Cleveland Clinic Journal of Medicine

We must work together to save health care in our country

To the Editor: Dr. Lansdale’s comments sadly illustrate all that is wrong with our health care system.1 Desperately ill patients are hospitalized for as few days as possible in order to receive substandard care from agency nurses. Physicians have become assembly-line workers who must order large batteries of tests and procedures because they don’t have the time to sit down, talk to, or examine their patients. This is the type of care that medical students, interns, and residents are learning to practice. Sadly, this is the type of care that patients now expect: an MRI provides better reassurance than a physician’s competent assessment. Business, not physicians, dictates how medicine is practiced.

Internists who care about quality, like Dr. Lansdale, are leaving the profession in droves. But rather than passively leave, they should become leaders in an effort to reclaim health care. If internists worked together, they might be able to enact major changes rather than passively watch as the ship sinks under them. There have been calls to do something.²

Some physicians are taking matters into their own hands by opting out of the system altogether; they no longer accept any type of insurance. While extreme, if done en masse this option could send a powerful message to policy makers and insurers that physicians will be pawns no longer. If physicians do decide to do this, they should make every effort to keep fees, tests, and procedures to a minimum in order to reduce costs.

The United States stands head and shoulders above all other industrialized countries in per-capita spending on health care.³ This level of spending is not sustainable, especially in a nation beset by worsening financial conditions. ⁴ The United States desperately needs its physicians to be leaders in addressing our health care woes. We must work together to save health care in our country: quitting should not be an option.

We must work together to save health care in our country

To the Editor: Dr. Lansdale’s comments sadly illustrate all that is wrong with our health care system.1 Desperately ill patients are hospitalized for as few days as possible in order to receive substandard care from agency nurses. Physicians have become assembly-line workers who must order large batteries of tests and procedures because they don’t have the time to sit down, talk to, or examine their patients. This is the type of care that medical students, interns, and residents are learning to practice. Sadly, this is the type of care that patients now expect: an MRI provides better reassurance than a physician’s competent assessment. Business, not physicians, dictates how medicine is practiced.

Internists who care about quality, like Dr. Lansdale, are leaving the profession in droves. But rather than passively leave, they should become leaders in an effort to reclaim health care. If internists worked together, they might be able to enact major changes rather than passively watch as the ship sinks under them. There have been calls to do something.²

Some physicians are taking matters into their own hands by opting out of the system altogether; they no longer accept any type of insurance. While extreme, if done en masse this option could send a powerful message to policy makers and insurers that physicians will be pawns no longer. If physicians do decide to do this, they should make every effort to keep fees, tests, and procedures to a minimum in order to reduce costs.

The United States stands head and shoulders above all other industrialized countries in per-capita spending on health care.³ This level of spending is not sustainable, especially in a nation beset by worsening financial conditions. ⁴ The United States desperately needs its physicians to be leaders in addressing our health care woes. We must work together to save health care in our country: quitting should not be an option.

We must work together to save health care in our country

To the Editor: Dr. Lansdale’s comments sadly illustrate all that is wrong with our health care system.1 Desperately ill patients are hospitalized for as few days as possible in order to receive substandard care from agency nurses. Physicians have become assembly-line workers who must order large batteries of tests and procedures because they don’t have the time to sit down, talk to, or examine their patients. This is the type of care that medical students, interns, and residents are learning to practice. Sadly, this is the type of care that patients now expect: an MRI provides better reassurance than a physician’s competent assessment. Business, not physicians, dictates how medicine is practiced.

Internists who care about quality, like Dr. Lansdale, are leaving the profession in droves. But rather than passively leave, they should become leaders in an effort to reclaim health care. If internists worked together, they might be able to enact major changes rather than passively watch as the ship sinks under them. There have been calls to do something.²

Some physicians are taking matters into their own hands by opting out of the system altogether; they no longer accept any type of insurance. While extreme, if done en masse this option could send a powerful message to policy makers and insurers that physicians will be pawns no longer. If physicians do decide to do this, they should make every effort to keep fees, tests, and procedures to a minimum in order to reduce costs.

The United States stands head and shoulders above all other industrialized countries in per-capita spending on health care.³ This level of spending is not sustainable, especially in a nation beset by worsening financial conditions. ⁴ The United States desperately needs its physicians to be leaders in addressing our health care woes. We must work together to save health care in our country: quitting should not be an option.

General internal medicine is extinct

To the Editor: General internal medicine has become extinct. Its practitioners have been pushed out of their leadership roles, have been pushed from clinical practice due to red tape and impediments of frustration, and have been marginalized by specialties and subspecialties, our so-called brethren. Only through revolutionary metamorphosis such as clinical homes or other unique systems by which primary care is delivered at high-quality levels such as MDVIP can general internal medicine survive.

Hospitalists are not general internists. Family practitioners are not general internists. Nurse practitioners are not general internists. And certainly none of the subspecialists are general internists. We must forge a new identity and role in the health care system because our previous identity has been destroyed.

Without our unique ability to temper high tech with clinical judgment, our system fails on quality and cost.

The article by Dr. Lansdale was more eloquent than I could express, but I believe the words written above are more accurate and to the point.

General internal medicine is extinct

To the Editor: General internal medicine has become extinct. Its practitioners have been pushed out of their leadership roles, have been pushed from clinical practice due to red tape and impediments of frustration, and have been marginalized by specialties and subspecialties, our so-called brethren. Only through revolutionary metamorphosis such as clinical homes or other unique systems by which primary care is delivered at high-quality levels such as MDVIP can general internal medicine survive.

Hospitalists are not general internists. Family practitioners are not general internists. Nurse practitioners are not general internists. And certainly none of the subspecialists are general internists. We must forge a new identity and role in the health care system because our previous identity has been destroyed.

Without our unique ability to temper high tech with clinical judgment, our system fails on quality and cost.

The article by Dr. Lansdale was more eloquent than I could express, but I believe the words written above are more accurate and to the point.

General internal medicine is extinct

To the Editor: General internal medicine has become extinct. Its practitioners have been pushed out of their leadership roles, have been pushed from clinical practice due to red tape and impediments of frustration, and have been marginalized by specialties and subspecialties, our so-called brethren. Only through revolutionary metamorphosis such as clinical homes or other unique systems by which primary care is delivered at high-quality levels such as MDVIP can general internal medicine survive.

Hospitalists are not general internists. Family practitioners are not general internists. Nurse practitioners are not general internists. And certainly none of the subspecialists are general internists. We must forge a new identity and role in the health care system because our previous identity has been destroyed.

Without our unique ability to temper high tech with clinical judgment, our system fails on quality and cost.

The article by Dr. Lansdale was more eloquent than I could express, but I believe the words written above are more accurate and to the point.

The name of the devil

To the Editor: Dr. Lansdale’s commentary¹ reveals the price we pay when we focus on one important goal to the exclusion of others. He illustrates that reductions in health care cost were paid for with reduced health care quality, and a loss of camaraderie and job satisfaction. Missing from his commentary, however, is any acknowledgment that reducing the cost of health care is an important and worthy goal—and his wistfulness for the old days suggests his willingness to trade increased cost for better quality and job satisfaction.

Unfortunately, the biggest problem in this conflict is not that Dr. Lansdale and his former administrators disagree on whether cost is more important than quality and job satisfaction, but that both mistakenly agree that each must be traded off for the others. This hidden agreement is the chief mischief in health care today.

For example, much of the effort to improve health care quality has been oblivious to costs and employee satisfaction. Efforts to reduce errors have led to additional process steps, new checkers and coordinators, and expensive IT systems. These have increased costs, while frequently reducing job satisfaction and in some cases even failing to improve quality. Computerized order entry systems have been shown, for example, to disrupt physician-nurse communication patterns that were one of the major ways the old system prevented errors, and were a source of job satisfaction to both parties.² In some cases, patient mortality rates increased after they were implemented.³ Another new system plans to police handwashing by putting video cameras in patient rooms.⁴ Costly, yes, and the consequences for clinical-staff jobsatisfaction are predictable.

The core problem is focusing on one-dimensional outcomes, instead of insisting that cost, quality, and job satisfaction are all vital, and that we will not truly achieve any of them until we achieve all three. Poor quality is wasteful, and waste costs money. Employees are most satisfied where they are productively employed providing high-quality services, and productive employees cost less in the long run than unproductive ones.

How can we have high-quality, low-cost, high-satisfaction health care? By fundamentally redesigning the way care is delivered, radically simplifying care processes to focus on the limited number of elements that produce health outcomes for the patient. Toyota has demonstrated that it is possible for a manufacturer to be high-quality, low-cost, and high-satisfaction by using an analogous approach, and the many manufacturers that have followed its example testify that Toyota was no fluke.⁵ Early efforts are underway to apply so-called lean approaches in health care settings, but most are pruning the branches of waste instead of pulling it out by the roots, for example, redesigning labs and supply closets far from the patient’s side.^6,7

A former boss was fond of quoting economist Kenneth Boulding: “The name of the devil is suboptimization!” Let’s begin by agreeing that cost, quality, and job satisfaction are all important, and commit to working to achieve all three together.

The name of the devil

To the Editor: Dr. Lansdale’s commentary¹ reveals the price we pay when we focus on one important goal to the exclusion of others. He illustrates that reductions in health care cost were paid for with reduced health care quality, and a loss of camaraderie and job satisfaction. Missing from his commentary, however, is any acknowledgment that reducing the cost of health care is an important and worthy goal—and his wistfulness for the old days suggests his willingness to trade increased cost for better quality and job satisfaction.

Unfortunately, the biggest problem in this conflict is not that Dr. Lansdale and his former administrators disagree on whether cost is more important than quality and job satisfaction, but that both mistakenly agree that each must be traded off for the others. This hidden agreement is the chief mischief in health care today.

