Ignazio Grattagliano, MD

CASE John L, a 63-year-old man taking lovastatin (40 mg/d) and ramipril (5 mg/d) for hypercholesterolemia and arterial hypertension was hospitalized with atrial fibrillation. Three days later, he was discharged, with a prescription for amiodarone (200 mg/d). After a month, he was readmitted to the hospital with dark urine and intensifying thigh weakness and achiness. Laboratory testing revealed aspartate aminotransferase and alanine aminotransferase levels 10 times the upper limit of normal, and elevated urine and serum myoglobin.

Drug-drug interactions (DDIs) like the one John experienced between lovastatin and amiodarone are a common cause of readmissions, as well as emergency department visits and hospitalizations, for everything from myopathy to electrolyte imbalance, gastrointestinal (GI) bleeding, hepatotoxicity, renal dysfunction, and changes in blood pressure and heart rate.^1-3

Yet many, if not most, DDIs can be avoided. With diligence and the right tools, you can do much to reduce the incidence of such interactions and adverse outcomes.

Polypharmacy and age pose the highest risks

The more medications a patient is taking, of course, the greater the likelihood of a clinically significant DDI. According to 1 study, 13% of patients taking 2 drugs develop a DDI; the incidence approaches 40% for patients taking 5 drugs, and exceeds 80% for patients taking 7 or more medications.⁴

Whether age, multiple medications, or both are to blame, the impact on the elderly is striking. One recent retrospective study found 25% of elderly outpatients to be at risk for DDIs.⁸

Very young patients (<5 years) are also at risk for DDIs because of the immaturity of their enzymatic metabolic system.^5,9,10 Additional risk factors, detailed in TABLE 1, include the presence of an infection or other acute medical condition, a metabolic or endocrine disorder, and taking 1 or more drugs with a narrow therapeutic range. Women are also at higher risk for DDIs than their male counterparts, the result of a slower metabolic capacity and interference with sex hormones.^3-5,8,9 Pharmacogenetics may also play a big part in DDIs, and more and more studies are focusing on identifying patients at greatest risk.

TABLE 1
Risk factors for drug-drug interactions^3-5,8,9

Lack of coordinated care also increases risk
Another risk factor involves the use of multiple providers.⁹ A woman may be treated by—and receive prescriptions from—an endocrinolo-gist, a gynecologist, and a family physician (FP), for instance, and get medications from a local pharmacy, a nationwide discount chain, and a mail order pharmacy. As with the number of medications being taken, the greater the number of health care professionals a patient sees, the higher the risk.

To mitigate the risk, encourage your patients to fill all their prescriptions at the same pharmacy—and for your part, take a complete medication history before writing a new prescription.

Medication history in doubt? Schedule a “brown bag review”
Ask patients to provide the name and dose of every medication they’re taking. Inquire specifically about over-the-counter (OTC) cough and cold remedies and complementary and alternative medicines, including herbal remedies, vitamins, and supplements. Patients often neglect to mention nonprescription remedies and may not even think of them as medicine, but OTC products with the potential to interact adversely with prescription drugs may otherwise remain undetected.^11-13

Consider a “brown bag review” for patients who don’t know what dosage they’re taking or have difficulty identifying the drugs other physicians have prescribed. Ask them to put all their medications in a brown bag and bring them in on their next visit.^14,15

Steps to take to reduce risk

Software systems. A number of free and low-cost software systems identify potential DDIs (See “Check for drug interactions: Software programs to consider”). While such electronic programs can indeed lower the risk,^16-18 they cannot be counted on to detect or avert every possible adverse interaction.

The downside. One problem is that some software programs fail to distinguish between clinically significant and nonsignificant interactions, causing some prescribers to override system alerts—and possibly miss an important warning.¹⁹ Another problem: While most systems do an excellent job of checking to see whether 2 drugs can be safely taken together, few are capable of checking for all potential interactions among multiple medications. What’s more, many drugs have not been evaluated for their potential to interact with other agents, so the absence of reported interactions is no guarantee of a lack of DDIs.

Other strategies to consider:

Minimize the number of prescriptions. While it may not be possible to avoid prescribing a new agent for a patient who is already taking multiple medications, limiting the number of new drugs to those that are absolutely essential will help to minimize DDIs. Whenever possible, select a compound with the desired effects. Prescribe a single agent with antihypertensive as well as uricosuric effects for a patient with elevated blood pressure and uric acid levels rather than 2 different drugs (eg, losartan instead of an anti-hypertensive agent plus allopurinol).

Alter the dosing regimen. Several active molecules may cause DDIs by interfering with intestinal absorption or GI transit time if they’re taken closely together. For example, a quinolone should not be administered at the same time as a cation because of possible chelation in the GI tract. If a patient needs both, however, you may be able to avert a DDI by advising the patient to take them at least 2 hours apart.²⁰ Another possibility is to temporarily discontinue a maintenance medication if it has the potential to interact adversely with a drug that is needed for only a short duration.

Choose a different drug (or drug class). Some drug classes should never be mixed—nitrates and phosphodiesterase type-5 inhibitors, taken together, greatly increase the risk of vasodilation and may result in severe hypotension, for example. There are also drug classes with a low potential for DDIs, including cholinesterase inhibitors and anti-hypertensives (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and thiazides).²¹

Frequently, though, medications within the same drug class do not share the same potential for DDIs. In such cases, an adverse outcome can often be averted by being aware of combinations likely to result in clinically significant DDIs (TABLE 2) and, whenever possible, prescribing another agent. If a patient taking carbamazepine needs a macro-lide antibiotic, for instance, azithromycin is a better choice than erythromycin. That’s because erythromycin inhibits the hepatic metabolism of the anticonvulsant, increasing the serum level of carbamazepine, while azithromycin does not interfere with carbamazepine metabolism.²²

TABLE 2
Clinically significant drug-drug interactions^21,22

How is the drug metabolized?

DDIs may occur as a result of pharmaco-dynamic interaction (when 2 drugs act on the same receptor, site of action, or physiologic system) or pharmacokinetic changes (interference with absorption, albumin binding, distribution, metabolism, or elimination).²³ As already noted, age-related changes in pharmacokinetics and pharmacodynamics contribute to the high prevalence of DDIs in elderly patients.

In the liver, drug metabolism, particularly via the cytochrome P450 (CYP450) system, is the cornerstone of drug transformation.²³ Al-though the CYP system consists of “superfami-lies” with more than 100 types of enzymes, only a few are responsible for the majority of biotransformation.²³ The CYP system is also subject to genetic polymorphism, making some patients especially prone to DDIs.

P-glycoproteins (PGPs), which regulate drug absorption by transporting the drugs across cell membranes, also play a key role. PGP inhibitors or inducers help determine whether the accumulation of the molecule or the increased delivery of toxic metabolites leads to adverse effects.¹⁰

Reviewing the mechanism of action of any drug you prescribe for a patient taking other medications may alert you to a potential DDI—and the need to either switch the newly prescribed agent or alter the individual’s drug regimen in some other way.

CASE When John was readmitted to the hospital, he was taken off both the lovastatin and amiodarone and hydrated with forced alkaline diuresis. After a week, his symptoms resolved, and he was discharged soon after. His blood tests normalized 1 month later. The severe DDI he experienced occurred because lovastatin (which is metabolized primarily by CYP3A4) and amiodarone (a CYP3A4 inhibitor) were taken together. (Statins that are substrates of CYP3A4 have the greatest potential for interacting with drugs known to inhibit the CYP450 system [eg, cyclosporine, morphine derivatives, ketoconazole, and amiodarone].)

This adverse interaction could have been avoided if the physician who started John on amiodarone had been aware of the potential DDI—and switched him to an HMG-CoA inhibitor other than lovastatin. Pravastatin, which is not metabolized via CYP450, would have been an excellent choice.

Warfarin warrants special attention
Medications that have a particularly high potential for adverse interactions require special attention and patient monitoring, warfarin foremost among them. Warfarin metabolism and its anticoagulant effects can be dramatically changed if it is administered with a drug with a higher affinity for PGPs or an agent that competes with it within the CYP450 system.²⁴ Because of warfarin’s narrow therapeutic range, there are many drugs and drug classes that patients on warfarin should avoid (TABLE 3)—a fact that patients as well as their physicians need to be aware of.²⁴ Indeed, warfarin is often involved in drug-related hospital admissions for DDIs, especially in elderly patients and in those who are also taking nonsteroidal anti-inflamma-tory drugs (NSAIDs) or macrolides—2 of the many drug classes that patients taking warfarin should avoid.²⁴

TABLE 3
Patient on warfarin? Steer clear of these drugs^10,20,23

Keep an eye on these drug combinations, as well

Among the many combinations likely to result in clinically significant DDIs (TABLE 2), the following are worth mentioning:

Clopidogrel + certain proton pump inhibitors. The addition of a PPI to clopidogrel has been associated with a significant increase of recurrent infarction.²⁵ This may occur because clopidogrel is a prodrug and is converted in the liver to its active form by CYP2C19, an enzyme specifically inhibited by various PPIs—thereby altering the effectiveness of the antiplatelet agent. However, a recent analysis suggests that there is no need to avoid the concomitant use of a PPI and clopidogrel—and that the interference appears to be limited to omeprazole and esomeprazole.²⁶

Oral contraceptives (OCs) + penicillins, phenobarbital, or tetracycline. Each of these drugs reduces the effect of OCs, and women who are taking them concomitantly need to be advised to use another means of contraception.

Phenobarbital + simvastatin. Pheno-barbital (a CYP3A4 inducer) may reduce the efficacy of simvastatin.

Repaglinide + diltiazem. Diltiazem inhibits the metabolism of repaglinide (a CYP3A4 substrate), thus increasing the risk of hypoglycemia.

Simvastatin + amiodarone or itraconazole. Either of these antiarrhythmic agents decreases simvastatin metabolism, raising the risk of myopathy; with amiodarone, however, the likelihood of an adverse outcome is especially high. In 2008, the US Food and Drug Administration (FDA) issued a warning to healthcare professionals of the increased risk for rhabdomyolysis when simvastatin doses greater than 20 mg are administered together with amiodarone.²⁷ The agency issued a safety review of simvastatin, warning of its potential for DDIs with amiodarone and numerous other medications, earlier this year.²⁸

As John’s case illustrates, use of lovastatin with amiodarone should be avoided, as well.

Keep others safe: Report adverse events
When a DDI occurs despite your best efforts, you can help ensure that other patients do not experience the same adverse outcome by reporting it to MedWatch, the FDA’s voluntary safety information and adverse event reporting program. Go to https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm to file a report online.

CORRESPONDENCE Ignazio Grattagliano, MD, General Medicine, Department of Internal and Public Medicine, University of Bari, P.zza G. Cesare, 11 – 70124, Bari, Italy; [email protected]

CASE John L, a 63-year-old man taking lovastatin (40 mg/d) and ramipril (5 mg/d) for hypercholesterolemia and arterial hypertension was hospitalized with atrial fibrillation. Three days later, he was discharged, with a prescription for amiodarone (200 mg/d). After a month, he was readmitted to the hospital with dark urine and intensifying thigh weakness and achiness. Laboratory testing revealed aspartate aminotransferase and alanine aminotransferase levels 10 times the upper limit of normal, and elevated urine and serum myoglobin.

