck, Kenilworth, NJ) had 21.4 mg of phosphorus per 10-mg dose, while a generic product (Blue Point Laboratories, Dublin, Ireland) had 32.6 mg. Different brands of generic amlodipine 10 mg varied in their phosphorus content from 8.6 mg (Lupin Pharmaceuticals, Mumbai, India) to 27.8 mg (Greenstone LLC, Peapack, NJ) to 40.1 mg (Qualitest Pharmaceuticals, Huntsville, AL. Rena-Vite (Cypress Pharmaceuticals, Madison, MS), a multivitamin marketed to patients with kidney disease, had 37.7 mg of phosphorus per tablet. Thus, just to bind the phosphorus content of these 3 tablets (lisinopril, amlodipine, and Rena-Vite), a patient could need at least 3 to 4 extra doses of phosphate binder.

The phosphate content of medications should be considered when prescribing. For example, Reno Caps (Nnodum Pharmaceuticals, Cincinnati, OH), another vitamin supplement, has only 1.7 mg of phosphorus per tablet and should be considered, especially in patients with poorly controlled serum phosphorus levels. However, the challenge is that medication labels do not provide the phosphorus content.

Reducing phosphorus absorption

Although these agents reduce serum phosphorus and help reduce symptoms, an important quality-of-life measure, it is uncertain whether they improve clinical outcomes.¹¹ To date, no specific phosphorus binder offers a survival benefit over placebo.¹¹

Based on the limited and conflicting evidence, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, recently updated, suggest that oral phosphorus binders should be used in patients with hyperphosphatemia to lower serum phosphorus levels toward the normal range.¹⁵ They further recommend not exceeding 1,500 mg of elemental calcium per day if a calcium-based binder is used, and they recommend avoiding calcium-based binders in patients with hypercalcemia, adynamic bone disease, or vascular calcification.

Phosphorus binders may account for up to 50% of the daily pill burden and may contribute to poor medication adherence.¹⁶ Dialysis patients need to take a lot of these drugs: by weight, 5 to 6 pounds per year.

These drugs can bind and interfere with the absorption of other vital medications and so should be taken with meals and separately from other medications.

Removing phosphorus

Removal of phosphorus by adequate dialysis or kidney transplant is the final strategy.

New agents under study

To improve phosphorus control, other agents that inhibit absorption of phosphate are being investigated.

Nicotinamide reduces expression of the sodium-phosphorus cotransporter NTP2b. Its use in combination with a low-phosphorus diet and phosphorus binders may maximize reductions in phosphorus absorption and is being studied in the CKD Optimal Management With Binders and Nicotinamide (COMBINE) study.

Tenapanor, an inhibitor of the sodium-hydrogen transporter NHE3, has been shown in animal studies to increase fecal phosphate excretion and decrease urinary phosphate excretion17 but requires further evaluation.

Phosphorus is essential for life. However, both low and high levels of phosphorus in the body have consequences, and its concentration in the blood is tightly regulated through dietary absorption, bone flux, and renal excretion and is influenced by calcitriol (1,25 hydroxyvitamin D₃), parathyroid hormone, and fibroblast growth factor 23 (FGF23).

See related articles by M. Shetty and A. Sekar

Sekar et al,¹ in this issue of the Journal, provide an extensive review of the pathophysiology of phosphorus metabolism and strategies to control phosphorus levels in patients with hyperphosphatemia and end-stage kidney disease.

PHOSPHORUS OR PHOSPHATE?

What's in a name? That which we call a rose
By any other word would smell as sweet.
—Shakespeare, Romeo and Juliet

The terms phosphate and phosphorus are often used interchangeably, though most writers still prefer phosphate over phosphorus.

