In 1958, shortly after the first descriptions of granulomatosis with polyangiitis, or GPA (Wegener’s granulomatosis), the 1-year mortality was 18%,¹ mainly due to renal failure. Physicians tried to combat the disease using various immunosuppressive drugs (nitrogen mustard and, in later years, azathioprine and methotrexate), but measurable success came only after investigators introduced cyclophosphamide (CYC) in combination with the glucocorticoid prednisone.²

A key 1992 study showed that the CYC/prednisone combination markedly improved the disease status in 91% of patients,³ with 75% achieving complete remission. The treatment came at a price, however, with almost all patients suffering serious morbidity or side effects. The results also highlighted concerns about potential malignancies caused by prolonged use of CYC and glucocorticoids. Those concerns motivated the European Vasculitis Study Group in the late 1980s and early 1990s to design and validate testing for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) and pursue consensus regarding treatment.⁴

ALTERNATIVES TO STANDARD THERAPY

The accepted therapeutic strategy for GPA is to first induce remission using high doses of CYC and then prevent relapse with longer-term, less toxic therapeutic alternatives. These less toxic therapies include newer agents as well as new methods of delivery, particularly for patients with nonsevere forms of disease.

Methotrexate—effective for early treatment

Methotrexate showed early promise in several nonrandomized trials of patients with nonsevere disease. In one such study, de Groot et al subclassified 100 patients at diagnosis according to the extent and severity of the disease.⁵ Patients were then randomized to receive either standard oral CYC or methotrexate, each combined with prednisolone. Remission rates (90% to 94%) were comparable regardless of whether patients received CYC or methotrexate, although patients with more severe disease who were taking methotrexate took longer to achieve remission. At the same time, relapse rates were higher for methotrexate-taking patients (70%) compared with the CYC group (47%). Thus, while methotrexate could replace CYC for initial treatment of early AAV, CYC had a greater influence on subsequent relapse rates, particularly in patients with more severe forms of disease.

Pulse cyclophosphamide—a new method

Investigators tested pulse delivery of CYC compared with oral daily administration as a means of reducing the CYC dose. An analysis of 14 relatively small studies showed that pulse CYC had the same survival and renal failure rates as continuous therapy.⁶

One such trial, the CYC Daily Oral Versus Pulsed (CYCLOPS) trial, involved 149 patients with generalized disease (nephritis, GPA, and microscopic polyangiitis [MPA]) who were administered either an intravenous (IV) pulse or a daily oral CYC regimen.⁷ The pulse CYC neither shortened patients’ time to remission nor increased the proportion of patients who achieved it. Patients receiving pulse CYC suffered one-third the rate of leukopenia experienced by patients who received the oral regimen. Since infection is a source of mortality in vasculitis, this finding is an important consideration when balancing the benefits of day-to-day control offered by oral administration against the safety of at-risk patients such as the elderly.

This treatment strategy may be relevant for patients with renal impairment. It was once thought that patients with renal failure after receiving CYC had more aggressive disease and therefore needed higher dosages. Investigators who studied the impact of renal insufficiency and hemodialysis on the pharmacokinetics of CYC found that clearance of CYC is impaired in patients with reduced renal function.⁸ Thus, when renal function is suppressed, the CYC dosage should be reduced rather than increased.

Mycophenolate mofetil—efficacy not yet confirmed

Another alternative to CYC, mycophenolate mofetil (MMF), has gained much attention, although its effectiveness is not yet certain. Pilot data show that 13 of 17 patients with MPA achieved remission after 6 months of treatment with MMF.⁹ Meanwhile, the so-called MYCYC trial, in which patients with newly diagnosed AAV receive either the CYCLOPS regimen or MMF, is under way.¹⁰

Deoxyspergualin—remission not sustained

A nonstandard drug that warrants attention is deoxyspergualin (now called gusperimus), licensed in Japan for 15 years. In a prospective, open-label trial of 45 patients with relapsing or refractory GPA, investigators showed that 95% achieved partial remission and 45% full remission, although remission was not sustained when therapy was stopped.¹¹ Because the drug must be administered daily for 21 days by subcutaneous injection, deoxyspergualin is not easy to use. It may represent an alternative, however, because it permitted prednisolone dosage reduction.

EVALUATING RISK AND CHOOSING THERAPIES

CONSIDERATIONS IN CHOOSING REMISSION THERAPY

Overall, when planning remission therapy and its duration, clinicians must balance the efficacy of CYC and glucocorticoids against their toxicity. Close monitoring and the patient’s capacity to adhere to instructions are two critical issues. Other important considerations include the risk and consequences of relapse, which vary in different circumstances, and the association of cancer with CYC therapy.