Drug-drug interactions (DDIs) like the one John experienced between lovastatin and amiodarone are a common cause of readmissions, as well as emergency department visits and hospitalizations, for everything from myopathy to electrolyte imbalance, gastrointestinal (GI) bleeding, hepatotoxicity, renal dysfunction, and changes in blood pressure and heart rate.^1-3

Yet many, if not most, DDIs can be avoided. With diligence and the right tools, you can do much to reduce the incidence of such interactions and adverse outcomes.

Polypharmacy and age pose the highest risks

The more medications a patient is taking, of course, the greater the likelihood of a clinically significant DDI. According to 1 study, 13% of patients taking 2 drugs develop a DDI; the incidence approaches 40% for patients taking 5 drugs, and exceeds 80% for patients taking 7 or more medications.⁴

Whether age, multiple medications, or both are to blame, the impact on the elderly is striking. One recent retrospective study found 25% of elderly outpatients to be at risk for DDIs.⁸

Very young patients (<5 years) are also at risk for DDIs because of the immaturity of their enzymatic metabolic system.^5,9,10 Additional risk factors, detailed in TABLE 1, include the presence of an infection or other acute medical condition, a metabolic or endocrine disorder, and taking 1 or more drugs with a narrow therapeutic range. Women are also at higher risk for DDIs than their male counterparts, the result of a slower metabolic capacity and interference with sex hormones.^3-5,8,9 Pharmacogenetics may also play a big part in DDIs, and more and more studies are focusing on identifying patients at greatest risk.

TABLE 1
Risk factors for drug-drug interactions^3-5,8,9

Lack of coordinated care also increases risk
Another risk factor involves the use of multiple providers.⁹ A woman may be treated by—and receive prescriptions from—an endocrinolo-gist, a gynecologist, and a family physician (FP), for instance, and get medications from a local pharmacy, a nationwide discount chain, and a mail order pharmacy. As with the number of medications being taken, the greater the number of health care professionals a patient sees, the higher the risk.

To mitigate the risk, encourage your patients to fill all their prescriptions at the same pharmacy—and for your part, take a complete medication history before writing a new prescription.

Medication history in doubt? Schedule a “brown bag review”
Ask patients to provide the name and dose of every medication they’re taking. Inquire specifically about over-the-counter (OTC) cough and cold remedies and complementary and alternative medicines, including herbal remedies, vitamins, and supplements. Patients often neglect to mention nonprescription remedies and may not even think of them as medicine, but OTC products with the potential to interact adversely with prescription drugs may otherwise remain undetected.^11-13

Consider a “brown bag review” for patients who don’t know what dosage they’re taking or have difficulty identifying the drugs other physicians have prescribed. Ask them to put all their medications in a brown bag and bring them in on their next visit.^14,15

Steps to take to reduce risk

Software systems. A number of free and low-cost software systems identify potential DDIs (See “Check for drug interactions: Software programs to consider”). While such electronic programs can indeed lower the risk,^16-18 they cannot be counted on to detect or avert every possible adverse interaction.

The downside. One problem is that some software programs fail to distinguish between clinically significant and nonsignificant interactions, causing some prescribers to override system alerts—and possibly miss an important warning.¹⁹ Another problem: While most systems do an excellent job of checking to see whether 2 drugs can be safely taken together, few are capable of checking for all potential interactions among multiple medications. What’s more, many drugs have not been evaluated for their potential to interact with other agents, so the absence of reported interactions is no guarantee of a lack of DDIs.

Other strategies to consider:

Minimize the number of prescriptions. While it may not be possible to avoid prescribing a new agent for a patient who is already taking multiple medications, limiting the number of new drugs to those that are absolutely essential will help to minimize DDIs. Whenever possible, select a compound with the desired effects. Prescribe a single agent with antihypertensive as well as uricosuric effects for a patient with elevated blood pressure and uric acid levels rather than 2 different drugs (eg, losartan instead of an anti-hypertensive agent plus allopurinol).

Alter the dosing regimen. Several active molecules may cause DDIs by interfering with intestinal absorption or GI transit time if they’re taken closely together. For example, a quinolone should not be administered at the same time as a cation because of possible chelation in the GI tract. If a patient needs both, however, you may be able to avert a DDI by advising the patient to take them at least 2 hours apart.²⁰ Another possibility is to temporarily discontinue a maintenance medication if it has the potential to interact adversely with a drug that is needed for only a short duration.

Choose a different drug (or drug class). Some drug classes should never be mixed—nitrates and phosphodiesterase type-5 inhibitors, taken together, greatly increase the risk of vasodilation and may result in severe hypotension, for example. There are also drug classes with a low potential for DDIs, including cholinesterase inhibitors and anti-hypertensives (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and thiazides).²¹

Frequently, though, medications within the same drug class do not share the same potential for DDIs. In such cases, an adverse outcome can often be averted by being aware of combinations likely to result in clinically significant DDIs (TABLE 2) and, whenever possible, prescribing another agent. If a patient taking carbamazepine needs a macro-lide antibiotic, for instance, azithromycin is a better choice than erythromycin. That’s because erythromycin inhibits the hepatic metabolism of the anticonvulsant, increasing the serum level of carbamazepine, while azithromycin does not interfere with carbamazepine metabolism.²²

TABLE 2
Clinically significant drug-drug interactions^21,22

How is the drug metabolized?

DDIs may occur as a result of pharmaco-dynamic interaction (when 2 drugs act on the same receptor, site of action, or physiologic system) or pharmacokinetic changes (interference with absorption, albumin binding, distribution, metabolism, or elimination).²³ As already noted, age-related changes in pharmacokinetics and pharmacodynamics contribute to the high prevalence of DDIs in elderly patients.

In the liver, drug metabolism, particularly via the cytochrome P450 (CYP450) system, is the cornerstone of drug transformation.²³ Al-though the CYP system consists of “superfami-lies” with more than 100 types of enzymes, only a few are responsible for the majority of biotransformation.²³ The CYP system is also subject to genetic polymorphism, making some patients especially prone to DDIs.

P-glycoproteins (PGPs), which regulate drug absorption by transporting the drugs across cell membranes, also play a key role. PGP inhibitors or inducers help determine whether the accumulation of the molecule or the increased delivery of toxic metabolites leads to adverse effects.¹⁰

Reviewing the mechanism of action of any drug you prescribe for a patient taking other medications may alert you to a potential DDI—and the need to either switch the newly prescribed agent or alter the individual’s drug regimen in some other way.

CASE When John was readmitted to the hospital, he was taken off both the lovastatin and amiodarone and hydrated with forced alkaline diuresis. After a week, his symptoms resolved, and he was discharged soon after. His blood tests normalized 1 month later. The severe DDI he experienced occurred because lovastatin (which is metabolized primarily by CYP3A4) and amiodarone (a CYP3A4 inhibitor) were taken together. (Statins that are substrates of CYP3A4 have the greatest potential for interacting with drugs known to inhibit the CYP450 system [eg, cyclosporine, morphine derivatives, ketoconazole, and amiodarone].)

This adverse interaction could have been avoided if the physician who started John on amiodarone had been aware of the potential DDI—and switched him to an HMG-CoA inhibitor other than lovastatin. Pravastatin, which is not metabolized via CYP450, would have been an excellent choice.

Warfarin warrants special attention
Medications that have a particularly high potential for adverse interactions require special attention and patient monitoring, warfarin foremost among them. Warfarin metabolism and its anticoagulant effects can be dramatically changed if it is administered with a drug with a higher affinity for PGPs or an agent that competes with it within the CYP450 system.²⁴ Because of warfarin’s narrow therapeutic range, there are many drugs and drug classes that patients on warfarin should avoid (TABLE 3)—a fact that patients as well as their physicians need to be aware of.²⁴ Indeed, warfarin is often involved in drug-related hospital admissions for DDIs, especially in elderly patients and in those who are also taking nonsteroidal anti-inflamma-tory drugs (NSAIDs) or macrolides—2 of the many drug classes that patients taking warfarin should avoid.²⁴

TABLE 3
Patient on warfarin? Steer clear of these drugs^10,20,23

Keep an eye on these drug combinations, as well

Among the many combinations likely to result in clinically significant DDIs (TABLE 2), the following are worth mentioning:

Clopidogrel + certain proton pump inhibitors. The addition of a PPI to clopidogrel has been associated with a significant increase of recurrent infarction.²⁵ This may occur because clopidogrel is a prodrug and is converted in the liver to its active form by CYP2C19, an enzyme specifically inhibited by various PPIs—thereby altering the effectiveness of the antiplatelet agent. However, a recent analysis suggests that there is no need to avoid the concomitant use of a PPI and clopidogrel—and that the interference appears to be limited to omeprazole and esomeprazole.²⁶

Oral contraceptives (OCs) + penicillins, phenobarbital, or tetracycline. Each of these drugs reduces the effect of OCs, and women who are taking them concomitantly need to be advised to use another means of contraception.

Phenobarbital + simvastatin. Pheno-barbital (a CYP3A4 inducer) may reduce the efficacy of simvastatin.

Repaglinide + diltiazem. Diltiazem inhibits the metabolism of repaglinide (a CYP3A4 substrate), thus increasing the risk of hypoglycemia.

Simvastatin + amiodarone or itraconazole. Either of these antiarrhythmic agents decreases simvastatin metabolism, raising the risk of myopathy; with amiodarone, however, the likelihood of an adverse outcome is especially high. In 2008, the US Food and Drug Administration (FDA) issued a warning to healthcare professionals of the increased risk for rhabdomyolysis when simvastatin doses greater than 20 mg are administered together with amiodarone.²⁷ The agency issued a safety review of simvastatin, warning of its potential for DDIs with amiodarone and numerous other medications, earlier this year.²⁸

As John’s case illustrates, use of lovastatin with amiodarone should be avoided, as well.

Keep others safe: Report adverse events
When a DDI occurs despite your best efforts, you can help ensure that other patients do not experience the same adverse outcome by reporting it to MedWatch, the FDA’s voluntary safety information and adverse event reporting program. Go to https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm to file a report online.

CORRESPONDENCE Ignazio Grattagliano, MD, General Medicine, Department of Internal and Public Medicine, University of Bari, P.zza G. Cesare, 11 – 70124, Bari, Italy; [email protected]

CASE John L, a 63-year-old man taking lovastatin (40 mg/d) and ramipril (5 mg/d) for hypercholesterolemia and arterial hypertension was hospitalized with atrial fibrillation. Three days later, he was discharged, with a prescription for amiodarone (200 mg/d). After a month, he was readmitted to the hospital with dark urine and intensifying thigh weakness and achiness. Laboratory testing revealed aspartate aminotransferase and alanine aminotransferase levels 10 times the upper limit of normal, and elevated urine and serum myoglobin.

Drug-drug interactions (DDIs) like the one John experienced between lovastatin and amiodarone are a common cause of readmissions, as well as emergency department visits and hospitalizations, for everything from myopathy to electrolyte imbalance, gastrointestinal (GI) bleeding, hepatotoxicity, renal dysfunction, and changes in blood pressure and heart rate.^1-3

Yet many, if not most, DDIs can be avoided. With diligence and the right tools, you can do much to reduce the incidence of such interactions and adverse outcomes.