The serum concentrations of phosphate and phosphorus are the same when expressed in millimoles per liter, as every mole of phosphate contains 1 mole of phosphorus, but not the same when expressed in milligrams per deciliter.² The molecular weight of phosphorus is 30.97, whereas the molecular weight of the phosphate ion (PO₄^3–) is 94.97—more than 3 times higher. Therefore, using these terms interchangeably in this context can lead to numerical error.³

Phosphorus, being highly reactive, does not exist by itself in nature and is typically present as phosphates in biologic systems. When describing phosphorus metabolism, the term phosphates should ideally be used because phosphates are the actual participants in the bodily processes. But in the clinical laboratory, all methods that measure serum phosphorus in fact measure inorganic phosphate and are expressed in terms of milligrams of phosphorus per deciliter rather than milligrams of phosphate per deciliter, and using these 2 terms interchangeably in clinical practice should not be of concern.⁴

THE PROBLEM

US adults typically ingest 1,200 mg of phosphorus each day, and about 60% to 70% of the ingested phosphorus is absorbed both by passive paracellular diffusion via tight junctions and by active transcellular transport via sodium-phosphate cotransport. The kidneys must excrete the same amount daily to maintain a steady state. As kidney function declines, phosphorus accumulates in the blood, leading to hyperphosphatemia.

Hyperphosphatemia is often asymptomatic, but it can cause generalized itching, red eyes, and adverse effects on the bone and parathyroid glands. Higher serum phosphorus levels have been shown to be associated with vascular calcification,⁵ cardiovascular events, and higher all-cause mortality rates in the general population,⁶ in patients with diabetes,⁷ and in those with chronic kidney disease.⁸ This association between higher serum phosphorus levels and the all-cause mortality rate led to the assumption that lowering serum phosphorus levels in these patients could reduce the rates of cardiovascular events and death, and to efforts to correct hyperphosphatemia.

Research into FGF23 continues, especially its role in cardiovascular complications of chronic kidney disease, as both phosphorus and FGF23 levels are elevated in chronic kidney disease and are implicated in poor clinical outcomes in these patients. However, both FGF23 and parathyroid hormone levels rise early in the course of kidney disease, long before overt hyperphosphatemia develops. Further, FGF23 rises earlier than parathyroid hormone and has been found to be an independent risk factor for cardiovascular events and death from any cause in end-stage kidney disease.⁹

Whether hyperphosphatemia is the culprit or merely an epiphenomenon of metabolic complications of chronic kidney disease is still unclear, as more molecules are being identified in the complex process of cardiovascular calcification.¹⁰

However, one thing is clear: vascular calcification is not just a simple precipitation of calcium and phosphorus. Instead, it is an active process that involves many regulators of mineral metabolism.¹⁰ The complex nature of this process is likely one of the reasons that evidence is conflicting¹¹ about the benefits of phosphorus binders in terms of cardiovascular events or all-cause mortality in these patients.

Reducing intake

Dietary phosphorus restriction is the first step in controlling serum phosphorus. But reducing phosphorus intake while otherwise trying to optimize the nutritional status can be challenging.

The recommended daily protein intake is 1.0 to 1.2 g/kg. But phosphorus is typically found in foods rich in proteins, and restricting protein severely can compromise nutritional status and may be as bad as elevated phosphate levels in terms of outcomes.

Although plant-based foods contain more phosphate per gram of protein (ie, they have a higher ratio of phosphorus to protein) than animal-based foods, the bioavailability of phosphorus from plant foods is lower. Phosphorus in plant-based foods is mainly in the form of phytate. Humans cannot hydrolyze phytate because we lack the phytase enzyme; hence, the phosphorus in plant-based foods is not well absorbed. Therefore, a vegetarian diet may be preferable and beneficial in patients with chronic kidney disease. A small study in humans showed that a vegetarian diet resulted in lower serum phosphorus and FGF23 levels, but the study was limited by its small sample size.¹²

Patients should be advised to avoid foods that have a high phosphate content, such as processed foods, fast foods, and cola beverages, which often have phosphate-based food additives.

Further, one should be cautious about using supplements with healthy-sounding names. A case in point is “vitamin water”: 12 oz of this fruit punch-flavored beverage contains 392 mg of phosphorus,¹³ and this alone would require 12 to 15 phosphate binder tablets to bind its phosphorus content.

In addition, many prescription drugs have significant amounts of phosphorus, and this is often unrecognized.