Relapse risk is variable

Certain patients are at higher risk of relapse than others. Patients with GPA or proteinase-3-ANCA–positive disease are at higher relapse risk than those who have MPA. ANCA-positive disease in remission or rising ANCA markers both increase the risk of relapse. Ear, nose, throat, and lung diseases increase the likelihood of relapse. Patients with GPA who are Staphylococcus aureus carriers have increased risk. Serum creatinine levels of 2.0 to 3.0 mg/dL at the end of induction therapy should arouse concern about renal relapse.

Most relapses affect the ear, nose, and throat system and do not threaten vital organs. Relapse does not increase the risk of end-stage renal disease or death.

Consider mortality and cancer data

Although the strongest predictor of early death is infection, advanced age and renal impairment also predict death. Chronic kidney disease stage at entry and glomerular filtration rate significantly predict mortality.²¹ More than 36 g CYC (equivalent to 9 to 12 months of standard oral therapy) increases the risk of bladder cancer 10-fold and myeloid leukemia 60-fold, but the cancer risk is time-dependent; malignancy requires 12 years on average to emerge.²²

CONCLUSION

Cyclophosphamide in combination with glucocorticoids remains the standard therapy for GPA and related vasculitides, despite the risk of significant treatment-related comorbidities. Several strategies can be employed to reduce exposure, such as sequential withdrawal of CYC and IV administration. The optimization of glucocorticoid dosing will be a major research focus in the next decade. Newer agents may improve the maintenance of remission; for example, azathioprine and methotrexate show equal efficacy and safety, while MMF is less effective. When planning remission maintenance therapy, the relapse risk should be considered carefully because it varies among clinical scenarios. Other factors in the decision include the consequences for the patient, monitoring requirements, and the patient’s ability to understand and adhere to instructions.

In 1958, shortly after the first descriptions of granulomatosis with polyangiitis, or GPA (Wegener’s granulomatosis), the 1-year mortality was 18%,¹ mainly due to renal failure. Physicians tried to combat the disease using various immunosuppressive drugs (nitrogen mustard and, in later years, azathioprine and methotrexate), but measurable success came only after investigators introduced cyclophosphamide (CYC) in combination with the glucocorticoid prednisone.²

A key 1992 study showed that the CYC/prednisone combination markedly improved the disease status in 91% of patients,³ with 75% achieving complete remission. The treatment came at a price, however, with almost all patients suffering serious morbidity or side effects. The results also highlighted concerns about potential malignancies caused by prolonged use of CYC and glucocorticoids. Those concerns motivated the European Vasculitis Study Group in the late 1980s and early 1990s to design and validate testing for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) and pursue consensus regarding treatment.⁴

ALTERNATIVES TO STANDARD THERAPY

The accepted therapeutic strategy for GPA is to first induce remission using high doses of CYC and then prevent relapse with longer-term, less toxic therapeutic alternatives. These less toxic therapies include newer agents as well as new methods of delivery, particularly for patients with nonsevere forms of disease.

Methotrexate—effective for early treatment

Methotrexate showed early promise in several nonrandomized trials of patients with nonsevere disease. In one such study, de Groot et al subclassified 100 patients at diagnosis according to the extent and severity of the disease.⁵ Patients were then randomized to receive either standard oral CYC or methotrexate, each combined with prednisolone. Remission rates (90% to 94%) were comparable regardless of whether patients received CYC or methotrexate, although patients with more severe disease who were taking methotrexate took longer to achieve remission. At the same time, relapse rates were higher for methotrexate-taking patients (70%) compared with the CYC group (47%). Thus, while methotrexate could replace CYC for initial treatment of early AAV, CYC had a greater influence on subsequent relapse rates, particularly in patients with more severe forms of disease.

Pulse cyclophosphamide—a new method

Investigators tested pulse delivery of CYC compared with oral daily administration as a means of reducing the CYC dose. An analysis of 14 relatively small studies showed that pulse CYC had the same survival and renal failure rates as continuous therapy.⁶

One such trial, the CYC Daily Oral Versus Pulsed (CYCLOPS) trial, involved 149 patients with generalized disease (nephritis, GPA, and microscopic polyangiitis [MPA]) who were administered either an intravenous (IV) pulse or a daily oral CYC regimen.⁷ The pulse CYC neither shortened patients’ time to remission nor increased the proportion of patients who achieved it. Patients receiving pulse CYC suffered one-third the rate of leukopenia experienced by patients who received the oral regimen. Since infection is a source of mortality in vasculitis, this finding is an important consideration when balancing the benefits of day-to-day control offered by oral administration against the safety of at-risk patients such as the elderly.