For example, much of the effort to improve health care quality has been oblivious to costs and employee satisfaction. Efforts to reduce errors have led to additional process steps, new checkers and coordinators, and expensive IT systems. These have increased costs, while frequently reducing job satisfaction and in some cases even failing to improve quality. Computerized order entry systems have been shown, for example, to disrupt physician-nurse communication patterns that were one of the major ways the old system prevented errors, and were a source of job satisfaction to both parties.² In some cases, patient mortality rates increased after they were implemented.³ Another new system plans to police handwashing by putting video cameras in patient rooms.⁴ Costly, yes, and the consequences for clinical-staff jobsatisfaction are predictable.

The core problem is focusing on one-dimensional outcomes, instead of insisting that cost, quality, and job satisfaction are all vital, and that we will not truly achieve any of them until we achieve all three. Poor quality is wasteful, and waste costs money. Employees are most satisfied where they are productively employed providing high-quality services, and productive employees cost less in the long run than unproductive ones.

How can we have high-quality, low-cost, high-satisfaction health care? By fundamentally redesigning the way care is delivered, radically simplifying care processes to focus on the limited number of elements that produce health outcomes for the patient. Toyota has demonstrated that it is possible for a manufacturer to be high-quality, low-cost, and high-satisfaction by using an analogous approach, and the many manufacturers that have followed its example testify that Toyota was no fluke.⁵ Early efforts are underway to apply so-called lean approaches in health care settings, but most are pruning the branches of waste instead of pulling it out by the roots, for example, redesigning labs and supply closets far from the patient’s side.^6,7

A former boss was fond of quoting economist Kenneth Boulding: “The name of the devil is suboptimization!” Let’s begin by agreeing that cost, quality, and job satisfaction are all important, and commit to working to achieve all three together.

The name of the devil

To the Editor: Dr. Lansdale’s commentary¹ reveals the price we pay when we focus on one important goal to the exclusion of others. He illustrates that reductions in health care cost were paid for with reduced health care quality, and a loss of camaraderie and job satisfaction. Missing from his commentary, however, is any acknowledgment that reducing the cost of health care is an important and worthy goal—and his wistfulness for the old days suggests his willingness to trade increased cost for better quality and job satisfaction.

Unfortunately, the biggest problem in this conflict is not that Dr. Lansdale and his former administrators disagree on whether cost is more important than quality and job satisfaction, but that both mistakenly agree that each must be traded off for the others. This hidden agreement is the chief mischief in health care today.

For example, much of the effort to improve health care quality has been oblivious to costs and employee satisfaction. Efforts to reduce errors have led to additional process steps, new checkers and coordinators, and expensive IT systems. These have increased costs, while frequently reducing job satisfaction and in some cases even failing to improve quality. Computerized order entry systems have been shown, for example, to disrupt physician-nurse communication patterns that were one of the major ways the old system prevented errors, and were a source of job satisfaction to both parties.² In some cases, patient mortality rates increased after they were implemented.³ Another new system plans to police handwashing by putting video cameras in patient rooms.⁴ Costly, yes, and the consequences for clinical-staff jobsatisfaction are predictable.

The core problem is focusing on one-dimensional outcomes, instead of insisting that cost, quality, and job satisfaction are all vital, and that we will not truly achieve any of them until we achieve all three. Poor quality is wasteful, and waste costs money. Employees are most satisfied where they are productively employed providing high-quality services, and productive employees cost less in the long run than unproductive ones.

How can we have high-quality, low-cost, high-satisfaction health care? By fundamentally redesigning the way care is delivered, radically simplifying care processes to focus on the limited number of elements that produce health outcomes for the patient. Toyota has demonstrated that it is possible for a manufacturer to be high-quality, low-cost, and high-satisfaction by using an analogous approach, and the many manufacturers that have followed its example testify that Toyota was no fluke.⁵ Early efforts are underway to apply so-called lean approaches in health care settings, but most are pruning the branches of waste instead of pulling it out by the roots, for example, redesigning labs and supply closets far from the patient’s side.^6,7

A former boss was fond of quoting economist Kenneth Boulding: “The name of the devil is suboptimization!” Let’s begin by agreeing that cost, quality, and job satisfaction are all important, and commit to working to achieve all three together.

Two errors appeared in: Monti J, Isaacson JH, Lashner B. A case of refractory diarrhea. Cleve Clin J Med 2008; 75:677–680. On page 679, the proprietary name of lansoprazole was incorrectly given as Prilosec and the proprietary name of omeprazole was incorrectly given as Prevacid. The proprietary names were reversed. The correct listing should have been: Lansoprazole (Prevacid) and omeprazole (Prilosec).

Two errors appeared in: Monti J, Isaacson JH, Lashner B. A case of refractory diarrhea. Cleve Clin J Med 2008; 75:677–680. On page 679, the proprietary name of lansoprazole was incorrectly given as Prilosec and the proprietary name of omeprazole was incorrectly given as Prevacid. The proprietary names were reversed. The correct listing should have been: Lansoprazole (Prevacid) and omeprazole (Prilosec).

Two errors appeared in: Monti J, Isaacson JH, Lashner B. A case of refractory diarrhea. Cleve Clin J Med 2008; 75:677–680. On page 679, the proprietary name of lansoprazole was incorrectly given as Prilosec and the proprietary name of omeprazole was incorrectly given as Prevacid. The proprietary names were reversed. The correct listing should have been: Lansoprazole (Prevacid) and omeprazole (Prilosec).

Our knowledge about hepatitis B and related diseases has dramatically increased since the discovery of the causative virus, HBV, in 1963. Despite effective vaccination, hepatitis B still constitutes a major public health problem.

In two parts, this comprehensive review will highlight a practical clinical approach to HBV infection. In this first part, we discuss the epidemiology, natural history, and diagnosis of HBV infection. In the second part, to be published in the next issue of this journal, we will review the general principles of its management, its management in patients on immunosuppressant therapy and in pregnant women, and HBV vaccination.

COMMON IN ASIA, LESS SO IN AMERICA

More than 2 billion people—one-third of the world’s population—alive today have been infected with HBV at some time in their life, and of these, about 350 million remain infected.¹ Every year, 1 million people die of HBV-related cirrhosis or hepatocellular carcinoma, which means that HBV takes a life every 30 seconds.²

World Health Organization. Introduction of hepatitis B vaccine into childhood immunization services. Geneva: WHO; 2001. WHO/V AND B/01.31.

The incidence of acute hepatitis B in the United States has declined from 8.5 per 100,000 population in 1990 to 2.1 per 100,000 population in 2004, with the greatest declines (94%) in children and adolescents, coincident with an increase in hepatitis B vaccination in these age groups.⁵ Despite these advances, HBV still causes a considerable number of cases of cirrhosis, cancer, and death—about 5,000 deaths each year in the United States.

HBV HAS FOUR GENES, EIGHT GENOTYPES

HBV is a DNA virus of the Hepadnaviridae family. Its genome is double-stranded with four genes, each one encoding a specific structural protein or proteins^6,7:

• S gene, for the viral envelope (surface antigen)
• C gene, for both the nucleocapsid (core) antigen and the pre-core (e) antigen
• X gene, for two regulatory proteins required for HBV replication
• P gene, for DNA polymerase.

Eight genotypes of HBV (labeled A though H) have been identified.13,14 All eight have been found in the United States, but genotype A accounts for 35% of cases, genotype B for 22%, and genotype C for 31%.¹⁵

The clinical significance of HBV genotypes is not as clear as that of hepatitis C virus genotypes. Although recent data have suggested that different HBV genotypes may be associated with different rates of progression of liver disease and different rates of response to interferon therapy,¹³ these data were not enough to recommend routine testing for HBV genotypes in clinical practice.¹⁶

In HBV infection, the virus itself does not injure liver cells. Rather, the damage of hepatitis is immune-mediated and begins to appear as the host’s immune system attempts to clear the virus.

MARKERS OF HBV INFECTION

HBV surface antigen and HBV DNA are often the first detectable markers of acute infection, appearing before the onset of symptoms or before elevation of alanine aminotransferase (ALT) occurs. By definition, an HBV infection is chronic if surface antigen persists longer than 6 months.

HBV e antigen, derived from pre-core protein, is considered a marker of HBV replication and infectivity. In chronic infection, e antigen can persist for years or decades.

HBV core antigen cannot be detected in the serum, but antibodies against it can, first immunoglobulin M (IgM) and later immunoglobulin G (IgG).

TRANSMISSION: VERTICAL OR HORIZONTAL

Because HBV replicates profusely and produces high titers in the blood (108 to 1,010 virions/ mL), any parenteral or mucosal exposure to infected blood poses a high risk of HBV acquisition. The risk of HBV transmission from a single needlestick is 1% to 6% if the blood is positive for HBV surface antigen but negative for HBV e antigen, and 22% to 40% if positive for both antigens.^17–19 Saliva, nasopharyngeal fluid, breast milk, semen, urine, and cervical secretions can also harbor HBV.²⁰

Worldwide, perinatal (vertical) transmission is the predominant mode of HBV transmission, whereas intravenous drug abuse and unprotected sexual intercourse are the main routes of infection in areas of low prevalence, such as the United States. In sub-Saharan Africa, Alaska, and Mediterranean countries, transmission of HBV usually occurs horizontally during childhood, presumably via contact with nonintact skin.^21–24 Saliva has also been thought to be the route of HBV transmission in sporadic cases through human bites.²⁵

People at risk of HBV infection include:

• Parenteral drug users
• People with multiple sexual partners
• Household contacts and sexual partners of people who are positive for HBV surface antigen
• Infants born to HBV-infected mothers
• Patients and staff in custodial institutions for the developmentally disabled
• Recipients of certain plasma-derived products (including patients with congenital coagulation defects)
• Hemodialysis patients
• Health and public-safety workers who have contact with blood
• People born in areas where HBV is endemic, and their children.