Polypharmacy and age pose the highest risks

The more medications a patient is taking, of course, the greater the likelihood of a clinically significant DDI. According to 1 study, 13% of patients taking 2 drugs develop a DDI; the incidence approaches 40% for patients taking 5 drugs, and exceeds 80% for patients taking 7 or more medications.⁴

Whether age, multiple medications, or both are to blame, the impact on the elderly is striking. One recent retrospective study found 25% of elderly outpatients to be at risk for DDIs.⁸

Very young patients (<5 years) are also at risk for DDIs because of the immaturity of their enzymatic metabolic system.^5,9,10 Additional risk factors, detailed in TABLE 1, include the presence of an infection or other acute medical condition, a metabolic or endocrine disorder, and taking 1 or more drugs with a narrow therapeutic range. Women are also at higher risk for DDIs than their male counterparts, the result of a slower metabolic capacity and interference with sex hormones.^3-5,8,9 Pharmacogenetics may also play a big part in DDIs, and more and more studies are focusing on identifying patients at greatest risk.

TABLE 1
Risk factors for drug-drug interactions^3-5,8,9

Lack of coordinated care also increases risk
Another risk factor involves the use of multiple providers.⁹ A woman may be treated by—and receive prescriptions from—an endocrinolo-gist, a gynecologist, and a family physician (FP), for instance, and get medications from a local pharmacy, a nationwide discount chain, and a mail order pharmacy. As with the number of medications being taken, the greater the number of health care professionals a patient sees, the higher the risk.

To mitigate the risk, encourage your patients to fill all their prescriptions at the same pharmacy—and for your part, take a complete medication history before writing a new prescription.

Medication history in doubt? Schedule a “brown bag review”
Ask patients to provide the name and dose of every medication they’re taking. Inquire specifically about over-the-counter (OTC) cough and cold remedies and complementary and alternative medicines, including herbal remedies, vitamins, and supplements. Patients often neglect to mention nonprescription remedies and may not even think of them as medicine, but OTC products with the potential to interact adversely with prescription drugs may otherwise remain undetected.^11-13

Consider a “brown bag review” for patients who don’t know what dosage they’re taking or have difficulty identifying the drugs other physicians have prescribed. Ask them to put all their medications in a brown bag and bring them in on their next visit.^14,15

Steps to take to reduce risk

Software systems. A number of free and low-cost software systems identify potential DDIs (See “Check for drug interactions: Software programs to consider”). While such electronic programs can indeed lower the risk,^16-18 they cannot be counted on to detect or avert every possible adverse interaction.

The downside. One problem is that some software programs fail to distinguish between clinically significant and nonsignificant interactions, causing some prescribers to override system alerts—and possibly miss an important warning.¹⁹ Another problem: While most systems do an excellent job of checking to see whether 2 drugs can be safely taken together, few are capable of checking for all potential interactions among multiple medications. What’s more, many drugs have not been evaluated for their potential to interact with other agents, so the absence of reported interactions is no guarantee of a lack of DDIs.

Other strategies to consider:

Minimize the number of prescriptions. While it may not be possible to avoid prescribing a new agent for a patient who is already taking multiple medications, limiting the number of new drugs to those that are absolutely essential will help to minimize DDIs. Whenever possible, select a compound with the desired effects. Prescribe a single agent with antihypertensive as well as uricosuric effects for a patient with elevated blood pressure and uric acid levels rather than 2 different drugs (eg, losartan instead of an anti-hypertensive agent plus allopurinol).

Alter the dosing regimen. Several active molecules may cause DDIs by interfering with intestinal absorption or GI transit time if they’re taken closely together. For example, a quinolone should not be administered at the same time as a cation because of possible chelation in the GI tract. If a patient needs both, however, you may be able to avert a DDI by advising the patient to take them at least 2 hours apart.²⁰ Another possibility is to temporarily discontinue a maintenance medication if it has the potential to interact adversely with a drug that is needed for only a short duration.

Choose a different drug (or drug class). Some drug classes should never be mixed—nitrates and phosphodiesterase type-5 inhibitors, taken together, greatly increase the risk of vasodilation and may result in severe hypotension, for example. There are also drug classes with a low potential for DDIs, including cholinesterase inhibitors and anti-hypertensives (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and thiazides).²¹

Frequently, though, medications within the same drug class do not share the same potential for DDIs. In such cases, an adverse outcome can often be averted by being aware of combinations likely to result in clinically significant DDIs (TABLE 2) and, whenever possible, prescribing another agent. If a patient taking carbamazepine needs a macro-lide antibiotic, for instance, azithromycin is a better choice than erythromycin. That’s because erythromycin inhibits the hepatic metabolism of the anticonvulsant, increasing the serum level of carbamazepine, while azithromycin does not interfere with carbamazepine metabolism.²²

TABLE 2
Clinically significant drug-drug interactions^21,22

How is the drug metabolized?

DDIs may occur as a result of pharmaco-dynamic interaction (when 2 drugs act on the same receptor, site of action, or physiologic system) or pharmacokinetic changes (interference with absorption, albumin binding, distribution, metabolism, or elimination).²³ As already noted, age-related changes in pharmacokinetics and pharmacodynamics contribute to the high prevalence of DDIs in elderly patients.

In the liver, drug metabolism, particularly via the cytochrome P450 (CYP450) system, is the cornerstone of drug transformation.²³ Al-though the CYP system consists of “superfami-lies” with more than 100 types of enzymes, only a few are responsible for the majority of biotransformation.²³ The CYP system is also subject to genetic polymorphism, making some patients especially prone to DDIs.

P-glycoproteins (PGPs), which regulate drug absorption by transporting the drugs across cell membranes, also play a key role. PGP inhibitors or inducers help determine whether the accumulation of the molecule or the increased delivery of toxic metabolites leads to adverse effects.¹⁰

Reviewing the mechanism of action of any drug you prescribe for a patient taking other medications may alert you to a potential DDI—and the need to either switch the newly prescribed agent or alter the individual’s drug regimen in some other way.

CASE When John was readmitted to the hospital, he was taken off both the lovastatin and amiodarone and hydrated with forced alkaline diuresis. After a week, his symptoms resolved, and he was discharged soon after. His blood tests normalized 1 month later. The severe DDI he experienced occurred because lovastatin (which is metabolized primarily by CYP3A4) and amiodarone (a CYP3A4 inhibitor) were taken together. (Statins that are substrates of CYP3A4 have the greatest potential for interacting with drugs known to inhibit the CYP450 system [eg, cyclosporine, morphine derivatives, ketoconazole, and amiodarone].)

This adverse interaction could have been avoided if the physician who started John on amiodarone had been aware of the potential DDI—and switched him to an HMG-CoA inhibitor other than lovastatin. Pravastatin, which is not metabolized via CYP450, would have been an excellent choice.

Warfarin warrants special attention
Medications that have a particularly high potential for adverse interactions require special attention and patient monitoring, warfarin foremost among them. Warfarin metabolism and its anticoagulant effects can be dramatically changed if it is administered with a drug with a higher affinity for PGPs or an agent that competes with it within the CYP450 system.²⁴ Because of warfarin’s narrow therapeutic range, there are many drugs and drug classes that patients on warfarin should avoid (TABLE 3)—a fact that patients as well as their physicians need to be aware of.²⁴ Indeed, warfarin is often involved in drug-related hospital admissions for DDIs, especially in elderly patients and in those who are also taking nonsteroidal anti-inflamma-tory drugs (NSAIDs) or macrolides—2 of the many drug classes that patients taking warfarin should avoid.²⁴

TABLE 3
Patient on warfarin? Steer clear of these drugs^10,20,23

Keep an eye on these drug combinations, as well

Among the many combinations likely to result in clinically significant DDIs (TABLE 2), the following are worth mentioning:

Clopidogrel + certain proton pump inhibitors. The addition of a PPI to clopidogrel has been associated with a significant increase of recurrent infarction.²⁵ This may occur because clopidogrel is a prodrug and is converted in the liver to its active form by CYP2C19, an enzyme specifically inhibited by various PPIs—thereby altering the effectiveness of the antiplatelet agent. However, a recent analysis suggests that there is no need to avoid the concomitant use of a PPI and clopidogrel—and that the interference appears to be limited to omeprazole and esomeprazole.²⁶

Oral contraceptives (OCs) + penicillins, phenobarbital, or tetracycline. Each of these drugs reduces the effect of OCs, and women who are taking them concomitantly need to be advised to use another means of contraception.

Phenobarbital + simvastatin. Pheno-barbital (a CYP3A4 inducer) may reduce the efficacy of simvastatin.

Repaglinide + diltiazem. Diltiazem inhibits the metabolism of repaglinide (a CYP3A4 substrate), thus increasing the risk of hypoglycemia.

Simvastatin + amiodarone or itraconazole. Either of these antiarrhythmic agents decreases simvastatin metabolism, raising the risk of myopathy; with amiodarone, however, the likelihood of an adverse outcome is especially high. In 2008, the US Food and Drug Administration (FDA) issued a warning to healthcare professionals of the increased risk for rhabdomyolysis when simvastatin doses greater than 20 mg are administered together with amiodarone.²⁷ The agency issued a safety review of simvastatin, warning of its potential for DDIs with amiodarone and numerous other medications, earlier this year.²⁸

As John’s case illustrates, use of lovastatin with amiodarone should be avoided, as well.

Keep others safe: Report adverse events
When a DDI occurs despite your best efforts, you can help ensure that other patients do not experience the same adverse outcome by reporting it to MedWatch, the FDA’s voluntary safety information and adverse event reporting program. Go to https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm to file a report online.

CORRESPONDENCE Ignazio Grattagliano, MD, General Medicine, Department of Internal and Public Medicine, University of Bari, P.zza G. Cesare, 11 – 70124, Bari, Italy; [email protected]

CASE 1: A patient with mildly elevated ALT and AST

John M., a 63-year-old truck driver with a family history of diabetes and arterial hypertension, is complaining of persistent fatigue—again. He has type 2 diabetes and takes metformin and repaglinide, but his blood pressure is normal. Lab tests reveal a recurrent mild elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels of unknown origin; Mr. M. has no history of virus or hepatotoxic drugs, and reports only modest alcohol intake. He is obese, however, with a BMI of 34.5 and a waist circumference of 41 inches.

CASE 2: A patient with abdominal swelling

Anna B., a slim 68-year-old, comes in with 2 acute conditions: About a week ago, she noticed abdominal swelling and low back pain that began suddenly, after she carried a heavy load. She’s taken nonsteroidal anti-inflammatory drugs for 6 days, but the pain has not improved. The patient’s only significant clinical history is a hysterectomy, with oophorectomy, at age 38, and a recurrent elevation of serum transaminase levels that has never been investigated. Examination reveals an important kyphosis, and finger pressure on the vertebral spine or a position change exacerbates the pain. Her abdomen is swollen and tense, with a tympanic sound on the upper abdomen and a dull sound on the lower portion.

If John M. and Anna B. were your patients, would you suspect that they both have advanced liver disease? What diagnostic tests would you order, and how would you manage their care?