This treatment strategy may be relevant for patients with renal impairment. It was once thought that patients with renal failure after receiving CYC had more aggressive disease and therefore needed higher dosages. Investigators who studied the impact of renal insufficiency and hemodialysis on the pharmacokinetics of CYC found that clearance of CYC is impaired in patients with reduced renal function.⁸ Thus, when renal function is suppressed, the CYC dosage should be reduced rather than increased.

Mycophenolate mofetil—efficacy not yet confirmed

Another alternative to CYC, mycophenolate mofetil (MMF), has gained much attention, although its effectiveness is not yet certain. Pilot data show that 13 of 17 patients with MPA achieved remission after 6 months of treatment with MMF.⁹ Meanwhile, the so-called MYCYC trial, in which patients with newly diagnosed AAV receive either the CYCLOPS regimen or MMF, is under way.¹⁰

Deoxyspergualin—remission not sustained

A nonstandard drug that warrants attention is deoxyspergualin (now called gusperimus), licensed in Japan for 15 years. In a prospective, open-label trial of 45 patients with relapsing or refractory GPA, investigators showed that 95% achieved partial remission and 45% full remission, although remission was not sustained when therapy was stopped.¹¹ Because the drug must be administered daily for 21 days by subcutaneous injection, deoxyspergualin is not easy to use. It may represent an alternative, however, because it permitted prednisolone dosage reduction.

EVALUATING RISK AND CHOOSING THERAPIES

CONSIDERATIONS IN CHOOSING REMISSION THERAPY

Overall, when planning remission therapy and its duration, clinicians must balance the efficacy of CYC and glucocorticoids against their toxicity. Close monitoring and the patient’s capacity to adhere to instructions are two critical issues. Other important considerations include the risk and consequences of relapse, which vary in different circumstances, and the association of cancer with CYC therapy.

Relapse risk is variable

Certain patients are at higher risk of relapse than others. Patients with GPA or proteinase-3-ANCA–positive disease are at higher relapse risk than those who have MPA. ANCA-positive disease in remission or rising ANCA markers both increase the risk of relapse. Ear, nose, throat, and lung diseases increase the likelihood of relapse. Patients with GPA who are Staphylococcus aureus carriers have increased risk. Serum creatinine levels of 2.0 to 3.0 mg/dL at the end of induction therapy should arouse concern about renal relapse.

Most relapses affect the ear, nose, and throat system and do not threaten vital organs. Relapse does not increase the risk of end-stage renal disease or death.

Consider mortality and cancer data

Although the strongest predictor of early death is infection, advanced age and renal impairment also predict death. Chronic kidney disease stage at entry and glomerular filtration rate significantly predict mortality.²¹ More than 36 g CYC (equivalent to 9 to 12 months of standard oral therapy) increases the risk of bladder cancer 10-fold and myeloid leukemia 60-fold, but the cancer risk is time-dependent; malignancy requires 12 years on average to emerge.²²

CONCLUSION

Cyclophosphamide in combination with glucocorticoids remains the standard therapy for GPA and related vasculitides, despite the risk of significant treatment-related comorbidities. Several strategies can be employed to reduce exposure, such as sequential withdrawal of CYC and IV administration. The optimization of glucocorticoid dosing will be a major research focus in the next decade. Newer agents may improve the maintenance of remission; for example, azathioprine and methotrexate show equal efficacy and safety, while MMF is less effective. When planning remission maintenance therapy, the relapse risk should be considered carefully because it varies among clinical scenarios. Other factors in the decision include the consequences for the patient, monitoring requirements, and the patient’s ability to understand and adhere to instructions.

In 1958, shortly after the first descriptions of granulomatosis with polyangiitis, or GPA (Wegener’s granulomatosis), the 1-year mortality was 18%,¹ mainly due to renal failure. Physicians tried to combat the disease using various immunosuppressive drugs (nitrogen mustard and, in later years, azathioprine and methotrexate), but measurable success came only after investigators introduced cyclophosphamide (CYC) in combination with the glucocorticoid prednisone.²

A key 1992 study showed that the CYC/prednisone combination markedly improved the disease status in 91% of patients,³ with 75% achieving complete remission. The treatment came at a price, however, with almost all patients suffering serious morbidity or side effects. The results also highlighted concerns about potential malignancies caused by prolonged use of CYC and glucocorticoids. Those concerns motivated the European Vasculitis Study Group in the late 1980s and early 1990s to design and validate testing for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) and pursue consensus regarding treatment.⁴

ALTERNATIVES TO STANDARD THERAPY

The accepted therapeutic strategy for GPA is to first induce remission using high doses of CYC and then prevent relapse with longer-term, less toxic therapeutic alternatives. These less toxic therapies include newer agents as well as new methods of delivery, particularly for patients with nonsevere forms of disease.