These people—as well as all pregnant women, patients infected with hepatitis C virus or human immunodeficiency virus, and patients with chronically elevated ALT or aspartate aminotransferase (AST) levels—should be screened for HBV infection with serologic markers.

CLINICAL MANIFESTATIONS VARY

HBV infection, acute or chronic, has variable manifestations. During the acute stage, HBV infection can manifest as anicteric (subclinical) hepatitis, icteric hepatitis, or, rarely, acute fulminant hepatitis. Chronic HBV infection can be asymptomatic (the HBV surface antigen carrier state), or it can be manifested by symptoms and signs of cirrhosis or hepatocellular carcinoma or both. Extrahepatic manifestations, including serum sickness, polyarteritis nodosa, essential mixed cryoglobulinemia, membranous glomerulonephritis, and aplastic anemia, have been reported in patients with HBV infection.²⁶

Acute hepatitis B

The incubation period of HBV ranges from 2 weeks to 4 months. Initially, patients complain of fatigue, malaise, anorexia, right upper quad-rant discomfort, or flu-like symptoms (coryza, photophobia, headache, and myalgia); then jaundice becomes apparent, usually within 10 days of the onset of symptoms. Low-grade fever, jaundice, and mildly tender hepatomegaly are the most common signs. Generalized lymphadenopathy is not a feature of acute HBV infection. If the patient also has hepatitis D virus infection or underlying liver disease (eg, alcoholic liver disease), then acute HBV infection may be more severe.

In the acute phase, ALT and AST levels rise, sometimes to values above 1,000 IU/L. In icteric hepatitis, bilirubin levels also rise, usually after the ALT level does. Although the peak ALT level reflects the hepatocellular injury, it has no prognostic value. With recovery, ALT levels normalize in 1 to 4 months.

Acute fulminant hepatitis B occurs in 0.1% to 0.5% of patients, and causes about 10% of cases of acute liver failure in the United States.²⁷ Patients typically present with rapidly progressive acute hepatitis characterized by signs of liver failure, such as coagulopathy, encephalopathy, and cerebral edema.

In the so-called window phase, laboratory testing may not reveal HBV surface antigen because of early clearance but shows IgM antibody against the HBV core antigen. HBV DNA may be low or undetected.

Chronic hepatitis B

Chronic hepatitis B is usually diagnosed as a result of a workup for abnormal liver function tests or as a result of screening patients at risk for HBV infection. Many patients with chronic hepatitis B have no symptoms or have nonspecific symptoms such as fatigue or right upper quadrant discomfort.

Acute exacerbations due to HBV e antigen seroreversion (ie, in which e antigen reappears) occasionally occur in patients with chronic hepatitis B. Most of these exacerbations are asymptomatic, but occasionally an acute hepatitis-like clinical picture with detectable IgM antibody against the core antigen occurs, leading to misdiagnosis of acute HBV infection in patients not previously known to have chronic HBV infection.²⁸

In late cases, signs of cirrhosis such as jaundice, ascites, splenomegaly, pedal edema, encephalopathy, or variceal bleeding can be present.

Hepatocellular carcinoma should be suspected in cirrhotic patients with new-onset right upper quadrant pain, rapidly developing ascites, a palpable liver mass, or hepatic encephalopathy. Other nonspecific features of hepatocellular carcinoma include watery diarrhea, hypoglycemia, and certain cutaneous manifestations such as acanthosis nigricans and the Leser-Trelat sign (multiple pruritic seborrheic keratoses of sudden onset).

In chronic hepatitis B, liver enzyme levels can be normal, even in patients with wellcompensated cirrhosis. ALT levels may range from normal to five times higher than normal. Thrombocytopenia, hypoalbuminemia, direct hyperbilirubinemia, and prolonged prothrombin time suggest cirrhosis.

Findings of chronic hepatitis B on liver biopsy range from minimal inflammation to cirrhosis. The most characteristic histologic feature of chronic HBV infection is the “ground-glass hepatocyte,” which is due to intracellular accumulation of HBV surface antigen. ²⁹

FEW ADULTS (BUT MANY CHILDREN) REMAIN CHRONICALLY INFECTED

HBV surface antigen can be detected in the blood approximately 2 to 4 weeks after inoculation. Simultaneously, HBV DNA, usually in very high levels, is also detectable in the blood. However, in the rare cases of acute fulminant hepatitis, HBV DNA levels can be low or undetectable at the time of presentation because the immune system mounts a robust response with extensive damage to HBVinfected hepatocytes.

The rate of spontaneous recovery from acute HBV infection varies, depending on the patient’s age at the time of HBV acquisition and the patient’s immune status. Fewer than 5% of immunocompetent adults infected with HBV remain chronically infected, defined as being positive for HBV surface antigen for more than 6 months. On the other hand, 80% to 90% of infected infants and about 20% to 50% of children 1 to 5 years old at the time of acute infection remain chronically infected.²¹

The immune tolerance phase, the initial phase of chronic HBV infection, is seen almost exclusively in those who acquired HBV infection vertically or during early childhood. Although patients have high HBV DNA levels, they do not have significant liver disease. This discrepancy is thought to be related to the immune tolerance to HBV; however, the exact mechanism of that tolerance is unclear.³¹

Only 15% of those with immune tolerance have spontaneous HBV e antigen seroconversion (ie, loss of e antigen and appearance of anti-e antibody) within 20 years after infection. ³²

The immune clearance phase (HBV e antigen-positive chronic hepatitis) appears about 20 to 30 years after the onset of the immune tolerance phase in patients who acquire HBV early in life. It is also often seen in patients with infections acquired late in childhood or in adulthood.

This phase marks the start of an immunemediated process aimed at clearing the viral infection, but it also leads to concomitant hepatocellular injury. Spontaneous clearance of the e antigen increases in this phase to an annual rate of 10% to 20%.^32,33 The strongest predictors of spontaneous e antigen seroconversion are old age, an elevated ALT level, and an acute exacerbation.²⁶

Although ALT levels are elevated and there is evidence on liver biopsy of chronic active hepatitis, this phase is usually asymptomatic. Rarely, however, it presents with an acute flare of hepatitis, sometimes accompanied by IgM antibodies against the HBV core antigen (in low titer), leading to an incorrect diagnosis of acute HBV infection.

Depending on the duration of the chronic hepatitis and the frequency and severity of flares, about 12% to 20% of patients in the immune-clearance phase develop serious liver disease within 5 years.³¹

The inactive carrier phase following HBV e antigen seroconversion is characterized by undetectable or low HBV DNA levels (< 1,000 copies/mL), normal ALT levels, and minimal or no necroinflammation on liver biopsy. 30 Such patients should be followed with serial testing, as 4% to 20% of them spontaneously revert to being positive for e antigen at least once.16 On the other hand, only 0.5% to 2% of surface antigen carriers in western countries clear themselves of surface antigen yearly, but up to half of those who clear the surface antigen have low-level HBV viremia. ³⁴

The reactivation phase (HBV e antigennegative chronic hepatitis) is seen in some HBV-infected patients, especially those from Asia and southern Europe, in whom the virus has a spontaneous pre-core or core mutation that makes infected cells unable to secrete the e antigen. Although these patients have no e antigen in their blood, they do have intermittent or persistent elevation of ALT, elevated HBV DNA, and histopathologic findings of chronic hepatitis. Compared with those in the immune clearance phase, patients in the reactivation phase tend to be older and to have lower HBV DNA levels but advanced hepatic damage.

Immunity to HBV infection is characterized by loss of HBV surface antigen, DNA, e antigen, and anti-core antigen IgM with development of anti-surface antigen antibody and anti-core antigen IgG (total anti-core antigen antibody). The presence of anti-surface antigen antibody and anti-core antigen IgG together differentiates natural immunity through resolved infection from that which is acquired through vaccination, which is denoted by isolated anti-surface antigen antibody.

Cirrhosis, liver failure, cancer

Cirrhosis, hepatic decompensation, and hepatocellular carcinoma are the major long-term complications of HBV infection. In untreated patients, the annual rate of progression to cirrhosis has been estimated to be 2% to 6% in patients with HBV e antigen-positive chronic hepatitis and 8% to 9% in those with e antigen- negative chronic hepatitis.³⁰

The likely explanation for these surprising cirrhosis rates is that e antigen-negative chronic hepatitis usually represents a late stage of the disease, and patients in this phase are usually older and have more advanced liver disease.

Subsequently, the annual rate of progression from compensated cirrhosis to hepatic decompensation has been estimated to be about 5%.³⁵

Across all the stages described above, a high serum HBV DNA level has been shown to be a strong predictor of progression to cirrhosis in patients with chronic HBV infection. In a population-based prospective cohort study of 3,582 untreated HBV-infected patients in Taiwan, Iloeje et al36 found that, compared with patients with serum HBV DNA levels lower than 104 copies/mL, those with levels of 104 or higher had an adjusted relative risk of cirrhosis of 2.5. The relative risk rose to 5.9 with HBV DNA levels of 105 or higher, and 9.8 with levels of 106 copies/mL or higher. More studies in different patient populations are needed for confirmation.