Cirrhosis has always been associated with high rates of morbidity and mortality. It is the 12th most common cause of death in the United States;¹ in some parts of the world, its ranking as a cause of death is considerably higher.^2,3 In recent years, however, cirrhosis has become the focus of greater attention both here and abroad, for 2 reasons: The first is the increasing prevalence of viral hepatitis and steatohepatitis, both of which are prominent causes of cirrhosis. The second is the improvement we’ve made in treatment: Not only can we slow the progression of cirrhosis, but in some cases, we can even restore hepatic function.⁴

The key to successful management of cirrhosis lies in spotting subtle signs and symptoms well in advance of the serious complications that can arise down the road. Here’s what to look for.

Early warnings you can’t afford to overlook

While the clinical presentation of a patient with liver cirrhosis is often asymptomatic, serum transminases—included in many standard laboratory tests as part of a routine examination—often provide the first sign of a problem.

Mildly elevated ALT in an asymptomatic patient may be transient and benign, or an indication of chronic liver disease.⁵ In fact, signs suggestive of significant liver disease have been reported in more than 20% of patients with ALT elevation.² But because abnormal ALT values are common and frequently resolve, many primary care physicians pay little attention to this potentially important finding—and miss a key opportunity for early identification and treatment.⁶

Look at other lab values, risk factors, as well

Additional lab values that suggest the possibility of cirrhosis include an elevated AST/ALT ratio, a low platelet count (<150,000/L), elevated alkaline phosphatase, elevated bilirubin (>1.1 mg/dL), low serum albumin (<2.5 g/dL), and decreased prothrombin time (<100%). Potential causes include viral hepatitis, heavy alcohol use, hepatotoxic drugs, steatosis, and steatohepatitis.

The next step for a patient with any of these abnormal values is a thorough medication review and medical history. Identify all prescription and nonprescription drugs the patient is taking, as well as any herbal products and supplements, in search of hepatotoxic agents. Amiodarone and valproic acid, among other drugs, may cause steatosis, and some herbal products—particularly kava kava extract, used to treat anxiety and insomnia—have been linked to hepatitis and even liver failure.⁷ Question the patient about alcohol consumption and a history of conditions associated with liver disease, such as diabetes, hyperlipidemia, and thyroid disorders, as well.

At a minimum, schedule follow-up testing of asymptomatic patients with abnormal laboratory findings in no more than 6 months. Persistent ALT elevation in such patients is most commonly caused by major viruses, alcohol abuse, nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH).⁸ Nonalcoholic fatty liver is especially likely in patients with clinical and demographic risk factors—those who, like John M., suffer from obesity or diabetes, or both.

Ultrasound yields further information

Further screening should be limited to patients who continue to have abnormal test results for 6 months or more or have multiple risk factors. While biopsy is still considered the gold standard for diagnosing and staging chronic liver disease, it should be considered, according to the American Gastroenterological Association, only if ultrasound and other tests have not been helpful in reaching a diagnosis.⁹

Often, though, ultrasonography aids in diagnosis. In the case of John M., ultrasound revealed an enlarged liver with diffuse echostructural dyshomogeneity and signs of severe steatosis and mild splenomegaly, but no increase in portal vein diameter and no ascites. For asymptomatic patients with cirrhosis or an earlier stage of liver disease, ultrasound at 6-month intervals, combined with blood alpha-fetoprotein measurement, can be used to track disease progression and screen for hepatocellular carcinoma.¹⁰

Newer, noninvasive methods aid in diagnosis

Noninvasive means of evaluating the presence and extent of liver fibrosis and differentiating cirrhosis from noncirrhosis, developed in recent years, have been found to have positive predictive values greater than 85% to 90%.¹¹ Transient elastography (FibroScan, London, England), which assesses liver stiffness, is 1 such method. Although it is often used successfully, however, morbid obesity, small intercostal spaces, and ascites limit the diagnostic capability of this medical device.¹²

Fibrosis can also be detected with the use of 1 or more algorithms—each testing blood samples for a different combination of serum surrogate markers for liver disease. Some widely used algorithms include the APRI (AST-to-platelets ratio index), the Fibrotest (aptoglobin, alpha-2 macroglobulin, apolipoprotein A1, gamma-glutamyl transpeptidase, and bilirubin), the Hepascore (bilirubin, gamma-glutamyl transpeptidase, haluronic acid, alpha-2 macroglobulin, age, sex), and the BARD (BMI, AST/ALT ratio, diabetes).

Hepatologists often use the results of ultrasonography, followed by transient elastography in conjunction with findings from 1 or more of these algorithms, to determine which patients are candidates for liver biopsy.^11,12

Staging is crucial, with or without biopsy

The decision to perform a liver biopsy should be based on a number of factors, including the patient’s age, lifestyle, liver chemistry abnormalities, desire for prognostic information, and associated comorbidities.⁹ Despite the value of biopsy, it is a costly procedure with potentially serious side effects and risks—and not always accepted by patients. In a recent survey of 1177 primary care physicians in France, as many as 59% of patients with chronic hepatitis C refused to undergo liver biopsy; what’s more, 22% of the doctors surveyed shared the patients’ hesitancy.¹³ Whether patients refuse biopsy or it is deemed unnecessary because ultrasound and other noninvasive tests result in a probable diagnosis, staging is necessary, both to guide therapy and to arrive at a prognosis.

Liver enzyme levels reveal little about organ integrity and are not useful for staging. But other parameters (specifically, bilirubin, albumin, and prothrombin time), combined with the presence (or absence) and severity of physical findings such as encephalopathy and ascites, are included in the Child-Pugh classification system ( TABLE 1 ),¹⁴ a widely used system that roughly indicates disease severity.¹⁵

The Model for End-stage Liver Disease (MELD)—and PELD, the pediatric model—use bilirubin, creatinine, and international normalized ratio values to classify disease severity. MELD and PELD scores are considered more accurate than the Child-Pugh score in determining short-term mortality,¹⁶ and are used by the United Network of Organ Sharing (UNOS) for liver allocation. You’ll find a calculator at http://optn.transplant.hrsa.gov/resources/MeldPeldCalculator.asp?index=97.¹⁷

Despite the progress in diagnostic techniques, the life expectancy and quality of life for patients with advanced cirrhosis remains poor. Patients routinely experience fatigue, pruritus, ascites, encephalopathy, and bleeding; dyspepsia and malnutrition are common, as well. Cirrhosis also carries the risk of life-threatening complications, partly due to comorbidities—most notably, osteoporosis, malabsorption, and rheumatic diseases. Liver transplantation has the potential to change the life expectancy of these patients, but because of the extensive waiting lists, candidates for transplant often die before a liver becomes available.

But for many patients who are in stable condition—those with compensated cirrhosis, that is—the prognosis is far more hopeful: In addition to providing standard medical care, including immunization, if necessary, and nutritional counseling, targeted therapy is crucial to slow, or stop, disease progression.

TABLE 1
Child-Pugh: Classifying cirrhosis, predicting survival*

Treatment for cirrhosis depends on the cause

Although primary care physicians can often provide most, or all, of the care for those in stable condition, a specialist may be helpful in determining further testing to identify the underlying cause of the cirrhosis, which is essential to determining the most appropriate treatment. What’s more, research has shown that patients with cirrhosis whose care is managed by a primary care physician and a hepatologist have better outcomes than those who are treated by a primary care doctor alone.¹⁸

What to test for?

Tests to determine the cause of cirrhosis are listed in TABLE 2 . For an individual patient, diagnostic tests would be based on the suspected cause. A patient with a family history of hereditary hemochromatosis would be tested for elevated serum ferritin levels and hepatic iron content on liver biopsy sample; the transferrin saturation index would also be obtained, and the patient might be tested for specific gene mutations. A patient who drinks heavily would be tested for elevated gamma-glutamyl transpeptidase and mean corpuscular volume. For someone with obesity, diabetes, and an enlarged liver, standard lab tests, including high-density lipoprotein (HDL) cholesterol, glucose, and triglycerides, may be sufficient.

Keep in mind, however, that cirrhosis may have more than 1 contributing factor—obesity or chronic alcohol use and a virus, for example; alcohol abuse and metabolic fatty liver; or virus and hemochromatosis. Thus, it may require more than 1 type of treatment.

Alcohol abuse is the cause of 25% of cases of liver cirrhosis, and a contributor to another 25% to 50%.¹⁹ The key treatment here—and an ideal role for a family physician—is to refer the patient to a detoxification and treatment program and provide ongoing monitoring and support. Antiviral treatment may be helpful for a recovering alcoholic who also tests positive for hepatitis B or C virus, but because of potential problems with compliance, some physicians delay therapy until the patient has had at least 6 months of continuous abstinence. Although this is not an absolute criterion, the same period of abstinence may be required before a patient becomes eligible for a liver transplant.

NAFLD/NASH is typically diagnosed on the basis of lab values and physical presentation. For a stable patient, the primary treatment includes lifestyle change—a low-calorie, low-carbohydrate diet and an exercise regimen—and a possible switch to insulin for better glycemic control.

For patients who are not candidates for such targeted treatments, either because their disease is too advanced or they’re unable to tolerate the recommended therapy, numerous pharmaceutical preparations claiming antioxidant or anti-inflammatory properties are available. But only 1—an herbal extract known as silymarin, derived from the milk thistle plant and taken with vitamin E—has been found to have some protective effects.²⁰

TABLE 2
Liver cirrhosis: Common causes, diagnostic tests, and treatments^4,34-38

Address systemic problems along with targeted treatment

Malnutrition is a serious problem for many patients with cirrhosis. Causes range from poor oral intake or malabsorption to ongoing alcohol use, chronic nausea, or early satiety because of compression from ascites. Dental problems that prevent the patient from chewing properly may be a contributing factor, as well.

Regardless of the cause, malnutrition is associated with muscle wasting, hypoalbuminemia, decreased resistance to infections, and variceal bleeding, and addressing it is a key part of treatment. Assess the nutritional status of every patient with cirrhosis, and stress the importance of multivitamin supplementation.²¹ If dental care is needed, take steps to see that the patient receives it.

Nutritional support, however, should be reserved for severely malnourished patients awaiting transplantation.²²

Osteoporosis. Reduced bone formation—the result of vitamin D deficiency, hypoparathyroidism, and hypogonadism—is a well-known complication of end-stage cirrhosis. However, osteopenia may occur in an earlier stage of disease, especially in patients with cholestatic disease and those receiving antiviral therapy. Prescribe bisphosphonates, together with calcium and vitamin D₃, to improve bone mineral density.²³

Diabetes. The relationship between diabetes and cirrhosis is particularly complex, because diabetes can be both a causal factor and a consequence of cirrhosis. Diabetes is common in patients with NASH, and prevalent among those with hepatitis C and hemochromatosis. Multivariate analyses have found that diabetes has an independent negative effect on the progression of liver disease.²⁴

Diet remains the first-line treatment for hyperglycemia, with metformin as the drug of choice if diet alone is unsuccessful. Sulfonylureas can be used, but require caution to avoid hypoglycemia. Glitazones are a newer alternative, but their value in patients with liver cirrhosis has not been studied. However, the use of any oral antidiabetic agent requires extra caution in patients with cirrhosis, and should be avoided in those with advanced liver disease. Although insulin requires intense self-monitoring of serum glucose levels, it is preferable to oral agents for this patient population.²⁵

Managing complications of cirrhosis

Hospital, home, or long-term care? Whether patients with advanced cirrhosis can be maintained at home or require hospitalization or long-term care is best decided in consultation with patient, family, and other members of the health care team. One helpful tool is the Karnofsky Performance Scale Index (http://www.pennmedicine.org/homecare/hcp/elig_worksheets/Karnofsky-Performance-Status.pdf), which scores patients from 0 to 100 based on their functional impairment.²⁶ (Patients with decompensated liver cirrhosis and limited self-sufficiency typically score <50, indicating that they require home health care, hospice, or institutional care.) Whatever the outcome, the patient may need to be reevaluated as the disease progresses and complications occur.