Methotrexate—effective for early treatment

Methotrexate showed early promise in several nonrandomized trials of patients with nonsevere disease. In one such study, de Groot et al subclassified 100 patients at diagnosis according to the extent and severity of the disease.⁵ Patients were then randomized to receive either standard oral CYC or methotrexate, each combined with prednisolone. Remission rates (90% to 94%) were comparable regardless of whether patients received CYC or methotrexate, although patients with more severe disease who were taking methotrexate took longer to achieve remission. At the same time, relapse rates were higher for methotrexate-taking patients (70%) compared with the CYC group (47%). Thus, while methotrexate could replace CYC for initial treatment of early AAV, CYC had a greater influence on subsequent relapse rates, particularly in patients with more severe forms of disease.

Pulse cyclophosphamide—a new method

Investigators tested pulse delivery of CYC compared with oral daily administration as a means of reducing the CYC dose. An analysis of 14 relatively small studies showed that pulse CYC had the same survival and renal failure rates as continuous therapy.⁶

One such trial, the CYC Daily Oral Versus Pulsed (CYCLOPS) trial, involved 149 patients with generalized disease (nephritis, GPA, and microscopic polyangiitis [MPA]) who were administered either an intravenous (IV) pulse or a daily oral CYC regimen.⁷ The pulse CYC neither shortened patients’ time to remission nor increased the proportion of patients who achieved it. Patients receiving pulse CYC suffered one-third the rate of leukopenia experienced by patients who received the oral regimen. Since infection is a source of mortality in vasculitis, this finding is an important consideration when balancing the benefits of day-to-day control offered by oral administration against the safety of at-risk patients such as the elderly.

This treatment strategy may be relevant for patients with renal impairment. It was once thought that patients with renal failure after receiving CYC had more aggressive disease and therefore needed higher dosages. Investigators who studied the impact of renal insufficiency and hemodialysis on the pharmacokinetics of CYC found that clearance of CYC is impaired in patients with reduced renal function.⁸ Thus, when renal function is suppressed, the CYC dosage should be reduced rather than increased.

Mycophenolate mofetil—efficacy not yet confirmed

Another alternative to CYC, mycophenolate mofetil (MMF), has gained much attention, although its effectiveness is not yet certain. Pilot data show that 13 of 17 patients with MPA achieved remission after 6 months of treatment with MMF.⁹ Meanwhile, the so-called MYCYC trial, in which patients with newly diagnosed AAV receive either the CYCLOPS regimen or MMF, is under way.¹⁰

Deoxyspergualin—remission not sustained

A nonstandard drug that warrants attention is deoxyspergualin (now called gusperimus), licensed in Japan for 15 years. In a prospective, open-label trial of 45 patients with relapsing or refractory GPA, investigators showed that 95% achieved partial remission and 45% full remission, although remission was not sustained when therapy was stopped.¹¹ Because the drug must be administered daily for 21 days by subcutaneous injection, deoxyspergualin is not easy to use. It may represent an alternative, however, because it permitted prednisolone dosage reduction.

EVALUATING RISK AND CHOOSING THERAPIES

CONSIDERATIONS IN CHOOSING REMISSION THERAPY

Overall, when planning remission therapy and its duration, clinicians must balance the efficacy of CYC and glucocorticoids against their toxicity. Close monitoring and the patient’s capacity to adhere to instructions are two critical issues. Other important considerations include the risk and consequences of relapse, which vary in different circumstances, and the association of cancer with CYC therapy.

Relapse risk is variable

Certain patients are at higher risk of relapse than others. Patients with GPA or proteinase-3-ANCA–positive disease are at higher relapse risk than those who have MPA. ANCA-positive disease in remission or rising ANCA markers both increase the risk of relapse. Ear, nose, throat, and lung diseases increase the likelihood of relapse. Patients with GPA who are Staphylococcus aureus carriers have increased risk. Serum creatinine levels of 2.0 to 3.0 mg/dL at the end of induction therapy should arouse concern about renal relapse.