The most important risk factor for hepatocellular carcinoma in HBV-infected patients is cirrhosis, but this cancer can also develop in noncirrhotic livers.37 The annual rate of hepatocelluar carcinoma has been estimated to be higher (2.5%–3%) in patients with cirrhosis than in noncirrhotic carriers (0.5%–1%).^30,35–38 Risk factors for cirrhosis and hepatocellular carcinoma are summarized in Table 4.^16,30

Our knowledge about hepatitis B and related diseases has dramatically increased since the discovery of the causative virus, HBV, in 1963. Despite effective vaccination, hepatitis B still constitutes a major public health problem.

In two parts, this comprehensive review will highlight a practical clinical approach to HBV infection. In this first part, we discuss the epidemiology, natural history, and diagnosis of HBV infection. In the second part, to be published in the next issue of this journal, we will review the general principles of its management, its management in patients on immunosuppressant therapy and in pregnant women, and HBV vaccination.

COMMON IN ASIA, LESS SO IN AMERICA

More than 2 billion people—one-third of the world’s population—alive today have been infected with HBV at some time in their life, and of these, about 350 million remain infected.¹ Every year, 1 million people die of HBV-related cirrhosis or hepatocellular carcinoma, which means that HBV takes a life every 30 seconds.²

World Health Organization. Introduction of hepatitis B vaccine into childhood immunization services. Geneva: WHO; 2001. WHO/V AND B/01.31.

The incidence of acute hepatitis B in the United States has declined from 8.5 per 100,000 population in 1990 to 2.1 per 100,000 population in 2004, with the greatest declines (94%) in children and adolescents, coincident with an increase in hepatitis B vaccination in these age groups.⁵ Despite these advances, HBV still causes a considerable number of cases of cirrhosis, cancer, and death—about 5,000 deaths each year in the United States.

HBV HAS FOUR GENES, EIGHT GENOTYPES

HBV is a DNA virus of the Hepadnaviridae family. Its genome is double-stranded with four genes, each one encoding a specific structural protein or proteins^6,7:

• S gene, for the viral envelope (surface antigen)
• C gene, for both the nucleocapsid (core) antigen and the pre-core (e) antigen
• X gene, for two regulatory proteins required for HBV replication
• P gene, for DNA polymerase.

Eight genotypes of HBV (labeled A though H) have been identified.13,14 All eight have been found in the United States, but genotype A accounts for 35% of cases, genotype B for 22%, and genotype C for 31%.¹⁵

The clinical significance of HBV genotypes is not as clear as that of hepatitis C virus genotypes. Although recent data have suggested that different HBV genotypes may be associated with different rates of progression of liver disease and different rates of response to interferon therapy,¹³ these data were not enough to recommend routine testing for HBV genotypes in clinical practice.¹⁶

In HBV infection, the virus itself does not injure liver cells. Rather, the damage of hepatitis is immune-mediated and begins to appear as the host’s immune system attempts to clear the virus.

MARKERS OF HBV INFECTION

HBV surface antigen and HBV DNA are often the first detectable markers of acute infection, appearing before the onset of symptoms or before elevation of alanine aminotransferase (ALT) occurs. By definition, an HBV infection is chronic if surface antigen persists longer than 6 months.

HBV e antigen, derived from pre-core protein, is considered a marker of HBV replication and infectivity. In chronic infection, e antigen can persist for years or decades.

HBV core antigen cannot be detected in the serum, but antibodies against it can, first immunoglobulin M (IgM) and later immunoglobulin G (IgG).

TRANSMISSION: VERTICAL OR HORIZONTAL

Because HBV replicates profusely and produces high titers in the blood (108 to 1,010 virions/ mL), any parenteral or mucosal exposure to infected blood poses a high risk of HBV acquisition. The risk of HBV transmission from a single needlestick is 1% to 6% if the blood is positive for HBV surface antigen but negative for HBV e antigen, and 22% to 40% if positive for both antigens.^17–19 Saliva, nasopharyngeal fluid, breast milk, semen, urine, and cervical secretions can also harbor HBV.²⁰

Worldwide, perinatal (vertical) transmission is the predominant mode of HBV transmission, whereas intravenous drug abuse and unprotected sexual intercourse are the main routes of infection in areas of low prevalence, such as the United States. In sub-Saharan Africa, Alaska, and Mediterranean countries, transmission of HBV usually occurs horizontally during childhood, presumably via contact with nonintact skin.^21–24 Saliva has also been thought to be the route of HBV transmission in sporadic cases through human bites.²⁵

People at risk of HBV infection include:

• Parenteral drug users
• People with multiple sexual partners
• Household contacts and sexual partners of people who are positive for HBV surface antigen
• Infants born to HBV-infected mothers
• Patients and staff in custodial institutions for the developmentally disabled
• Recipients of certain plasma-derived products (including patients with congenital coagulation defects)
• Hemodialysis patients
• Health and public-safety workers who have contact with blood
• People born in areas where HBV is endemic, and their children.

These people—as well as all pregnant women, patients infected with hepatitis C virus or human immunodeficiency virus, and patients with chronically elevated ALT or aspartate aminotransferase (AST) levels—should be screened for HBV infection with serologic markers.

CLINICAL MANIFESTATIONS VARY

HBV infection, acute or chronic, has variable manifestations. During the acute stage, HBV infection can manifest as anicteric (subclinical) hepatitis, icteric hepatitis, or, rarely, acute fulminant hepatitis. Chronic HBV infection can be asymptomatic (the HBV surface antigen carrier state), or it can be manifested by symptoms and signs of cirrhosis or hepatocellular carcinoma or both. Extrahepatic manifestations, including serum sickness, polyarteritis nodosa, essential mixed cryoglobulinemia, membranous glomerulonephritis, and aplastic anemia, have been reported in patients with HBV infection.²⁶

Acute hepatitis B

The incubation period of HBV ranges from 2 weeks to 4 months. Initially, patients complain of fatigue, malaise, anorexia, right upper quad-rant discomfort, or flu-like symptoms (coryza, photophobia, headache, and myalgia); then jaundice becomes apparent, usually within 10 days of the onset of symptoms. Low-grade fever, jaundice, and mildly tender hepatomegaly are the most common signs. Generalized lymphadenopathy is not a feature of acute HBV infection. If the patient also has hepatitis D virus infection or underlying liver disease (eg, alcoholic liver disease), then acute HBV infection may be more severe.

In the acute phase, ALT and AST levels rise, sometimes to values above 1,000 IU/L. In icteric hepatitis, bilirubin levels also rise, usually after the ALT level does. Although the peak ALT level reflects the hepatocellular injury, it has no prognostic value. With recovery, ALT levels normalize in 1 to 4 months.

Acute fulminant hepatitis B occurs in 0.1% to 0.5% of patients, and causes about 10% of cases of acute liver failure in the United States.²⁷ Patients typically present with rapidly progressive acute hepatitis characterized by signs of liver failure, such as coagulopathy, encephalopathy, and cerebral edema.

In the so-called window phase, laboratory testing may not reveal HBV surface antigen because of early clearance but shows IgM antibody against the HBV core antigen. HBV DNA may be low or undetected.

Chronic hepatitis B

Chronic hepatitis B is usually diagnosed as a result of a workup for abnormal liver function tests or as a result of screening patients at risk for HBV infection. Many patients with chronic hepatitis B have no symptoms or have nonspecific symptoms such as fatigue or right upper quadrant discomfort.

Acute exacerbations due to HBV e antigen seroreversion (ie, in which e antigen reappears) occasionally occur in patients with chronic hepatitis B. Most of these exacerbations are asymptomatic, but occasionally an acute hepatitis-like clinical picture with detectable IgM antibody against the core antigen occurs, leading to misdiagnosis of acute HBV infection in patients not previously known to have chronic HBV infection.²⁸

In late cases, signs of cirrhosis such as jaundice, ascites, splenomegaly, pedal edema, encephalopathy, or variceal bleeding can be present.

Hepatocellular carcinoma should be suspected in cirrhotic patients with new-onset right upper quadrant pain, rapidly developing ascites, a palpable liver mass, or hepatic encephalopathy. Other nonspecific features of hepatocellular carcinoma include watery diarrhea, hypoglycemia, and certain cutaneous manifestations such as acanthosis nigricans and the Leser-Trelat sign (multiple pruritic seborrheic keratoses of sudden onset).

In chronic hepatitis B, liver enzyme levels can be normal, even in patients with wellcompensated cirrhosis. ALT levels may range from normal to five times higher than normal. Thrombocytopenia, hypoalbuminemia, direct hyperbilirubinemia, and prolonged prothrombin time suggest cirrhosis.

Findings of chronic hepatitis B on liver biopsy range from minimal inflammation to cirrhosis. The most characteristic histologic feature of chronic HBV infection is the “ground-glass hepatocyte,” which is due to intracellular accumulation of HBV surface antigen. ²⁹

FEW ADULTS (BUT MANY CHILDREN) REMAIN CHRONICALLY INFECTED

HBV surface antigen can be detected in the blood approximately 2 to 4 weeks after inoculation. Simultaneously, HBV DNA, usually in very high levels, is also detectable in the blood. However, in the rare cases of acute fulminant hepatitis, HBV DNA levels can be low or undetectable at the time of presentation because the immune system mounts a robust response with extensive damage to HBVinfected hepatocytes.

The rate of spontaneous recovery from acute HBV infection varies, depending on the patient’s age at the time of HBV acquisition and the patient’s immune status. Fewer than 5% of immunocompetent adults infected with HBV remain chronically infected, defined as being positive for HBV surface antigen for more than 6 months. On the other hand, 80% to 90% of infected infants and about 20% to 50% of children 1 to 5 years old at the time of acute infection remain chronically infected.²¹

The immune tolerance phase, the initial phase of chronic HBV infection, is seen almost exclusively in those who acquired HBV infection vertically or during early childhood. Although patients have high HBV DNA levels, they do not have significant liver disease. This discrepancy is thought to be related to the immune tolerance to HBV; however, the exact mechanism of that tolerance is unclear.³¹

Only 15% of those with immune tolerance have spontaneous HBV e antigen seroconversion (ie, loss of e antigen and appearance of anti-e antibody) within 20 years after infection. ³²

The immune clearance phase (HBV e antigen-positive chronic hepatitis) appears about 20 to 30 years after the onset of the immune tolerance phase in patients who acquire HBV early in life. It is also often seen in patients with infections acquired late in childhood or in adulthood.