Ascites, the most common complication of cirrhosis,²⁷ is a primary reason for hospitalization, but may be managed on an outpatient basis, depending on the patient presentation. Determining factors include the presence or absence of portal hypertension, impaired albumin synthesis, decreased plasma oncotic pressure, and sodium retention. Diagnosis is based on physical exam and ultrasonography.

Initial treatment for ascites includes salt restriction^28,29 and avoidance of NSAIDs, which promote renal sodium retention, followed by spironolactone (100–400 mg/d). Add furosemide (40-160 mg/d) if the fluid retention does not begin to resolve after 3 to 5 days of treatment. If the condition persists despite maximum tolerable doses of diuretics, large-volume paracentesis to remove transudative fluid (albumin <1 g/dL; serum/ascites albumin gradient >1.1) may be needed. A patient with recurrent or refractory ascites should see a specialist for further evaluation and the possibility of a transjugular intrahepatic portosystemic shunt (TIPS).

Abdominal pain and an ascitic granulocyte count >250/mm³ suggest spontaneous bacterial peritonitis (SBP)—a severe complication of ascites that can result in renal and liver failure. In addition to pain, patients may present with tense ascites and fever, followed by encephalopathy, shock, and increased serum creatinine levels. Hospitalization is required for SBP; therapy includes high-dose albumin and intravenous antibiotics, typically cephalosporin. Long-term prophylaxis with norfloxacin to prevent the recurrence of SBP is indicated.³⁰

If your patient has ascites and is being cared for at home, talk to the patient and his or her family about the importance of a daily weight check. Tell them to contact you if the patient gains more than 4 to 8 lbs within a few days. Frequent electrolyte checks are needed, as well. An albumin infusion is required when serum levels are particularly low, or after large-volume paracentesis.³¹ Patients with SBP or refractory ascites generally have more advanced disease and a poor prognosis.

Portal hypertension/esophageal varices. The main aim of treating portal hypertension is to prevent esophageal variceal bleeding. The appearance of varices should be checked by endoscopy every 2 to 3 years, or yearly for patients at high risk of bleeding. Patients with varices can be managed with nonselective beta-blockers at doses that are sufficient to elicit a 25% reduction in resting heart rate. Those at high risk for bleeding and patients who have already had esophageal bleeding may require endoscopic band ligation.³² TIPS is an alternative for those whose previous treatments have failed.³³

Hepatic encephalopathy. This potentially reversible decrease in neuropsychiatric function mainly affects patients with portal hypertension. Caused by reduced hepatic clearance of gut-deriving neurotoxins, hepatic encephalopathy is associated with a range of signs and symptoms—from subtle personality changes to coma, with flapping tremor as a frequent initial finding. Acid-base and electrolyte disturbances, constipation, infections, gastrointestinal bleeding, and sedatives can precipitate encephalopathy. Hepatic encephalopathy is a diagnosis of exclusion, however, requiring the exclusion of all other etiologies of altered mental status.

Treatment consists of identifying and correcting the precipitating factors, and includes electrolyte correction, colon cleansing, and acidification with lactulose. Dietary protein restriction is no longer advocated, because it may facilitate malnutrition and complications. Oral rifaximine is useful and well tolerated for suppression of intestinal bacterial flora. Venous infusion of branched-chain amino acids or flumazenil may be effective in case of coma.

Fever and sepsis. Infection is a high-risk factor for mortality in patients with cirrhosis, as it can lead to renal and liver failure, variceal bleeding, and hepatic encephalopathy. However, individuals with cirrhosis often do not develop the typical signs and symptoms of infection; leukocytosis may be absent because of severe leukopenia, for instance, and patients may be afebrile.

Thus, the general appearance of systemic illness is an indication for antibiotics, with quinolones and cephalosporins as first-line agents. Infections most commonly involve the urinary tract (25%-55%) or the respiratory tract (20%), or are related to SBP (10%-30%).³³ Hospitalization is suggested in case of poor general health status or the appearance of organ dysfunction.

When medical therapy and other interventions fail to control complications, transplantation is the only alternative. Primary care physicians can play a role here, too, in referring potential candidates for liver transplants to specialists for further consideration.

CASE 1: Resolution

As we’ve already seen, John M.’s ultrasound revealed an enlarged liver. The results led to a probable diagnosis of an advanced form of NASH. Other lab tests indicated that he had poorly controlled diabetes, high triglyceride levels, and—for the first time—a low platelet count. His physician stressed the importance of following a low-calorie, low-carbohydrate diet and exercising regularly, prescribed insulin, and referred the patient to a hepatologist for further noninvasive evaluation of fibrosis and to determine whether liver biopsy was needed.

CASE 2: Resolution

Blood tests revealed that Anna B. had a low platelet count (64,000/mm³), elevated liver enzymes (AST 2× upper limit of normal [ULN], ALT 1.5× ULN, GGT 2.5× ULN), and high gamma-globulins (33.6%) with no monoclonal bands. Ultrasound revealed an enlarged liver with diffuse echostructural dyshomogeneity, portal vein dilatation, and moderate ascites. She also tested positive for HCV and had an HCV-RNA reading of 15×10⁶ IU/mL. No other cause of chronic liver disease emerged. Ms. B.’s physician told her that she had an osteoporotic vertebral fracture—a frequent comorbidity in patients with liver cirrhosis—and decompensated liver cirrhosis from an old HCV infection. He added that her abdomen was distended because of fluid retention. The physician recommended bed rest, prescribed paracetamol (1 g tid) and spironolactone (100 mg/d), and referred the patient to an orthopedist for treatment of the fracture and to a hepatologist to be evaluated for transplantation.

CORRESPONDENCE
Ignazio Grattagliano, MD, Department of Internal Medicine, University Medical School of Bari, P.zza G. Cesare, 11 – 70124, Bari, Italy; [email protected]

CASE 1: A patient with mildly elevated ALT and AST

John M., a 63-year-old truck driver with a family history of diabetes and arterial hypertension, is complaining of persistent fatigue—again. He has type 2 diabetes and takes metformin and repaglinide, but his blood pressure is normal. Lab tests reveal a recurrent mild elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels of unknown origin; Mr. M. has no history of virus or hepatotoxic drugs, and reports only modest alcohol intake. He is obese, however, with a BMI of 34.5 and a waist circumference of 41 inches.

CASE 2: A patient with abdominal swelling

Anna B., a slim 68-year-old, comes in with 2 acute conditions: About a week ago, she noticed abdominal swelling and low back pain that began suddenly, after she carried a heavy load. She’s taken nonsteroidal anti-inflammatory drugs for 6 days, but the pain has not improved. The patient’s only significant clinical history is a hysterectomy, with oophorectomy, at age 38, and a recurrent elevation of serum transaminase levels that has never been investigated. Examination reveals an important kyphosis, and finger pressure on the vertebral spine or a position change exacerbates the pain. Her abdomen is swollen and tense, with a tympanic sound on the upper abdomen and a dull sound on the lower portion.

If John M. and Anna B. were your patients, would you suspect that they both have advanced liver disease? What diagnostic tests would you order, and how would you manage their care?

Cirrhosis has always been associated with high rates of morbidity and mortality. It is the 12th most common cause of death in the United States;¹ in some parts of the world, its ranking as a cause of death is considerably higher.^2,3 In recent years, however, cirrhosis has become the focus of greater attention both here and abroad, for 2 reasons: The first is the increasing prevalence of viral hepatitis and steatohepatitis, both of which are prominent causes of cirrhosis. The second is the improvement we’ve made in treatment: Not only can we slow the progression of cirrhosis, but in some cases, we can even restore hepatic function.⁴

The key to successful management of cirrhosis lies in spotting subtle signs and symptoms well in advance of the serious complications that can arise down the road. Here’s what to look for.

Early warnings you can’t afford to overlook

While the clinical presentation of a patient with liver cirrhosis is often asymptomatic, serum transminases—included in many standard laboratory tests as part of a routine examination—often provide the first sign of a problem.

Mildly elevated ALT in an asymptomatic patient may be transient and benign, or an indication of chronic liver disease.⁵ In fact, signs suggestive of significant liver disease have been reported in more than 20% of patients with ALT elevation.² But because abnormal ALT values are common and frequently resolve, many primary care physicians pay little attention to this potentially important finding—and miss a key opportunity for early identification and treatment.⁶

Look at other lab values, risk factors, as well

Additional lab values that suggest the possibility of cirrhosis include an elevated AST/ALT ratio, a low platelet count (<150,000/L), elevated alkaline phosphatase, elevated bilirubin (>1.1 mg/dL), low serum albumin (<2.5 g/dL), and decreased prothrombin time (<100%). Potential causes include viral hepatitis, heavy alcohol use, hepatotoxic drugs, steatosis, and steatohepatitis.

The next step for a patient with any of these abnormal values is a thorough medication review and medical history. Identify all prescription and nonprescription drugs the patient is taking, as well as any herbal products and supplements, in search of hepatotoxic agents. Amiodarone and valproic acid, among other drugs, may cause steatosis, and some herbal products—particularly kava kava extract, used to treat anxiety and insomnia—have been linked to hepatitis and even liver failure.⁷ Question the patient about alcohol consumption and a history of conditions associated with liver disease, such as diabetes, hyperlipidemia, and thyroid disorders, as well.

At a minimum, schedule follow-up testing of asymptomatic patients with abnormal laboratory findings in no more than 6 months. Persistent ALT elevation in such patients is most commonly caused by major viruses, alcohol abuse, nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH).⁸ Nonalcoholic fatty liver is especially likely in patients with clinical and demographic risk factors—those who, like John M., suffer from obesity or diabetes, or both.