Most relapses affect the ear, nose, and throat system and do not threaten vital organs. Relapse does not increase the risk of end-stage renal disease or death.

Consider mortality and cancer data

Although the strongest predictor of early death is infection, advanced age and renal impairment also predict death. Chronic kidney disease stage at entry and glomerular filtration rate significantly predict mortality.²¹ More than 36 g CYC (equivalent to 9 to 12 months of standard oral therapy) increases the risk of bladder cancer 10-fold and myeloid leukemia 60-fold, but the cancer risk is time-dependent; malignancy requires 12 years on average to emerge.²²

CONCLUSION

Cyclophosphamide in combination with glucocorticoids remains the standard therapy for GPA and related vasculitides, despite the risk of significant treatment-related comorbidities. Several strategies can be employed to reduce exposure, such as sequential withdrawal of CYC and IV administration. The optimization of glucocorticoid dosing will be a major research focus in the next decade. Newer agents may improve the maintenance of remission; for example, azathioprine and methotrexate show equal efficacy and safety, while MMF is less effective. When planning remission maintenance therapy, the relapse risk should be considered carefully because it varies among clinical scenarios. Other factors in the decision include the consequences for the patient, monitoring requirements, and the patient’s ability to understand and adhere to instructions.

Granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]) is a vasculitis that affects the renal and respiratory systems. Remission can be induced in most patients with the combination of glucocorticoids and cyclophosphamide. Unfortunately, patients often suffer disease relapses requiring re-treatment and exposure to the cumulative toxicities of repeated cyclophosphamide use. In recent years, improved understanding of the mechanisms of action of cyclophosphamide has led to investigation of treatment strategies that target the role of B cells more specifically in the pathogenesis of the disease.

This article reviews the results of recent studies involving the use of biologic therapy in the treatment of GPA, with a brief examination of historic events that influenced the design of recent trials.

HISTORICAL PERSPECTIVE

The natural history of GPA was characterized in 1958¹ in a retrospective study showing that 50% of those afflicted died within 6 months, and 80% died by 18 months. Prednisone and cyclophosphamide changed this dismal outcome. The combination markedly improved the status of 91% to 93% of patients,^2,3 with most achieving complete remission. Treatment came with a price, however. Almost all patients suffered serious morbidity or side effects, including chronic renal insufficiency (11% requiring dialysis), recurrent infections, hearing loss, infertility, and diabetes. In addition, most patients (99 of 155 in one study) suffered relapse and a significant number (19 of 155) died because of the disease or its treatment.

Investigators’ pursuit of treatment alternatives included foregoing cyclophosphamide in patients who had limited or early systemic GPA and reducing the duration of treatment for patients with severe disease.⁴ Studies conducted in the late 1990s defined what eventually became standard therapy for GPA: remission induction with glucocorticoids and methotrexate for limited GPA and with glucocorticoids and cyclophosphamide for severe disease. Following remission induction, after 3 to 6 months cyclophosphamide is replaced by azathioprine or methotrexate for remission maintenance. While helpful, these alternatives still fell short of achieving safe, long-term remission.

THERAPY WITH BIOLOGICS

Targeting tumor necrosis factor

The first randomized placebo-controlled trial of a biologic agent in GPA, the Wegener’s Granulomatosis Etanercept Trial (WGET),⁴ evaluated whether etanercept, a soluble inhibitor of tumor necrosis factor (TNF), would be an effective adjunct to standard therapy. The results showed that etanercept did not confer any beneficial effect and, in fact, if combined with exposure to cyclophosphamide, etanercept increased the risk for solid tumors. Thus, anti-TNF therapy has a limited or no role in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

Targeting B cells

The mechanisms of cyclophosphamide effects on disease activity were not clearly understood. In the late 1970s, however, National Institutes of Health investigators found that cyclophosphamide, at the doses administered for GPA, had a profound effect on B-cell function.⁵ Later investigations showed that disease activity of GPA was clearly related to the frequency of activated B cells detectable in the peripheral blood, while abnormally activated T cells were also detectable in patients in remission.⁶ These findings suggested that activated B cells might be responsible for disease activity, whereas persistently activated T cells might explain the chronically relapsing nature of the disease.⁶