Sherman et al¹⁴ reviewed 200 of the most commonly prescribed drugs in dialysis patients and found that 23 (11.5%) of the drug labels listed phosphorus-containing ingredients, but the actual amount of phosphorus was not listed. The phosphorus content ranged from 1.4 mg (clonidine 0.2 mg, Blue Point Laboratories, Dublin, Ireland) to 111.5 mg (paroxetine 40 mg, GlaxoSmith Kline, Philadelphia, PA). The phosphorus content was inconsistent and varied with the dose of the agent, type of formulation (tablet or syrup), branded or generic formulation, and manufacturer.

Branded lisinopril (Merck, Kenilworth, NJ) had 21.4 mg of phosphorus per 10-mg dose, while a generic product (Blue Point Laboratories, Dublin, Ireland) had 32.6 mg. Different brands of generic amlodipine 10 mg varied in their phosphorus content from 8.6 mg (Lupin Pharmaceuticals, Mumbai, India) to 27.8 mg (Greenstone LLC, Peapack, NJ) to 40.1 mg (Qualitest Pharmaceuticals, Huntsville, AL. Rena-Vite (Cypress Pharmaceuticals, Madison, MS), a multivitamin marketed to patients with kidney disease, had 37.7 mg of phosphorus per tablet. Thus, just to bind the phosphorus content of these 3 tablets (lisinopril, amlodipine, and Rena-Vite), a patient could need at least 3 to 4 extra doses of phosphate binder.

The phosphate content of medications should be considered when prescribing. For example, Reno Caps (Nnodum Pharmaceuticals, Cincinnati, OH), another vitamin supplement, has only 1.7 mg of phosphorus per tablet and should be considered, especially in patients with poorly controlled serum phosphorus levels. However, the challenge is that medication labels do not provide the phosphorus content.

Reducing phosphorus absorption

Although these agents reduce serum phosphorus and help reduce symptoms, an important quality-of-life measure, it is uncertain whether they improve clinical outcomes.¹¹ To date, no specific phosphorus binder offers a survival benefit over placebo.¹¹

Based on the limited and conflicting evidence, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, recently updated, suggest that oral phosphorus binders should be used in patients with hyperphosphatemia to lower serum phosphorus levels toward the normal range.¹⁵ They further recommend not exceeding 1,500 mg of elemental calcium per day if a calcium-based binder is used, and they recommend avoiding calcium-based binders in patients with hypercalcemia, adynamic bone disease, or vascular calcification.

Phosphorus binders may account for up to 50% of the daily pill burden and may contribute to poor medication adherence.¹⁶ Dialysis patients need to take a lot of these drugs: by weight, 5 to 6 pounds per year.

These drugs can bind and interfere with the absorption of other vital medications and so should be taken with meals and separately from other medications.

Removing phosphorus

Removal of phosphorus by adequate dialysis or kidney transplant is the final strategy.

New agents under study

To improve phosphorus control, other agents that inhibit absorption of phosphate are being investigated.

Nicotinamide reduces expression of the sodium-phosphorus cotransporter NTP2b. Its use in combination with a low-phosphorus diet and phosphorus binders may maximize reductions in phosphorus absorption and is being studied in the CKD Optimal Management With Binders and Nicotinamide (COMBINE) study.

Tenapanor, an inhibitor of the sodium-hydrogen transporter NHE3, has been shown in animal studies to increase fecal phosphate excretion and decrease urinary phosphate excretion17 but requires further evaluation.

A 51-year-old man with end-stage renal disease, on peritoneal dialysis for the past 4 years, presented to the emergency department with severe pain in both legs. The pain had started 2 months previously and had progressively worsened. After multiple admissions in the past for hyperkalemia and volume overload due to noncompliance, he had been advised to switch to hemodialysis.

See related article and editorial

Laboratory analysis revealed the following values:

• Serum creatinine 12.62 mg/dL (reference range 0.73–1.22)
• Blood urea nitrogen 159 mg/dL (9–24)
• Serum calcium corrected for serum albumin 8.1 mg/dL (8.4–10.0)
• Serum phosphorus 10.6 mg/dL (2.7–4.8).