Ultrasound yields further information

Further screening should be limited to patients who continue to have abnormal test results for 6 months or more or have multiple risk factors. While biopsy is still considered the gold standard for diagnosing and staging chronic liver disease, it should be considered, according to the American Gastroenterological Association, only if ultrasound and other tests have not been helpful in reaching a diagnosis.⁹

Often, though, ultrasonography aids in diagnosis. In the case of John M., ultrasound revealed an enlarged liver with diffuse echostructural dyshomogeneity and signs of severe steatosis and mild splenomegaly, but no increase in portal vein diameter and no ascites. For asymptomatic patients with cirrhosis or an earlier stage of liver disease, ultrasound at 6-month intervals, combined with blood alpha-fetoprotein measurement, can be used to track disease progression and screen for hepatocellular carcinoma.¹⁰

Newer, noninvasive methods aid in diagnosis

Noninvasive means of evaluating the presence and extent of liver fibrosis and differentiating cirrhosis from noncirrhosis, developed in recent years, have been found to have positive predictive values greater than 85% to 90%.¹¹ Transient elastography (FibroScan, London, England), which assesses liver stiffness, is 1 such method. Although it is often used successfully, however, morbid obesity, small intercostal spaces, and ascites limit the diagnostic capability of this medical device.¹²

Fibrosis can also be detected with the use of 1 or more algorithms—each testing blood samples for a different combination of serum surrogate markers for liver disease. Some widely used algorithms include the APRI (AST-to-platelets ratio index), the Fibrotest (aptoglobin, alpha-2 macroglobulin, apolipoprotein A1, gamma-glutamyl transpeptidase, and bilirubin), the Hepascore (bilirubin, gamma-glutamyl transpeptidase, haluronic acid, alpha-2 macroglobulin, age, sex), and the BARD (BMI, AST/ALT ratio, diabetes).

Hepatologists often use the results of ultrasonography, followed by transient elastography in conjunction with findings from 1 or more of these algorithms, to determine which patients are candidates for liver biopsy.^11,12

Staging is crucial, with or without biopsy

The decision to perform a liver biopsy should be based on a number of factors, including the patient’s age, lifestyle, liver chemistry abnormalities, desire for prognostic information, and associated comorbidities.⁹ Despite the value of biopsy, it is a costly procedure with potentially serious side effects and risks—and not always accepted by patients. In a recent survey of 1177 primary care physicians in France, as many as 59% of patients with chronic hepatitis C refused to undergo liver biopsy; what’s more, 22% of the doctors surveyed shared the patients’ hesitancy.¹³ Whether patients refuse biopsy or it is deemed unnecessary because ultrasound and other noninvasive tests result in a probable diagnosis, staging is necessary, both to guide therapy and to arrive at a prognosis.

Liver enzyme levels reveal little about organ integrity and are not useful for staging. But other parameters (specifically, bilirubin, albumin, and prothrombin time), combined with the presence (or absence) and severity of physical findings such as encephalopathy and ascites, are included in the Child-Pugh classification system ( TABLE 1 ),¹⁴ a widely used system that roughly indicates disease severity.¹⁵

The Model for End-stage Liver Disease (MELD)—and PELD, the pediatric model—use bilirubin, creatinine, and international normalized ratio values to classify disease severity. MELD and PELD scores are considered more accurate than the Child-Pugh score in determining short-term mortality,¹⁶ and are used by the United Network of Organ Sharing (UNOS) for liver allocation. You’ll find a calculator at http://optn.transplant.hrsa.gov/resources/MeldPeldCalculator.asp?index=97.¹⁷

Despite the progress in diagnostic techniques, the life expectancy and quality of life for patients with advanced cirrhosis remains poor. Patients routinely experience fatigue, pruritus, ascites, encephalopathy, and bleeding; dyspepsia and malnutrition are common, as well. Cirrhosis also carries the risk of life-threatening complications, partly due to comorbidities—most notably, osteoporosis, malabsorption, and rheumatic diseases. Liver transplantation has the potential to change the life expectancy of these patients, but because of the extensive waiting lists, candidates for transplant often die before a liver becomes available.

But for many patients who are in stable condition—those with compensated cirrhosis, that is—the prognosis is far more hopeful: In addition to providing standard medical care, including immunization, if necessary, and nutritional counseling, targeted therapy is crucial to slow, or stop, disease progression.

TABLE 1
Child-Pugh: Classifying cirrhosis, predicting survival*

Treatment for cirrhosis depends on the cause

Although primary care physicians can often provide most, or all, of the care for those in stable condition, a specialist may be helpful in determining further testing to identify the underlying cause of the cirrhosis, which is essential to determining the most appropriate treatment. What’s more, research has shown that patients with cirrhosis whose care is managed by a primary care physician and a hepatologist have better outcomes than those who are treated by a primary care doctor alone.¹⁸

What to test for?

Tests to determine the cause of cirrhosis are listed in TABLE 2 . For an individual patient, diagnostic tests would be based on the suspected cause. A patient with a family history of hereditary hemochromatosis would be tested for elevated serum ferritin levels and hepatic iron content on liver biopsy sample; the transferrin saturation index would also be obtained, and the patient might be tested for specific gene mutations. A patient who drinks heavily would be tested for elevated gamma-glutamyl transpeptidase and mean corpuscular volume. For someone with obesity, diabetes, and an enlarged liver, standard lab tests, including high-density lipoprotein (HDL) cholesterol, glucose, and triglycerides, may be sufficient.

Keep in mind, however, that cirrhosis may have more than 1 contributing factor—obesity or chronic alcohol use and a virus, for example; alcohol abuse and metabolic fatty liver; or virus and hemochromatosis. Thus, it may require more than 1 type of treatment.

Alcohol abuse is the cause of 25% of cases of liver cirrhosis, and a contributor to another 25% to 50%.¹⁹ The key treatment here—and an ideal role for a family physician—is to refer the patient to a detoxification and treatment program and provide ongoing monitoring and support. Antiviral treatment may be helpful for a recovering alcoholic who also tests positive for hepatitis B or C virus, but because of potential problems with compliance, some physicians delay therapy until the patient has had at least 6 months of continuous abstinence. Although this is not an absolute criterion, the same period of abstinence may be required before a patient becomes eligible for a liver transplant.

NAFLD/NASH is typically diagnosed on the basis of lab values and physical presentation. For a stable patient, the primary treatment includes lifestyle change—a low-calorie, low-carbohydrate diet and an exercise regimen—and a possible switch to insulin for better glycemic control.

For patients who are not candidates for such targeted treatments, either because their disease is too advanced or they’re unable to tolerate the recommended therapy, numerous pharmaceutical preparations claiming antioxidant or anti-inflammatory properties are available. But only 1—an herbal extract known as silymarin, derived from the milk thistle plant and taken with vitamin E—has been found to have some protective effects.²⁰

TABLE 2
Liver cirrhosis: Common causes, diagnostic tests, and treatments^4,34-38

Address systemic problems along with targeted treatment

Malnutrition is a serious problem for many patients with cirrhosis. Causes range from poor oral intake or malabsorption to ongoing alcohol use, chronic nausea, or early satiety because of compression from ascites. Dental problems that prevent the patient from chewing properly may be a contributing factor, as well.

Regardless of the cause, malnutrition is associated with muscle wasting, hypoalbuminemia, decreased resistance to infections, and variceal bleeding, and addressing it is a key part of treatment. Assess the nutritional status of every patient with cirrhosis, and stress the importance of multivitamin supplementation.²¹ If dental care is needed, take steps to see that the patient receives it.

Nutritional support, however, should be reserved for severely malnourished patients awaiting transplantation.²²

Osteoporosis. Reduced bone formation—the result of vitamin D deficiency, hypoparathyroidism, and hypogonadism—is a well-known complication of end-stage cirrhosis. However, osteopenia may occur in an earlier stage of disease, especially in patients with cholestatic disease and those receiving antiviral therapy. Prescribe bisphosphonates, together with calcium and vitamin D₃, to improve bone mineral density.²³

Diabetes. The relationship between diabetes and cirrhosis is particularly complex, because diabetes can be both a causal factor and a consequence of cirrhosis. Diabetes is common in patients with NASH, and prevalent among those with hepatitis C and hemochromatosis. Multivariate analyses have found that diabetes has an independent negative effect on the progression of liver disease.²⁴

Diet remains the first-line treatment for hyperglycemia, with metformin as the drug of choice if diet alone is unsuccessful. Sulfonylureas can be used, but require caution to avoid hypoglycemia. Glitazones are a newer alternative, but their value in patients with liver cirrhosis has not been studied. However, the use of any oral antidiabetic agent requires extra caution in patients with cirrhosis, and should be avoided in those with advanced liver disease. Although insulin requires intense self-monitoring of serum glucose levels, it is preferable to oral agents for this patient population.²⁵

Managing complications of cirrhosis

Hospital, home, or long-term care? Whether patients with advanced cirrhosis can be maintained at home or require hospitalization or long-term care is best decided in consultation with patient, family, and other members of the health care team. One helpful tool is the Karnofsky Performance Scale Index (http://www.pennmedicine.org/homecare/hcp/elig_worksheets/Karnofsky-Performance-Status.pdf), which scores patients from 0 to 100 based on their functional impairment.²⁶ (Patients with decompensated liver cirrhosis and limited self-sufficiency typically score <50, indicating that they require home health care, hospice, or institutional care.) Whatever the outcome, the patient may need to be reevaluated as the disease progresses and complications occur.

Ascites, the most common complication of cirrhosis,²⁷ is a primary reason for hospitalization, but may be managed on an outpatient basis, depending on the patient presentation. Determining factors include the presence or absence of portal hypertension, impaired albumin synthesis, decreased plasma oncotic pressure, and sodium retention. Diagnosis is based on physical exam and ultrasonography.

Initial treatment for ascites includes salt restriction^28,29 and avoidance of NSAIDs, which promote renal sodium retention, followed by spironolactone (100–400 mg/d). Add furosemide (40-160 mg/d) if the fluid retention does not begin to resolve after 3 to 5 days of treatment. If the condition persists despite maximum tolerable doses of diuretics, large-volume paracentesis to remove transudative fluid (albumin <1 g/dL; serum/ascites albumin gradient >1.1) may be needed. A patient with recurrent or refractory ascites should see a specialist for further evaluation and the possibility of a transjugular intrahepatic portosystemic shunt (TIPS).

Abdominal pain and an ascitic granulocyte count >250/mm³ suggest spontaneous bacterial peritonitis (SBP)—a severe complication of ascites that can result in renal and liver failure. In addition to pain, patients may present with tense ascites and fever, followed by encephalopathy, shock, and increased serum creatinine levels. Hospitalization is required for SBP; therapy includes high-dose albumin and intravenous antibiotics, typically cephalosporin. Long-term prophylaxis with norfloxacin to prevent the recurrence of SBP is indicated.³⁰

If your patient has ascites and is being cared for at home, talk to the patient and his or her family about the importance of a daily weight check. Tell them to contact you if the patient gains more than 4 to 8 lbs within a few days. Frequent electrolyte checks are needed, as well. An albumin infusion is required when serum levels are particularly low, or after large-volume paracentesis.³¹ Patients with SBP or refractory ascites generally have more advanced disease and a poor prognosis.

Portal hypertension/esophageal varices. The main aim of treating portal hypertension is to prevent esophageal variceal bleeding. The appearance of varices should be checked by endoscopy every 2 to 3 years, or yearly for patients at high risk of bleeding. Patients with varices can be managed with nonselective beta-blockers at doses that are sufficient to elicit a 25% reduction in resting heart rate. Those at high risk for bleeding and patients who have already had esophageal bleeding may require endoscopic band ligation.³² TIPS is an alternative for those whose previous treatments have failed.³³

Hepatic encephalopathy. This potentially reversible decrease in neuropsychiatric function mainly affects patients with portal hypertension. Caused by reduced hepatic clearance of gut-deriving neurotoxins, hepatic encephalopathy is associated with a range of signs and symptoms—from subtle personality changes to coma, with flapping tremor as a frequent initial finding. Acid-base and electrolyte disturbances, constipation, infections, gastrointestinal bleeding, and sedatives can precipitate encephalopathy. Hepatic encephalopathy is a diagnosis of exclusion, however, requiring the exclusion of all other etiologies of altered mental status.