This phase marks the start of an immunemediated process aimed at clearing the viral infection, but it also leads to concomitant hepatocellular injury. Spontaneous clearance of the e antigen increases in this phase to an annual rate of 10% to 20%.^32,33 The strongest predictors of spontaneous e antigen seroconversion are old age, an elevated ALT level, and an acute exacerbation.²⁶

Although ALT levels are elevated and there is evidence on liver biopsy of chronic active hepatitis, this phase is usually asymptomatic. Rarely, however, it presents with an acute flare of hepatitis, sometimes accompanied by IgM antibodies against the HBV core antigen (in low titer), leading to an incorrect diagnosis of acute HBV infection.

Depending on the duration of the chronic hepatitis and the frequency and severity of flares, about 12% to 20% of patients in the immune-clearance phase develop serious liver disease within 5 years.³¹

The inactive carrier phase following HBV e antigen seroconversion is characterized by undetectable or low HBV DNA levels (< 1,000 copies/mL), normal ALT levels, and minimal or no necroinflammation on liver biopsy. 30 Such patients should be followed with serial testing, as 4% to 20% of them spontaneously revert to being positive for e antigen at least once.16 On the other hand, only 0.5% to 2% of surface antigen carriers in western countries clear themselves of surface antigen yearly, but up to half of those who clear the surface antigen have low-level HBV viremia. ³⁴

The reactivation phase (HBV e antigennegative chronic hepatitis) is seen in some HBV-infected patients, especially those from Asia and southern Europe, in whom the virus has a spontaneous pre-core or core mutation that makes infected cells unable to secrete the e antigen. Although these patients have no e antigen in their blood, they do have intermittent or persistent elevation of ALT, elevated HBV DNA, and histopathologic findings of chronic hepatitis. Compared with those in the immune clearance phase, patients in the reactivation phase tend to be older and to have lower HBV DNA levels but advanced hepatic damage.

Immunity to HBV infection is characterized by loss of HBV surface antigen, DNA, e antigen, and anti-core antigen IgM with development of anti-surface antigen antibody and anti-core antigen IgG (total anti-core antigen antibody). The presence of anti-surface antigen antibody and anti-core antigen IgG together differentiates natural immunity through resolved infection from that which is acquired through vaccination, which is denoted by isolated anti-surface antigen antibody.

Cirrhosis, liver failure, cancer

Cirrhosis, hepatic decompensation, and hepatocellular carcinoma are the major long-term complications of HBV infection. In untreated patients, the annual rate of progression to cirrhosis has been estimated to be 2% to 6% in patients with HBV e antigen-positive chronic hepatitis and 8% to 9% in those with e antigen- negative chronic hepatitis.³⁰

The likely explanation for these surprising cirrhosis rates is that e antigen-negative chronic hepatitis usually represents a late stage of the disease, and patients in this phase are usually older and have more advanced liver disease.

Subsequently, the annual rate of progression from compensated cirrhosis to hepatic decompensation has been estimated to be about 5%.³⁵

Across all the stages described above, a high serum HBV DNA level has been shown to be a strong predictor of progression to cirrhosis in patients with chronic HBV infection. In a population-based prospective cohort study of 3,582 untreated HBV-infected patients in Taiwan, Iloeje et al36 found that, compared with patients with serum HBV DNA levels lower than 104 copies/mL, those with levels of 104 or higher had an adjusted relative risk of cirrhosis of 2.5. The relative risk rose to 5.9 with HBV DNA levels of 105 or higher, and 9.8 with levels of 106 copies/mL or higher. More studies in different patient populations are needed for confirmation.

The most important risk factor for hepatocellular carcinoma in HBV-infected patients is cirrhosis, but this cancer can also develop in noncirrhotic livers.37 The annual rate of hepatocelluar carcinoma has been estimated to be higher (2.5%–3%) in patients with cirrhosis than in noncirrhotic carriers (0.5%–1%).^30,35–38 Risk factors for cirrhosis and hepatocellular carcinoma are summarized in Table 4.^16,30

Our knowledge about hepatitis B and related diseases has dramatically increased since the discovery of the causative virus, HBV, in 1963. Despite effective vaccination, hepatitis B still constitutes a major public health problem.

In two parts, this comprehensive review will highlight a practical clinical approach to HBV infection. In this first part, we discuss the epidemiology, natural history, and diagnosis of HBV infection. In the second part, to be published in the next issue of this journal, we will review the general principles of its management, its management in patients on immunosuppressant therapy and in pregnant women, and HBV vaccination.

COMMON IN ASIA, LESS SO IN AMERICA

More than 2 billion people—one-third of the world’s population—alive today have been infected with HBV at some time in their life, and of these, about 350 million remain infected.¹ Every year, 1 million people die of HBV-related cirrhosis or hepatocellular carcinoma, which means that HBV takes a life every 30 seconds.²

World Health Organization. Introduction of hepatitis B vaccine into childhood immunization services. Geneva: WHO; 2001. WHO/V AND B/01.31.

The incidence of acute hepatitis B in the United States has declined from 8.5 per 100,000 population in 1990 to 2.1 per 100,000 population in 2004, with the greatest declines (94%) in children and adolescents, coincident with an increase in hepatitis B vaccination in these age groups.⁵ Despite these advances, HBV still causes a considerable number of cases of cirrhosis, cancer, and death—about 5,000 deaths each year in the United States.

HBV HAS FOUR GENES, EIGHT GENOTYPES

HBV is a DNA virus of the Hepadnaviridae family. Its genome is double-stranded with four genes, each one encoding a specific structural protein or proteins^6,7:

• S gene, for the viral envelope (surface antigen)
• C gene, for both the nucleocapsid (core) antigen and the pre-core (e) antigen
• X gene, for two regulatory proteins required for HBV replication
• P gene, for DNA polymerase.

Eight genotypes of HBV (labeled A though H) have been identified.13,14 All eight have been found in the United States, but genotype A accounts for 35% of cases, genotype B for 22%, and genotype C for 31%.¹⁵

The clinical significance of HBV genotypes is not as clear as that of hepatitis C virus genotypes. Although recent data have suggested that different HBV genotypes may be associated with different rates of progression of liver disease and different rates of response to interferon therapy,¹³ these data were not enough to recommend routine testing for HBV genotypes in clinical practice.¹⁶

In HBV infection, the virus itself does not injure liver cells. Rather, the damage of hepatitis is immune-mediated and begins to appear as the host’s immune system attempts to clear the virus.

MARKERS OF HBV INFECTION

HBV surface antigen and HBV DNA are often the first detectable markers of acute infection, appearing before the onset of symptoms or before elevation of alanine aminotransferase (ALT) occurs. By definition, an HBV infection is chronic if surface antigen persists longer than 6 months.

HBV e antigen, derived from pre-core protein, is considered a marker of HBV replication and infectivity. In chronic infection, e antigen can persist for years or decades.

HBV core antigen cannot be detected in the serum, but antibodies against it can, first immunoglobulin M (IgM) and later immunoglobulin G (IgG).

TRANSMISSION: VERTICAL OR HORIZONTAL

Because HBV replicates profusely and produces high titers in the blood (108 to 1,010 virions/ mL), any parenteral or mucosal exposure to infected blood poses a high risk of HBV acquisition. The risk of HBV transmission from a single needlestick is 1% to 6% if the blood is positive for HBV surface antigen but negative for HBV e antigen, and 22% to 40% if positive for both antigens.^17–19 Saliva, nasopharyngeal fluid, breast milk, semen, urine, and cervical secretions can also harbor HBV.²⁰

Worldwide, perinatal (vertical) transmission is the predominant mode of HBV transmission, whereas intravenous drug abuse and unprotected sexual intercourse are the main routes of infection in areas of low prevalence, such as the United States. In sub-Saharan Africa, Alaska, and Mediterranean countries, transmission of HBV usually occurs horizontally during childhood, presumably via contact with nonintact skin.^21–24 Saliva has also been thought to be the route of HBV transmission in sporadic cases through human bites.²⁵

People at risk of HBV infection include:

• Parenteral drug users
• People with multiple sexual partners
• Household contacts and sexual partners of people who are positive for HBV surface antigen
• Infants born to HBV-infected mothers
• Patients and staff in custodial institutions for the developmentally disabled
• Recipients of certain plasma-derived products (including patients with congenital coagulation defects)
• Hemodialysis patients
• Health and public-safety workers who have contact with blood
• People born in areas where HBV is endemic, and their children.

These people—as well as all pregnant women, patients infected with hepatitis C virus or human immunodeficiency virus, and patients with chronically elevated ALT or aspartate aminotransferase (AST) levels—should be screened for HBV infection with serologic markers.