B cells are the precursors of short-lived plasma cells, which are thought to be the primary source of autoantibodies, including ANCA. Based on clinical observations as well as in vitro and some animal model experiments, investigators have ascribed pathogenic roles to ANCA. Consequently, targeting the cells that produce these autoantibodies (short-lived plasma cells of B-cell origin) might form the basis of a novel treatment. Why not target cells of the B-cell lineage, thereby eliminating the short-lived plasma cells that would otherwise produce autoantibodies? This might be achieved with rituximab, a monoclonal antibody directed against the CD20 molecule found on pre-B and mature B cells.⁷ Our group first successfully deployed this strategy in the early 2000s, followed by an open-label pilot study.^8–10

The RAVE trial

The Rituximab in ANCA-Associated Vasculitis (RAVE) trial was a multicenter, randomized, placebo-controlled trial that compared rituximab for remission induction and maintenance with standard therapy consisting of cyclophosphamide followed by azathioprine in patients with severe AAV.¹¹ The results of a pilot trial in 2006¹⁰ set the stage for the RAVE trial, which hypothesized that treatment with rituximab plus glucocorticoids would not be inferior to daily cyclophosphamide plus glucocorticoids. Both would induce remission and permit discontinuation of prednisone after 6 months.

Nine centers enrolled a total of 197 patients with severe GPA or microscopic polyangiitis (MPA), all positive for ANCA, with active disease severe enough to warrant treatment with prednisone and cyclophosphamide. All participants received 1 to 3 g of methyl-prednisolone intravenously followed by prednisone (1 mg/kg per day). The treatment group received rituximab (375 mg/m² once weekly for 4 weeks) and the control group received standard therapy with cyclophosphamide (2 mg/kg per day) followed by azathioprine (2 mg/kg per day) after 3 to 6 months when remission was achieved.

The primary end point was complete remission, defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) of 0 and successful tapering of prednisone by 6 months. Secondary end points included rates of disease flares, cumulative glucocorticoid doses, rates of adverse events, and Medical Outcomes Study 36-item short-form health survey (SF-36, a measure of quality of life) scores. Among patients receiving rituximab, 64% reached the primary end point compared with 53% of patients in the control group. Rituximab was judged not inferior to standard therapy.

Results were similar for the secondary end point of disease remission while taking less than 10 mg/d of prednisone, with 71% of rituximab patients and 62% of control-group patients achieving remission. Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. Most strikingly, rituximab proved superior to the cyclophosphamide-based regimen for inducing remission in patients who entered the trial with relapsing disease (67% rituximab versus 42% cyclophosphamide) (Figure 1). Those who entered the trial with a new diagnosis did not show the same difference in efficacy.

Rituximab also proved significantly more effective than cyclophosphamide for patients who had proteinase-3 (PR3) ANCA, whereas the efficacy of both agents was equivalent among patients who had myeloperoxidase ANCA. Patients in the cyclophosphamide arm experienced more leukopenia compared with the rituximab arm, but this did not lead to more infections.

In summary, the RAVE trial showed that rituximab matched the efficacy of cyclophosphamide (standard therapy) in inducing remission in patients with severe AAV. The results held true for subsets of patients with major renal disease and those with alveolar hemorrhage. Most strikingly, among patients who entered the trial with a severe relapse, those who received rituximab responded better than those treated with cyclophosphamide. There were no significant differences in flare rates by 6 months and no difference in the rate of severe adverse events. However, participants receiving cyclophosphamide experienced more selected adverse events, particularly leukopenias.

Clinically speaking, rituximab represents the first proven alternative to cyclophosphamide for remission induction in this patient population. The treatment presents the preferred option for patients interested in preserving fertility or who need to be re-treated for a severe disease flare. Based on these data, the US Food and Drug Administration recently extended the labeling of rituximab for treatment of GPA and MPA.

The European Vasculitis Study Group (EUVAS) launched another trial comparing the efficacy of rituximab with cyclophosphamide for remission induction.¹² The trial design differed from that of the RAVE trial in that investigators did not discontinue prednisone in all patients, followed patients for 12 months, and assessed sustained remission as the primary end point. In this trial, patients in the rituximab arm also received two single intravenous cyclophosphamide infusions, and cyclophosphamide in the control arm was given intravenously. All 44 patients enrolled in the trial and randomized 3:1 to the rituximab versus the cyclophosphamide control arm were ANCA-positive and had active renal disease. The patient population overall was older and had more severe renal disease than the patients enrolled in the RAVE trial. Overall, one course of rituximab achieved the same results as 6 months of intravenous pulse cyclophosphamide followed by oral azathioprine in terms of rate of sustained remission at 12 months, time to relapse, improvement of renal function, and rate of adverse events.