Treatment consists of identifying and correcting the precipitating factors, and includes electrolyte correction, colon cleansing, and acidification with lactulose. Dietary protein restriction is no longer advocated, because it may facilitate malnutrition and complications. Oral rifaximine is useful and well tolerated for suppression of intestinal bacterial flora. Venous infusion of branched-chain amino acids or flumazenil may be effective in case of coma.

Fever and sepsis. Infection is a high-risk factor for mortality in patients with cirrhosis, as it can lead to renal and liver failure, variceal bleeding, and hepatic encephalopathy. However, individuals with cirrhosis often do not develop the typical signs and symptoms of infection; leukocytosis may be absent because of severe leukopenia, for instance, and patients may be afebrile.

Thus, the general appearance of systemic illness is an indication for antibiotics, with quinolones and cephalosporins as first-line agents. Infections most commonly involve the urinary tract (25%-55%) or the respiratory tract (20%), or are related to SBP (10%-30%).³³ Hospitalization is suggested in case of poor general health status or the appearance of organ dysfunction.

When medical therapy and other interventions fail to control complications, transplantation is the only alternative. Primary care physicians can play a role here, too, in referring potential candidates for liver transplants to specialists for further consideration.

CASE 1: Resolution

As we’ve already seen, John M.’s ultrasound revealed an enlarged liver. The results led to a probable diagnosis of an advanced form of NASH. Other lab tests indicated that he had poorly controlled diabetes, high triglyceride levels, and—for the first time—a low platelet count. His physician stressed the importance of following a low-calorie, low-carbohydrate diet and exercising regularly, prescribed insulin, and referred the patient to a hepatologist for further noninvasive evaluation of fibrosis and to determine whether liver biopsy was needed.

CASE 2: Resolution

Blood tests revealed that Anna B. had a low platelet count (64,000/mm³), elevated liver enzymes (AST 2× upper limit of normal [ULN], ALT 1.5× ULN, GGT 2.5× ULN), and high gamma-globulins (33.6%) with no monoclonal bands. Ultrasound revealed an enlarged liver with diffuse echostructural dyshomogeneity, portal vein dilatation, and moderate ascites. She also tested positive for HCV and had an HCV-RNA reading of 15×10⁶ IU/mL. No other cause of chronic liver disease emerged. Ms. B.’s physician told her that she had an osteoporotic vertebral fracture—a frequent comorbidity in patients with liver cirrhosis—and decompensated liver cirrhosis from an old HCV infection. He added that her abdomen was distended because of fluid retention. The physician recommended bed rest, prescribed paracetamol (1 g tid) and spironolactone (100 mg/d), and referred the patient to an orthopedist for treatment of the fracture and to a hepatologist to be evaluated for transplantation.

CORRESPONDENCE
Ignazio Grattagliano, MD, Department of Internal Medicine, University Medical School of Bari, P.zza G. Cesare, 11 – 70124, Bari, Italy; [email protected]

CASE 1: A patient with mildly elevated ALT and AST

John M., a 63-year-old truck driver with a family history of diabetes and arterial hypertension, is complaining of persistent fatigue—again. He has type 2 diabetes and takes metformin and repaglinide, but his blood pressure is normal. Lab tests reveal a recurrent mild elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels of unknown origin; Mr. M. has no history of virus or hepatotoxic drugs, and reports only modest alcohol intake. He is obese, however, with a BMI of 34.5 and a waist circumference of 41 inches.

CASE 2: A patient with abdominal swelling

Anna B., a slim 68-year-old, comes in with 2 acute conditions: About a week ago, she noticed abdominal swelling and low back pain that began suddenly, after she carried a heavy load. She’s taken nonsteroidal anti-inflammatory drugs for 6 days, but the pain has not improved. The patient’s only significant clinical history is a hysterectomy, with oophorectomy, at age 38, and a recurrent elevation of serum transaminase levels that has never been investigated. Examination reveals an important kyphosis, and finger pressure on the vertebral spine or a position change exacerbates the pain. Her abdomen is swollen and tense, with a tympanic sound on the upper abdomen and a dull sound on the lower portion.

If John M. and Anna B. were your patients, would you suspect that they both have advanced liver disease? What diagnostic tests would you order, and how would you manage their care?

Cirrhosis has always been associated with high rates of morbidity and mortality. It is the 12th most common cause of death in the United States;¹ in some parts of the world, its ranking as a cause of death is considerably higher.^2,3 In recent years, however, cirrhosis has become the focus of greater attention both here and abroad, for 2 reasons: The first is the increasing prevalence of viral hepatitis and steatohepatitis, both of which are prominent causes of cirrhosis. The second is the improvement we’ve made in treatment: Not only can we slow the progression of cirrhosis, but in some cases, we can even restore hepatic function.⁴

The key to successful management of cirrhosis lies in spotting subtle signs and symptoms well in advance of the serious complications that can arise down the road. Here’s what to look for.

Early warnings you can’t afford to overlook

While the clinical presentation of a patient with liver cirrhosis is often asymptomatic, serum transminases—included in many standard laboratory tests as part of a routine examination—often provide the first sign of a problem.

Mildly elevated ALT in an asymptomatic patient may be transient and benign, or an indication of chronic liver disease.⁵ In fact, signs suggestive of significant liver disease have been reported in more than 20% of patients with ALT elevation.² But because abnormal ALT values are common and frequently resolve, many primary care physicians pay little attention to this potentially important finding—and miss a key opportunity for early identification and treatment.⁶

Look at other lab values, risk factors, as well

Additional lab values that suggest the possibility of cirrhosis include an elevated AST/ALT ratio, a low platelet count (<150,000/L), elevated alkaline phosphatase, elevated bilirubin (>1.1 mg/dL), low serum albumin (<2.5 g/dL), and decreased prothrombin time (<100%). Potential causes include viral hepatitis, heavy alcohol use, hepatotoxic drugs, steatosis, and steatohepatitis.

The next step for a patient with any of these abnormal values is a thorough medication review and medical history. Identify all prescription and nonprescription drugs the patient is taking, as well as any herbal products and supplements, in search of hepatotoxic agents. Amiodarone and valproic acid, among other drugs, may cause steatosis, and some herbal products—particularly kava kava extract, used to treat anxiety and insomnia—have been linked to hepatitis and even liver failure.⁷ Question the patient about alcohol consumption and a history of conditions associated with liver disease, such as diabetes, hyperlipidemia, and thyroid disorders, as well.

At a minimum, schedule follow-up testing of asymptomatic patients with abnormal laboratory findings in no more than 6 months. Persistent ALT elevation in such patients is most commonly caused by major viruses, alcohol abuse, nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH).⁸ Nonalcoholic fatty liver is especially likely in patients with clinical and demographic risk factors—those who, like John M., suffer from obesity or diabetes, or both.

Ultrasound yields further information

Further screening should be limited to patients who continue to have abnormal test results for 6 months or more or have multiple risk factors. While biopsy is still considered the gold standard for diagnosing and staging chronic liver disease, it should be considered, according to the American Gastroenterological Association, only if ultrasound and other tests have not been helpful in reaching a diagnosis.⁹

Often, though, ultrasonography aids in diagnosis. In the case of John M., ultrasound revealed an enlarged liver with diffuse echostructural dyshomogeneity and signs of severe steatosis and mild splenomegaly, but no increase in portal vein diameter and no ascites. For asymptomatic patients with cirrhosis or an earlier stage of liver disease, ultrasound at 6-month intervals, combined with blood alpha-fetoprotein measurement, can be used to track disease progression and screen for hepatocellular carcinoma.¹⁰

Newer, noninvasive methods aid in diagnosis

Noninvasive means of evaluating the presence and extent of liver fibrosis and differentiating cirrhosis from noncirrhosis, developed in recent years, have been found to have positive predictive values greater than 85% to 90%.¹¹ Transient elastography (FibroScan, London, England), which assesses liver stiffness, is 1 such method. Although it is often used successfully, however, morbid obesity, small intercostal spaces, and ascites limit the diagnostic capability of this medical device.¹²

Fibrosis can also be detected with the use of 1 or more algorithms—each testing blood samples for a different combination of serum surrogate markers for liver disease. Some widely used algorithms include the APRI (AST-to-platelets ratio index), the Fibrotest (aptoglobin, alpha-2 macroglobulin, apolipoprotein A1, gamma-glutamyl transpeptidase, and bilirubin), the Hepascore (bilirubin, gamma-glutamyl transpeptidase, haluronic acid, alpha-2 macroglobulin, age, sex), and the BARD (BMI, AST/ALT ratio, diabetes).

Hepatologists often use the results of ultrasonography, followed by transient elastography in conjunction with findings from 1 or more of these algorithms, to determine which patients are candidates for liver biopsy.^11,12

Staging is crucial, with or without biopsy

The decision to perform a liver biopsy should be based on a number of factors, including the patient’s age, lifestyle, liver chemistry abnormalities, desire for prognostic information, and associated comorbidities.⁹ Despite the value of biopsy, it is a costly procedure with potentially serious side effects and risks—and not always accepted by patients. In a recent survey of 1177 primary care physicians in France, as many as 59% of patients with chronic hepatitis C refused to undergo liver biopsy; what’s more, 22% of the doctors surveyed shared the patients’ hesitancy.¹³ Whether patients refuse biopsy or it is deemed unnecessary because ultrasound and other noninvasive tests result in a probable diagnosis, staging is necessary, both to guide therapy and to arrive at a prognosis.

Liver enzyme levels reveal little about organ integrity and are not useful for staging. But other parameters (specifically, bilirubin, albumin, and prothrombin time), combined with the presence (or absence) and severity of physical findings such as encephalopathy and ascites, are included in the Child-Pugh classification system ( TABLE 1 ),¹⁴ a widely used system that roughly indicates disease severity.¹⁵

The Model for End-stage Liver Disease (MELD)—and PELD, the pediatric model—use bilirubin, creatinine, and international normalized ratio values to classify disease severity. MELD and PELD scores are considered more accurate than the Child-Pugh score in determining short-term mortality,¹⁶ and are used by the United Network of Organ Sharing (UNOS) for liver allocation. You’ll find a calculator at http://optn.transplant.hrsa.gov/resources/MeldPeldCalculator.asp?index=97.¹⁷

Despite the progress in diagnostic techniques, the life expectancy and quality of life for patients with advanced cirrhosis remains poor. Patients routinely experience fatigue, pruritus, ascites, encephalopathy, and bleeding; dyspepsia and malnutrition are common, as well. Cirrhosis also carries the risk of life-threatening complications, partly due to comorbidities—most notably, osteoporosis, malabsorption, and rheumatic diseases. Liver transplantation has the potential to change the life expectancy of these patients, but because of the extensive waiting lists, candidates for transplant often die before a liver becomes available.