CLINICAL MANIFESTATIONS VARY

HBV infection, acute or chronic, has variable manifestations. During the acute stage, HBV infection can manifest as anicteric (subclinical) hepatitis, icteric hepatitis, or, rarely, acute fulminant hepatitis. Chronic HBV infection can be asymptomatic (the HBV surface antigen carrier state), or it can be manifested by symptoms and signs of cirrhosis or hepatocellular carcinoma or both. Extrahepatic manifestations, including serum sickness, polyarteritis nodosa, essential mixed cryoglobulinemia, membranous glomerulonephritis, and aplastic anemia, have been reported in patients with HBV infection.²⁶

Acute hepatitis B

The incubation period of HBV ranges from 2 weeks to 4 months. Initially, patients complain of fatigue, malaise, anorexia, right upper quad-rant discomfort, or flu-like symptoms (coryza, photophobia, headache, and myalgia); then jaundice becomes apparent, usually within 10 days of the onset of symptoms. Low-grade fever, jaundice, and mildly tender hepatomegaly are the most common signs. Generalized lymphadenopathy is not a feature of acute HBV infection. If the patient also has hepatitis D virus infection or underlying liver disease (eg, alcoholic liver disease), then acute HBV infection may be more severe.

In the acute phase, ALT and AST levels rise, sometimes to values above 1,000 IU/L. In icteric hepatitis, bilirubin levels also rise, usually after the ALT level does. Although the peak ALT level reflects the hepatocellular injury, it has no prognostic value. With recovery, ALT levels normalize in 1 to 4 months.

Acute fulminant hepatitis B occurs in 0.1% to 0.5% of patients, and causes about 10% of cases of acute liver failure in the United States.²⁷ Patients typically present with rapidly progressive acute hepatitis characterized by signs of liver failure, such as coagulopathy, encephalopathy, and cerebral edema.

In the so-called window phase, laboratory testing may not reveal HBV surface antigen because of early clearance but shows IgM antibody against the HBV core antigen. HBV DNA may be low or undetected.

Chronic hepatitis B

Chronic hepatitis B is usually diagnosed as a result of a workup for abnormal liver function tests or as a result of screening patients at risk for HBV infection. Many patients with chronic hepatitis B have no symptoms or have nonspecific symptoms such as fatigue or right upper quadrant discomfort.

Acute exacerbations due to HBV e antigen seroreversion (ie, in which e antigen reappears) occasionally occur in patients with chronic hepatitis B. Most of these exacerbations are asymptomatic, but occasionally an acute hepatitis-like clinical picture with detectable IgM antibody against the core antigen occurs, leading to misdiagnosis of acute HBV infection in patients not previously known to have chronic HBV infection.²⁸

In late cases, signs of cirrhosis such as jaundice, ascites, splenomegaly, pedal edema, encephalopathy, or variceal bleeding can be present.

Hepatocellular carcinoma should be suspected in cirrhotic patients with new-onset right upper quadrant pain, rapidly developing ascites, a palpable liver mass, or hepatic encephalopathy. Other nonspecific features of hepatocellular carcinoma include watery diarrhea, hypoglycemia, and certain cutaneous manifestations such as acanthosis nigricans and the Leser-Trelat sign (multiple pruritic seborrheic keratoses of sudden onset).

In chronic hepatitis B, liver enzyme levels can be normal, even in patients with wellcompensated cirrhosis. ALT levels may range from normal to five times higher than normal. Thrombocytopenia, hypoalbuminemia, direct hyperbilirubinemia, and prolonged prothrombin time suggest cirrhosis.

Findings of chronic hepatitis B on liver biopsy range from minimal inflammation to cirrhosis. The most characteristic histologic feature of chronic HBV infection is the “ground-glass hepatocyte,” which is due to intracellular accumulation of HBV surface antigen. ²⁹

FEW ADULTS (BUT MANY CHILDREN) REMAIN CHRONICALLY INFECTED

HBV surface antigen can be detected in the blood approximately 2 to 4 weeks after inoculation. Simultaneously, HBV DNA, usually in very high levels, is also detectable in the blood. However, in the rare cases of acute fulminant hepatitis, HBV DNA levels can be low or undetectable at the time of presentation because the immune system mounts a robust response with extensive damage to HBVinfected hepatocytes.

The rate of spontaneous recovery from acute HBV infection varies, depending on the patient’s age at the time of HBV acquisition and the patient’s immune status. Fewer than 5% of immunocompetent adults infected with HBV remain chronically infected, defined as being positive for HBV surface antigen for more than 6 months. On the other hand, 80% to 90% of infected infants and about 20% to 50% of children 1 to 5 years old at the time of acute infection remain chronically infected.²¹

The immune tolerance phase, the initial phase of chronic HBV infection, is seen almost exclusively in those who acquired HBV infection vertically or during early childhood. Although patients have high HBV DNA levels, they do not have significant liver disease. This discrepancy is thought to be related to the immune tolerance to HBV; however, the exact mechanism of that tolerance is unclear.³¹

Only 15% of those with immune tolerance have spontaneous HBV e antigen seroconversion (ie, loss of e antigen and appearance of anti-e antibody) within 20 years after infection. ³²

The immune clearance phase (HBV e antigen-positive chronic hepatitis) appears about 20 to 30 years after the onset of the immune tolerance phase in patients who acquire HBV early in life. It is also often seen in patients with infections acquired late in childhood or in adulthood.

This phase marks the start of an immunemediated process aimed at clearing the viral infection, but it also leads to concomitant hepatocellular injury. Spontaneous clearance of the e antigen increases in this phase to an annual rate of 10% to 20%.^32,33 The strongest predictors of spontaneous e antigen seroconversion are old age, an elevated ALT level, and an acute exacerbation.²⁶

Although ALT levels are elevated and there is evidence on liver biopsy of chronic active hepatitis, this phase is usually asymptomatic. Rarely, however, it presents with an acute flare of hepatitis, sometimes accompanied by IgM antibodies against the HBV core antigen (in low titer), leading to an incorrect diagnosis of acute HBV infection.

Depending on the duration of the chronic hepatitis and the frequency and severity of flares, about 12% to 20% of patients in the immune-clearance phase develop serious liver disease within 5 years.³¹

The inactive carrier phase following HBV e antigen seroconversion is characterized by undetectable or low HBV DNA levels (< 1,000 copies/mL), normal ALT levels, and minimal or no necroinflammation on liver biopsy. 30 Such patients should be followed with serial testing, as 4% to 20% of them spontaneously revert to being positive for e antigen at least once.16 On the other hand, only 0.5% to 2% of surface antigen carriers in western countries clear themselves of surface antigen yearly, but up to half of those who clear the surface antigen have low-level HBV viremia. ³⁴

The reactivation phase (HBV e antigennegative chronic hepatitis) is seen in some HBV-infected patients, especially those from Asia and southern Europe, in whom the virus has a spontaneous pre-core or core mutation that makes infected cells unable to secrete the e antigen. Although these patients have no e antigen in their blood, they do have intermittent or persistent elevation of ALT, elevated HBV DNA, and histopathologic findings of chronic hepatitis. Compared with those in the immune clearance phase, patients in the reactivation phase tend to be older and to have lower HBV DNA levels but advanced hepatic damage.

Immunity to HBV infection is characterized by loss of HBV surface antigen, DNA, e antigen, and anti-core antigen IgM with development of anti-surface antigen antibody and anti-core antigen IgG (total anti-core antigen antibody). The presence of anti-surface antigen antibody and anti-core antigen IgG together differentiates natural immunity through resolved infection from that which is acquired through vaccination, which is denoted by isolated anti-surface antigen antibody.

Cirrhosis, liver failure, cancer

Cirrhosis, hepatic decompensation, and hepatocellular carcinoma are the major long-term complications of HBV infection. In untreated patients, the annual rate of progression to cirrhosis has been estimated to be 2% to 6% in patients with HBV e antigen-positive chronic hepatitis and 8% to 9% in those with e antigen- negative chronic hepatitis.³⁰

The likely explanation for these surprising cirrhosis rates is that e antigen-negative chronic hepatitis usually represents a late stage of the disease, and patients in this phase are usually older and have more advanced liver disease.

Subsequently, the annual rate of progression from compensated cirrhosis to hepatic decompensation has been estimated to be about 5%.³⁵

Across all the stages described above, a high serum HBV DNA level has been shown to be a strong predictor of progression to cirrhosis in patients with chronic HBV infection. In a population-based prospective cohort study of 3,582 untreated HBV-infected patients in Taiwan, Iloeje et al36 found that, compared with patients with serum HBV DNA levels lower than 104 copies/mL, those with levels of 104 or higher had an adjusted relative risk of cirrhosis of 2.5. The relative risk rose to 5.9 with HBV DNA levels of 105 or higher, and 9.8 with levels of 106 copies/mL or higher. More studies in different patient populations are needed for confirmation.

The most important risk factor for hepatocellular carcinoma in HBV-infected patients is cirrhosis, but this cancer can also develop in noncirrhotic livers.37 The annual rate of hepatocelluar carcinoma has been estimated to be higher (2.5%–3%) in patients with cirrhosis than in noncirrhotic carriers (0.5%–1%).^30,35–38 Risk factors for cirrhosis and hepatocellular carcinoma are summarized in Table 4.^16,30

Recent case reports have linked bisphosphonate drugs to osteonecrosis of the jaw, and these reports have been widely publicized. Many patients receiving these drugs are asking their dentists and doctors whether the drugs do more harm than good, and some have even stopped taking them against medical advice. Health care professionals may be unsure what to tell patients and may be fearful of litigation.

However, most of the cases reported were in cancer patients, who are at significantly higher risk of osteonecrosis of the jaw for several reasons, and who receive much higher doses of bisphosphonates than do patients with osteoporosis or Paget disease of bone.

Moreover, although case reports have clearly documented an association between these drugs and osteonecrosis of the jaw, there is a lack of robust scientific evidence to support a cause-and-effect relationship. In fact, wellcontrolled clinical studies have not shown an increased risk of this complication in patients with osteoporosis or Paget disease of bone who were exposed to these agents, nor have they elucidated definite pathogenic mechanisms by which it might occur.