Mayo Clinic cohort study

Our group at Mayo Clinic evaluated the safety and effectiveness of rituximab when used repeatedly in order to maintain long-term remission.¹³ The study involved 53 patients who had a long-term (10 years, on average) diagnosis of refractory AAV. The patients received, on average, four courses of rituximab. All of these patients had GPA and all but one were PR3-ANCA–positive.

In this cohort, rituximab was effective and safe for induction and maintenance of remission in patients with relapsing GPA. The study showed that B-cell depletion effectively maintains remission in these patients, supporting the notion that B cells play an important role in GPA. Because rituximab works by depleting B cells and ANCA, timing of re-treatment can be individualized based on B-cell counts and ANCA levels. Thus, rituximab represents a promising alternative to standard therapy and a means for long-term patient management, particularly for those in whom other agents have failed to achieve or maintain remission in the past.

On a cautionary note, rituximab is an immunosuppressive agent. Risk of infection during treatment seems similar to that associated with carefully monitored cyclophosphamide followed by azathioprine. To avoid complications, physicians should also maintain Pneumocystis prophylaxis for at least the duration of B-cell depletion.

CONCLUSION

Enhanced understanding of the mechanism of action of cyclophosphamide has led to investigation of the role of B cells in the development of AAV and, from there, to the potential for treatment with biologics such as rituximab. Rituximab is equivalent in efficacy to cyclophosphamide for remission induction in AAV. It effectively restores remission and prevents relapse, and it is a better option than cyclophosphamide for PR3-ANCA–associated relapsing vasculitis. Future investigations should further address how to best prevent relapses after B-cell reconstitution.

Granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]) is a vasculitis that affects the renal and respiratory systems. Remission can be induced in most patients with the combination of glucocorticoids and cyclophosphamide. Unfortunately, patients often suffer disease relapses requiring re-treatment and exposure to the cumulative toxicities of repeated cyclophosphamide use. In recent years, improved understanding of the mechanisms of action of cyclophosphamide has led to investigation of treatment strategies that target the role of B cells more specifically in the pathogenesis of the disease.

This article reviews the results of recent studies involving the use of biologic therapy in the treatment of GPA, with a brief examination of historic events that influenced the design of recent trials.

HISTORICAL PERSPECTIVE

The natural history of GPA was characterized in 1958¹ in a retrospective study showing that 50% of those afflicted died within 6 months, and 80% died by 18 months. Prednisone and cyclophosphamide changed this dismal outcome. The combination markedly improved the status of 91% to 93% of patients,^2,3 with most achieving complete remission. Treatment came with a price, however. Almost all patients suffered serious morbidity or side effects, including chronic renal insufficiency (11% requiring dialysis), recurrent infections, hearing loss, infertility, and diabetes. In addition, most patients (99 of 155 in one study) suffered relapse and a significant number (19 of 155) died because of the disease or its treatment.

Investigators’ pursuit of treatment alternatives included foregoing cyclophosphamide in patients who had limited or early systemic GPA and reducing the duration of treatment for patients with severe disease.⁴ Studies conducted in the late 1990s defined what eventually became standard therapy for GPA: remission induction with glucocorticoids and methotrexate for limited GPA and with glucocorticoids and cyclophosphamide for severe disease. Following remission induction, after 3 to 6 months cyclophosphamide is replaced by azathioprine or methotrexate for remission maintenance. While helpful, these alternatives still fell short of achieving safe, long-term remission.

THERAPY WITH BIOLOGICS

Targeting tumor necrosis factor

The first randomized placebo-controlled trial of a biologic agent in GPA, the Wegener’s Granulomatosis Etanercept Trial (WGET),⁴ evaluated whether etanercept, a soluble inhibitor of tumor necrosis factor (TNF), would be an effective adjunct to standard therapy. The results showed that etanercept did not confer any beneficial effect and, in fact, if combined with exposure to cyclophosphamide, etanercept increased the risk for solid tumors. Thus, anti-TNF therapy has a limited or no role in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

Targeting B cells

The mechanisms of cyclophosphamide effects on disease activity were not clearly understood. In the late 1970s, however, National Institutes of Health investigators found that cyclophosphamide, at the doses administered for GPA, had a profound effect on B-cell function.⁵ Later investigations showed that disease activity of GPA was clearly related to the frequency of activated B cells detectable in the peripheral blood, while abnormally activated T cells were also detectable in patients in remission.⁶ These findings suggested that activated B cells might be responsible for disease activity, whereas persistently activated T cells might explain the chronically relapsing nature of the disease.⁶