But for many patients who are in stable condition—those with compensated cirrhosis, that is—the prognosis is far more hopeful: In addition to providing standard medical care, including immunization, if necessary, and nutritional counseling, targeted therapy is crucial to slow, or stop, disease progression.

TABLE 1
Child-Pugh: Classifying cirrhosis, predicting survival*

Treatment for cirrhosis depends on the cause

Although primary care physicians can often provide most, or all, of the care for those in stable condition, a specialist may be helpful in determining further testing to identify the underlying cause of the cirrhosis, which is essential to determining the most appropriate treatment. What’s more, research has shown that patients with cirrhosis whose care is managed by a primary care physician and a hepatologist have better outcomes than those who are treated by a primary care doctor alone.¹⁸

What to test for?

Tests to determine the cause of cirrhosis are listed in TABLE 2 . For an individual patient, diagnostic tests would be based on the suspected cause. A patient with a family history of hereditary hemochromatosis would be tested for elevated serum ferritin levels and hepatic iron content on liver biopsy sample; the transferrin saturation index would also be obtained, and the patient might be tested for specific gene mutations. A patient who drinks heavily would be tested for elevated gamma-glutamyl transpeptidase and mean corpuscular volume. For someone with obesity, diabetes, and an enlarged liver, standard lab tests, including high-density lipoprotein (HDL) cholesterol, glucose, and triglycerides, may be sufficient.

Keep in mind, however, that cirrhosis may have more than 1 contributing factor—obesity or chronic alcohol use and a virus, for example; alcohol abuse and metabolic fatty liver; or virus and hemochromatosis. Thus, it may require more than 1 type of treatment.

Alcohol abuse is the cause of 25% of cases of liver cirrhosis, and a contributor to another 25% to 50%.¹⁹ The key treatment here—and an ideal role for a family physician—is to refer the patient to a detoxification and treatment program and provide ongoing monitoring and support. Antiviral treatment may be helpful for a recovering alcoholic who also tests positive for hepatitis B or C virus, but because of potential problems with compliance, some physicians delay therapy until the patient has had at least 6 months of continuous abstinence. Although this is not an absolute criterion, the same period of abstinence may be required before a patient becomes eligible for a liver transplant.

NAFLD/NASH is typically diagnosed on the basis of lab values and physical presentation. For a stable patient, the primary treatment includes lifestyle change—a low-calorie, low-carbohydrate diet and an exercise regimen—and a possible switch to insulin for better glycemic control.

For patients who are not candidates for such targeted treatments, either because their disease is too advanced or they’re unable to tolerate the recommended therapy, numerous pharmaceutical preparations claiming antioxidant or anti-inflammatory properties are available. But only 1—an herbal extract known as silymarin, derived from the milk thistle plant and taken with vitamin E—has been found to have some protective effects.²⁰

TABLE 2
Liver cirrhosis: Common causes, diagnostic tests, and treatments^4,34-38

Address systemic problems along with targeted treatment

Malnutrition is a serious problem for many patients with cirrhosis. Causes range from poor oral intake or malabsorption to ongoing alcohol use, chronic nausea, or early satiety because of compression from ascites. Dental problems that prevent the patient from chewing properly may be a contributing factor, as well.

Regardless of the cause, malnutrition is associated with muscle wasting, hypoalbuminemia, decreased resistance to infections, and variceal bleeding, and addressing it is a key part of treatment. Assess the nutritional status of every patient with cirrhosis, and stress the importance of multivitamin supplementation.²¹ If dental care is needed, take steps to see that the patient receives it.

Nutritional support, however, should be reserved for severely malnourished patients awaiting transplantation.²²

Osteoporosis. Reduced bone formation—the result of vitamin D deficiency, hypoparathyroidism, and hypogonadism—is a well-known complication of end-stage cirrhosis. However, osteopenia may occur in an earlier stage of disease, especially in patients with cholestatic disease and those receiving antiviral therapy. Prescribe bisphosphonates, together with calcium and vitamin D₃, to improve bone mineral density.²³

Diabetes. The relationship between diabetes and cirrhosis is particularly complex, because diabetes can be both a causal factor and a consequence of cirrhosis. Diabetes is common in patients with NASH, and prevalent among those with hepatitis C and hemochromatosis. Multivariate analyses have found that diabetes has an independent negative effect on the progression of liver disease.²⁴

Diet remains the first-line treatment for hyperglycemia, with metformin as the drug of choice if diet alone is unsuccessful. Sulfonylureas can be used, but require caution to avoid hypoglycemia. Glitazones are a newer alternative, but their value in patients with liver cirrhosis has not been studied. However, the use of any oral antidiabetic agent requires extra caution in patients with cirrhosis, and should be avoided in those with advanced liver disease. Although insulin requires intense self-monitoring of serum glucose levels, it is preferable to oral agents for this patient population.²⁵

Managing complications of cirrhosis

Hospital, home, or long-term care? Whether patients with advanced cirrhosis can be maintained at home or require hospitalization or long-term care is best decided in consultation with patient, family, and other members of the health care team. One helpful tool is the Karnofsky Performance Scale Index (http://www.pennmedicine.org/homecare/hcp/elig_worksheets/Karnofsky-Performance-Status.pdf), which scores patients from 0 to 100 based on their functional impairment.²⁶ (Patients with decompensated liver cirrhosis and limited self-sufficiency typically score <50, indicating that they require home health care, hospice, or institutional care.) Whatever the outcome, the patient may need to be reevaluated as the disease progresses and complications occur.

Ascites, the most common complication of cirrhosis,²⁷ is a primary reason for hospitalization, but may be managed on an outpatient basis, depending on the patient presentation. Determining factors include the presence or absence of portal hypertension, impaired albumin synthesis, decreased plasma oncotic pressure, and sodium retention. Diagnosis is based on physical exam and ultrasonography.

Initial treatment for ascites includes salt restriction^28,29 and avoidance of NSAIDs, which promote renal sodium retention, followed by spironolactone (100–400 mg/d). Add furosemide (40-160 mg/d) if the fluid retention does not begin to resolve after 3 to 5 days of treatment. If the condition persists despite maximum tolerable doses of diuretics, large-volume paracentesis to remove transudative fluid (albumin <1 g/dL; serum/ascites albumin gradient >1.1) may be needed. A patient with recurrent or refractory ascites should see a specialist for further evaluation and the possibility of a transjugular intrahepatic portosystemic shunt (TIPS).

Abdominal pain and an ascitic granulocyte count >250/mm³ suggest spontaneous bacterial peritonitis (SBP)—a severe complication of ascites that can result in renal and liver failure. In addition to pain, patients may present with tense ascites and fever, followed by encephalopathy, shock, and increased serum creatinine levels. Hospitalization is required for SBP; therapy includes high-dose albumin and intravenous antibiotics, typically cephalosporin. Long-term prophylaxis with norfloxacin to prevent the recurrence of SBP is indicated.³⁰

If your patient has ascites and is being cared for at home, talk to the patient and his or her family about the importance of a daily weight check. Tell them to contact you if the patient gains more than 4 to 8 lbs within a few days. Frequent electrolyte checks are needed, as well. An albumin infusion is required when serum levels are particularly low, or after large-volume paracentesis.³¹ Patients with SBP or refractory ascites generally have more advanced disease and a poor prognosis.

Portal hypertension/esophageal varices. The main aim of treating portal hypertension is to prevent esophageal variceal bleeding. The appearance of varices should be checked by endoscopy every 2 to 3 years, or yearly for patients at high risk of bleeding. Patients with varices can be managed with nonselective beta-blockers at doses that are sufficient to elicit a 25% reduction in resting heart rate. Those at high risk for bleeding and patients who have already had esophageal bleeding may require endoscopic band ligation.³² TIPS is an alternative for those whose previous treatments have failed.³³

Hepatic encephalopathy. This potentially reversible decrease in neuropsychiatric function mainly affects patients with portal hypertension. Caused by reduced hepatic clearance of gut-deriving neurotoxins, hepatic encephalopathy is associated with a range of signs and symptoms—from subtle personality changes to coma, with flapping tremor as a frequent initial finding. Acid-base and electrolyte disturbances, constipation, infections, gastrointestinal bleeding, and sedatives can precipitate encephalopathy. Hepatic encephalopathy is a diagnosis of exclusion, however, requiring the exclusion of all other etiologies of altered mental status.

Treatment consists of identifying and correcting the precipitating factors, and includes electrolyte correction, colon cleansing, and acidification with lactulose. Dietary protein restriction is no longer advocated, because it may facilitate malnutrition and complications. Oral rifaximine is useful and well tolerated for suppression of intestinal bacterial flora. Venous infusion of branched-chain amino acids or flumazenil may be effective in case of coma.

Fever and sepsis. Infection is a high-risk factor for mortality in patients with cirrhosis, as it can lead to renal and liver failure, variceal bleeding, and hepatic encephalopathy. However, individuals with cirrhosis often do not develop the typical signs and symptoms of infection; leukocytosis may be absent because of severe leukopenia, for instance, and patients may be afebrile.

Thus, the general appearance of systemic illness is an indication for antibiotics, with quinolones and cephalosporins as first-line agents. Infections most commonly involve the urinary tract (25%-55%) or the respiratory tract (20%), or are related to SBP (10%-30%).³³ Hospitalization is suggested in case of poor general health status or the appearance of organ dysfunction.

When medical therapy and other interventions fail to control complications, transplantation is the only alternative. Primary care physicians can play a role here, too, in referring potential candidates for liver transplants to specialists for further consideration.

CASE 1: Resolution

As we’ve already seen, John M.’s ultrasound revealed an enlarged liver. The results led to a probable diagnosis of an advanced form of NASH. Other lab tests indicated that he had poorly controlled diabetes, high triglyceride levels, and—for the first time—a low platelet count. His physician stressed the importance of following a low-calorie, low-carbohydrate diet and exercising regularly, prescribed insulin, and referred the patient to a hepatologist for further noninvasive evaluation of fibrosis and to determine whether liver biopsy was needed.

CASE 2: Resolution

Blood tests revealed that Anna B. had a low platelet count (64,000/mm³), elevated liver enzymes (AST 2× upper limit of normal [ULN], ALT 1.5× ULN, GGT 2.5× ULN), and high gamma-globulins (33.6%) with no monoclonal bands. Ultrasound revealed an enlarged liver with diffuse echostructural dyshomogeneity, portal vein dilatation, and moderate ascites. She also tested positive for HCV and had an HCV-RNA reading of 15×10⁶ IU/mL. No other cause of chronic liver disease emerged. Ms. B.’s physician told her that she had an osteoporotic vertebral fracture—a frequent comorbidity in patients with liver cirrhosis—and decompensated liver cirrhosis from an old HCV infection. He added that her abdomen was distended because of fluid retention. The physician recommended bed rest, prescribed paracetamol (1 g tid) and spironolactone (100 mg/d), and referred the patient to an orthopedist for treatment of the fracture and to a hepatologist to be evaluated for transplantation.

CORRESPONDENCE
Ignazio Grattagliano, MD, Department of Internal Medicine, University Medical School of Bari, P.zza G. Cesare, 11 – 70124, Bari, Italy; [email protected]