For these reasons, we believe that patients with osteoporosis should be advised of:

• Their risk of fracture
• The significant risk of morbidity and death following such a fracture
• The effectiveness and excellent safety of bisphosphonate therapy in preventing fractures
• The evidence that such therapy for osteoporosis and Paget disease poses little or no risk of osteonecrosis of the jaw
• The need for further research.

WHAT IS OSTEONECROSIS OF THE JAW?

Osteonecrosis—a general loss of bone tissue as a result of cell death¹—can occur at any skeletal site, but it typically involves the long bones, ie, the femur, tibia, and humerus.

Osteonecrosis of the jaw is a rare disorder characterized by exposure and loss of bone in the maxillofacial complex. It can result in significant morbidity and can be resistant or refractory to conventional therapy.

This condition is not new, having been described in 19th century factory workers exposed to white phosphorus used in matchstick manufacturing. Known then as “phossy jaw,” it was associated with poor dentition and often resulted in severe disfigurement, disease, and death. Use of white phosphorus, and matches containing it, were subsequently banned in many countries.²

In the early 20th century, radiation therapy for cancers of the head and neck area came into vogue, but its side effects included damage to the skeleton, or osteoradionecrosis.³ In 1950, LaDow⁴ described a case of osteoradionecrosis of the jaw and reviewed the literature available at that time. He concluded that there were three main causes of osteonecrosis of the jaw, namely, radiation therapy, trauma, and infection.

Although many such cases have since been reported in association with radiation therapy, chemotherapy, or both, and involvement of other skeletal sites is well described,^5–8 the actual incidence of osteoradionecrosis in the general population remains unclear because no large epidemiologic studies to elucidate accurate numbers have been published.

BISPHOSPHONATE-ASSOCIATED OSTEONECROSIS OF THE JAW

Bisphosphonate-associated osteonecrosis of the jaw is a relatively new condition, having been first reported in three case series^9–11 published in 2003 and 2004. The patients had exposure of areas of alveolar bone, mostly after oral surgery, eg, mucogingival flap elevation procedures (such as tooth extraction), that did not respond or were refractory to conventional treatment. All had received a bisphosphonate drug.

After these articles were published, the number of reported cases rose dramatically, including a case presented by one of us.¹² By the end of January 2008, more than 500 papers on this condition were listed in PubMed. More than 60% had been printed since 2003, and approximately 85% concerned the association between osteonecrosis of the jaw and bisphosphonate use (search terms: “osteonecrosis of the jaw” and “bisphosphonate”).¹³

Although some dentists and oral surgeons claim to have seen many patients with this disorder, physicians who specialize in osteoporosis and metabolic bone disease do not. The medical literature and popular press have suggested that bisphosphonates are the cause of this malady. However, such articles are more perspective than evidence, as they are not scientific studies but rather reports of cases or series, or reviews of these. High-impact journals have given such articles prominent positions, highlighting the issue further, rather than balancing what is known and what is not known.

Thus, medicine safety boards, physicians, dentists, and oral surgeons have become increasingly concerned about the possible risk of this disorder in their patients on long-term bisphosphonate therapy, prompting organizations to issue management guidelines for this disorder and regulatory bodies to mandate warning labels on all drugs in this class about the possible risk.^14–18 Funding agencies have highlighted this as an area in need of further investigation.¹⁷

However, robust evidence of a causal relationship is lacking. Contributing to the problem, other disorders can have similar presentations.

As a result, the diagnosis requires a dental examination and dental imaging, which are often impossible or impractical in a medical setting. Well-designed studies have relied on blinded panels of dental specialists using clinical and imaging data to adjudicate cases as osteonecrosis of the jaw before including them in published reports; case reports, however, often do not.

HOW IS OSTEONECROSIS OF THE JAW DIAGNOSED AND MANAGED?

A working definition of osteonecrosis of the jaw has recently emerged, and it will likely continue to evolve as results of further investigation become available.

A confirmed case is defined as an area of exposed bone in the maxillofacial region that does not heal within 8 weeks after being identified by a health care provider, in a patient who is currently receiving or has been exposed to a bisphosphonate and who has not had radiation therapy to the craniofacial region.^14,17 This 8-week duration is consistent with the time frame in which soft tissue would be expected to close and exposed bone would be expected to heal under normal conditions after oral surgery such as dental extraction or a flap elevation procedure.

Patients may have no symptoms at the time of presentation. However, symptoms can include oral or jaw pain, difficulty chewing, evidence of infection, and dental loss. Bone loss is often apparent radiographically, and it may be focal or generalized. Other imaging studies such as cone beam computed tomography provide greater detail on the extent and nature of the lesions, and thus provide a better assessment.

Histologically, there is evidence of necrosis, cell death, and, usually, concomitant infection.^9–12,17

Management can be difficult

Osteonecrosis of the jaw can be difficult to manage, and extensive guidelines have been published.^14–17 Its treatment is complicated because resection of the necrotic area often only makes the necrotic area bigger. Unlike in osteoradionecrosis, surgical removal of the affected area often results in necrosis at the margins of resected bone. This creates a potential situation of “chasing” affected bone in procedure after procedure, which results in significant morbidity.

A preventive protocol for cancer patients

Most of the cases reported so far have been in cancer patients receiving long-term treatment with potent bisphosphonates in high intravenous doses (12 times the usual dose for osteoporosis) after a mucoperiosteal flap elevation dental procedure (many of which were performed on an emergency basis).^{9–12,14–20} Authors have thus concluded that a preventive protocol should be followed for all patients being considered for intensive bisphosphonate treatment, similar to that adopted for patients receiving head and neck radiation.

Specifically, all chronic dental and periodontal conditions should be identified and stabilized before starting intensive bisphosphonate therapy. Experts today believe that controlling all chronic dental problems before starting intensive intravenous bisphosphonate therapy may be the best method to avoid dental surgery after bisphosphonate therapy has begun, particularly since the washout period (time to elimination of the drug) for bisphosphonates in alveolar bone is unknown.^14–20

Although authors seem to agree that such a preventive protocol is prudent for intensive intravenous therapy, it does not appear to be necessary for patients without cancer.^14,17 Indeed, such an approach is impractical, given the huge numbers involved and the lack of evidence to support it.

WHAT ARE BISPHOSPHONATES, AND WHY THE CONCERN?

Bisphosphonates are analogues of pyrophosphates, inorganic compounds developed to remove calcium carbonate from water in industrial pipes and laundry machines. Pyrophosphate use in humans arose from their affinity for calcium phosphate, which proved beneficial in scintigraphic imaging studies and in preventing tartar build-up, resulting in their incorporation into toothpastes. Modifications of the pyrophosphate molecule led to the development of diphosphonate compounds (later known as bisphosphonates), which have gained widespread use in treating a variety of disorders of the skeleton and of calcium metabolism.

These drugs prevent bone resorption by selectively inhibiting osteoclastic activity through several mechanisms (depending on the compound), thus helping prevent bone loss, bone pain, and hypercalcemia in diseases of the skeleton.

Today, oral and intravenous bisphosphonates are widely prescribed for several skeletal disorders, including metastatic disease, malignant hypercalcemia, Paget disease of bone, and prevention and treatment of osteoporosis.^21–23

More than 10 million Americans and more than 200 million people worldwide may have osteoporosis, which results in more than 1 million fractures each year. The lifetime risk of fracture for a postmenopausal white woman today is approximately 40% (approximately 15% for a 50-year-old man), and her annual risk of fracture is greater than her combined risk of stroke, heart attack, and breast cancer.²² Several bisphosphonates have been shown to safely and significantly reduce the risk of fracture in patients with osteoporosis and to be effective therapies for Paget disease of bone.^24–31

Bisphosphonates are the most widely prescribed drugs for osteoporosis,^22,23,29 with almost 200 million prescriptions for oral bisphosphonates worldwide. As of 2004, exposure to alendronate (Fosamax) was estimated to be about 20 million patient-years.³² Noncompliance limits their effectiveness in practice, due in part to concerns about adverse effects.

Since bisphosphonates are so widely prescribed, concern has been raised that they may be causing a new epidemic of osteonecrosis of the jaw.⁹ However, most reported cases have been in cancer patients, who are known to be at increased risk of this condition and who receive doses of bisphosphonates up to 12 times higher than in patients with osteoporosis or Paget disease of bone.^{9–12,33–38}

The optimal duration of bisphosphonate therapy for these diseases to obtain the maximum benefit and minimize cost and harm remains unclear. Although a recent report suggests a bisphosphonate “drug holiday” may be an option when treating postmenopausal osteoporosis, larger, more robust studies of longer duration are needed.³⁹ Outcomes of osteonecrosis of the jaw related to drug holidays have not been investigated.

‘IF I TAKE THIS TO STOP BONE LOSS, WILL IT HURT MY JAWS?’

The recently described association between bisphosphonates and osteonecrosis of the jaw has received considerable attention. Guidelines have been drawn up, some based on the assumption that bisphosphonates cause the osteonecrosis, but not based on scientific research.^14–18 More than 90% of reported cases have been in cancer patients, a group known to be at increased risk of osteonecrosis of the jaw and other skeletal sites, for reasons that include radiation therapy, chemotherapy, corticosteroid use, and increased risk of infections.^{4,6,9–12,33–38} Nevertheless, it has been assumed that these patients are the same as osteoporosis patients, and sometimes that causation is beyond dispute. This is problematic for two main reasons:

• Since noncompliance and lack of adherence (due to lack of knowledge about the dangers posed by osteoporosis, cost of the drugs, difficulty with dosing regimens, and fear of adverse effects) limit the effectiveness of these therapies in clinical practice, such attention has already persuaded patients to discontinue or refuse therapy (J.J. Carey, personal experience and communications from colleagues); and
• Patients with osteoporosis and osteoporotic fractures have increased rates of morbidity and mortality and significantly higher fracture risk, which can be prevented with these agents if they are willing to take them.

Association does not prove causation

However, association does not prove causation. A relationship between a drug and a disease may be due to chance alone or to confounding factors.⁴⁰ To judge the exact nature of this relationship, several issues need to be considered when reviewing the available evidence.

Substantiating that an agent causes a disease requires careful consideration of several aspects of their relationship: temporality, strength, dose-response, reversibility, consistency, biologic plausibility, and specificity.⁴¹ Correct interpretation of the strength of the evidence should also incorporate an evaluation of the study design, size, and reporting mechanism. Accordingly, case reports and case series are considered to constitute the weakest evidence, while randomized controlled trials and meta-analyses are usually considered the strongest.

When a true cause-and-effect relationship does exist, the situation can be a simple one in which only a single agent is involved. However, the issue can be decidedly more complex when the cause is an effect-modifier, requiring the interaction of additional factors.

When a cause has been assumed, demonstration of the dose-response relationship is also important: whether the risk is related in a continuous fashion to dose and duration of therapy (all patients), is seen only with particular doses or regimens (such as frequent use of high doses of potent bisphosphonates), or exists only in people who have passed a certain threshold value (for example, it may only occur in those who have received 0.5 g of an intravenous or 10 g of an oral bisphosphonate). Bearing in mind these considerations, the nature of the relationship between an agent and a disease can be better understood.^40–43

A cause-and-effect relationship has not been established

A cause-and-effect relationship between bisphosphonates and osteonecrosis of the jaw has not been clearly established.^14,17 Although case series highlight a relationship between the two, large controlled trials evaluating the occurrence of osteonecrosis of the jaw as the primary outcome have not been conducted. To date, most cases have been reported as uncontrolled case series, generally considered the weakest form of evidence.⁴³

Most cases of osteonecrosis of the jaw were in patients with cancer (particularly breast cancer and multiple myeloma) receiving potent intravenous bisphosphonates in high doses, most of whom had other documented risk factors, including recent dental procedures such as tooth extraction.^{9–12,15–19,33–38}

One of the most compelling studies supporting causation examined the prevalence of osteonecrosis of the jaw in a cohort of 303 myeloma patients from 1991 to 2003. Osteonecrosis of the jaw developed only in those taking bisphosphonates (28 of 254), and the risk appeared greatest in those treated with both zoledronic acid (Zometa) and thalidomide (Thalomid). The importance of additional chemotherapies, concomitant diseases, and baseline dental pathology was not described.³⁵ Biases, including channeling bias (in which patients who appear at increased risk of this rare condition also appear to be most likely to receive this medication), referral bias, and survivor bias, were not addressed in this paper or in others claiming that the risk is related to the type of bisphosphonate used and the duration of its use.^15,33–38

A review of all cases of osteonecrosis of the jaw over a 5-year period in one institution (N = 163) found that only 17 (10%) were associated with bisphosphonate use, and all 17 patients had other risk factors, such as concomitant therapy for malignancy and recent dental surgery.³⁴ The authors’ concern that longer follow-up may have shown a higher incidence of this problem is supported by the temporal relationship seen in other reports in which cancer patients with osteonecrosis of the jaw appear to have had higher cumulative doses of intravenous bisphosphonates than those without.^{9–12,15,34,35,37,38} Unfortunately, only one study had a control group to highlight the incidence of osteonecrosis of the jaw in similar patients not treated with bisphosphonates.³⁵ The incidence in cancer patients treated with intravenous bisphosphonates has been reported as between 0% and 11%, and the incidence is higher following dental procedures and with a greater duration of drug exposure.^{11,14,15,17,35,38,44}

Interestingly, in a recent survey of oncologists prescribing bisphosphonate medications for metastatic indications, two-thirds said they believe their patients probably have undiagnosed chronic oral conditions that could increase the risk of osteonecrosis of the jaw following bisphosphonate therapy and dental surgery procedures. A similar number reported that their patients receive routine dental care (access to and cost of dental care and the difficulty in physician prescreening are cited as obstacles), but only about one-third actually refer their patients to dentists before starting bisphosphonate therapy.⁴⁵

What recent studies in osteoporosis and Paget disease showed

Controlled scientific studies in osteoporosis and Paget disease of bone have not shown osteonecrosis of the jaw to emerge, even after years of treatment with bisphosphonate drugs.^{24–31,46–49} To date, more than 50,000 patients have been treated with oral bisphosphonates— more than 100,000 patient-years for each drug: alendronate, risedronate (Actonel), and ibandronate (Boniva)—in clinical trials, and there has not been a single case of bisphosphonate-associated osteonecrosis in any of these studies.⁴⁸

Recent publications have addressed the results of clinical trials comparing zoledronic acid (the drug most often associated with this condition in published case series) and risedronate in more than 300 patients with Paget disease of bone,³¹ and with placebo in postmenopausal women with osteoporosis and persons over 50 years of age suffering a hip fracture treated for up to 3 years following their fracture.^29,30

In the largest trial, almost 4,000 osteoporotic women were treated with 5 mg of zoledronic acid annually for 3 years, and a similar number received placebo. Despite a rigorous search for any potential cases of bisphosphonate-associated osteonecrosis of the jaw—adjudicated by a blinded panel of ex on the basis of clinical and dental diagnostic imaging—only two possible cases were found: one in the placebo group and one in the treatment group (a case of osteomyelitis that preceded any treatment with zoledronic acid). Both patients recovered following a course of oral antibiotics and debridement. There was no increase in osteonecrosis at other skeletal sites.^29,49

Observational studies have yielded conflicting results. An Australian postal survey of oral surgeons and dentists combined with drug adverse events data suggested the frequency of osteonecrosis of the jaw was 1:2,260 to 1:8,470 in patients on weekly alendronate treatment for osteoporosis, and 1:56 to 1:380 in patients with Paget disease. Following dental extractions, this rose to 1:296 to 1:1,130 and 1:7.4 to 1:48, respectively. Results in patients with malignancy were similar to those in other studies.⁴⁴ The study raises issues similar to those in other studies: lack of an appropriate control group, reporting bias, and the possibility of multiple reportings of the same patients.

Unpublished information from pharmaceutical companies has suggested the incidence of unconfirmed cases of osteonecrosis of the jaw in persons taking alendronate is 0.7/100,000 person-years.^14,17 One study using administrative claims data did not find evidence of increased bisphosphonate use in patients undergoing jaw surgery (used as a surrogate for osteonecrosis of the jaw),⁵⁰ while another actually found that oral bisphosphonates had a protective effect against osteonecrosis of the jaw, inflammatory conditions of the jaw, and need for major jaw surgery.⁵¹

This information suggests that if these drugs, used at the recommended dose, really do pose a risk, it is probably very small: less than 1 case in 100,000 patient-years if taking an oral bisphosphonate such as alendronate.^14,17 This is significantly less than the risk of fracture in these patients (which may be higher than 1 in 10), the risk of death following such a fracture,^22–30 or the risk of death from drowning, house fire, or motor vehicle accident.⁵²

The cases of osteonecrosis of the jaw that we have personally seen—all in cancer patients treated with chemotherapy and highdose bisphosphonates—all showed histologic evidence of necrosis and concomitant infections, suggesting the actual diagnosis was osteomyelitis. Bone biopsies from affected but macroscopically normal mandibles at the time of surgical debridement for osteonecrosis of the jaw showed normal or increased osteoclastic activity, in contrast to what one would expect if there were oversuppression of bone turnover (unpublished data, J. Christian, J. Carey, Cleveland Clinic).

Recently, this family of drugs has shown some promise in limiting the progression of alveolar bone loss in periodontal disease (though they are not approved for this indication).^53–55 Finally, published studies suggest bisphosphonate therapy may even be beneficial in animals and humans with osteonecrosis,^56–58 and in conditions that mimic osteonecrosis such as SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) of the mandible, in which the histologic appearance may resemble that of osteonecrosis.⁵⁹

WHAT SHOULD WE TELL OUR PATIENTS?

Several things are worth emphasizing from the published data and guidelines:

• Many things are unknown about osteonecrosis of the jaw and the risk in people taking bisphosphonates.
• The best evidence today does not support a cause-and-effect relationship between osteonecrosis of the jaw and bisphosphonate therapy.
• If bisphosphonates are causative, the risk appears very low in patients without cancer.
• It is important to distinguish between cancer and noncancer patients because of different risk factors, the markedly higher doses of bisphosphonates used in cancer patients, and the much greater incidence of osteonecrosis of the jaw seen in cancer patients irrespective of the cause.
• The higher risk in cancer patients is likely modified or confounded by additional risk factors, possibly including long-term use of high-dose intravenous bisphosphonates.
• About 90% of cases of bisphosphonate-associated osteonecrosis of the jaw have been in cancer patients, in whom a substantial temporal relationship to bisphosphonate therapy has been seen.^{9–12,15–17,19,49,54–57}
• Prevention will likely be the most effective management strategy because of the significant morbidity associated with and the refractory nature of osteonecrosis of the jaw.
• Prophylactic dental examinations and any needed repair work are probably best done before starting bisphosphonate therapy in cancer patients; however, studies supporting such a strategy are needed.
• There is no evidence to support routine dental examinations before starting such therapy for disorders other than cancer, or for stopping such therapy before, during, or after dental surgery. Whether this is true for patients who have been taking these drugs for several years or more is unclear.
• Good communication between patients and their physicians, dentists, periodontists, and surgeons will help provide them with the best possible care.

Clearly, much further research is needed on the causes, risks, diagnosis, and management of this disorder to optimize patient outcomes.