B cells are the precursors of short-lived plasma cells, which are thought to be the primary source of autoantibodies, including ANCA. Based on clinical observations as well as in vitro and some animal model experiments, investigators have ascribed pathogenic roles to ANCA. Consequently, targeting the cells that produce these autoantibodies (short-lived plasma cells of B-cell origin) might form the basis of a novel treatment. Why not target cells of the B-cell lineage, thereby eliminating the short-lived plasma cells that would otherwise produce autoantibodies? This might be achieved with rituximab, a monoclonal antibody directed against the CD20 molecule found on pre-B and mature B cells.⁷ Our group first successfully deployed this strategy in the early 2000s, followed by an open-label pilot study.^8–10

The RAVE trial

The Rituximab in ANCA-Associated Vasculitis (RAVE) trial was a multicenter, randomized, placebo-controlled trial that compared rituximab for remission induction and maintenance with standard therapy consisting of cyclophosphamide followed by azathioprine in patients with severe AAV.¹¹ The results of a pilot trial in 2006¹⁰ set the stage for the RAVE trial, which hypothesized that treatment with rituximab plus glucocorticoids would not be inferior to daily cyclophosphamide plus glucocorticoids. Both would induce remission and permit discontinuation of prednisone after 6 months.

Nine centers enrolled a total of 197 patients with severe GPA or microscopic polyangiitis (MPA), all positive for ANCA, with active disease severe enough to warrant treatment with prednisone and cyclophosphamide. All participants received 1 to 3 g of methyl-prednisolone intravenously followed by prednisone (1 mg/kg per day). The treatment group received rituximab (375 mg/m² once weekly for 4 weeks) and the control group received standard therapy with cyclophosphamide (2 mg/kg per day) followed by azathioprine (2 mg/kg per day) after 3 to 6 months when remission was achieved.

The primary end point was complete remission, defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) of 0 and successful tapering of prednisone by 6 months. Secondary end points included rates of disease flares, cumulative glucocorticoid doses, rates of adverse events, and Medical Outcomes Study 36-item short-form health survey (SF-36, a measure of quality of life) scores. Among patients receiving rituximab, 64% reached the primary end point compared with 53% of patients in the control group. Rituximab was judged not inferior to standard therapy.

Results were similar for the secondary end point of disease remission while taking less than 10 mg/d of prednisone, with 71% of rituximab patients and 62% of control-group patients achieving remission. Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. Most strikingly, rituximab proved superior to the cyclophosphamide-based regimen for inducing remission in patients who entered the trial with relapsing disease (67% rituximab versus 42% cyclophosphamide) (Figure 1). Those who entered the trial with a new diagnosis did not show the same difference in efficacy.

Rituximab also proved significantly more effective than cyclophosphamide for patients who had proteinase-3 (PR3) ANCA, whereas the efficacy of both agents was equivalent among patients who had myeloperoxidase ANCA. Patients in the cyclophosphamide arm experienced more leukopenia compared with the rituximab arm, but this did not lead to more infections.

In summary, the RAVE trial showed that rituximab matched the efficacy of cyclophosphamide (standard therapy) in inducing remission in patients with severe AAV. The results held true for subsets of patients with major renal disease and those with alveolar hemorrhage. Most strikingly, among patients who entered the trial with a severe relapse, those who received rituximab responded better than those treated with cyclophosphamide. There were no significant differences in flare rates by 6 months and no difference in the rate of severe adverse events. However, participants receiving cyclophosphamide experienced more selected adverse events, particularly leukopenias.

Clinically speaking, rituximab represents the first proven alternative to cyclophosphamide for remission induction in this patient population. The treatment presents the preferred option for patients interested in preserving fertility or who need to be re-treated for a severe disease flare. Based on these data, the US Food and Drug Administration recently extended the labeling of rituximab for treatment of GPA and MPA.

The European Vasculitis Study Group (EUVAS) launched another trial comparing the efficacy of rituximab with cyclophosphamide for remission induction.¹² The trial design differed from that of the RAVE trial in that investigators did not discontinue prednisone in all patients, followed patients for 12 months, and assessed sustained remission as the primary end point. In this trial, patients in the rituximab arm also received two single intravenous cyclophosphamide infusions, and cyclophosphamide in the control arm was given intravenously. All 44 patients enrolled in the trial and randomized 3:1 to the rituximab versus the cyclophosphamide control arm were ANCA-positive and had active renal disease. The patient population overall was older and had more severe renal disease than the patients enrolled in the RAVE trial. Overall, one course of rituximab achieved the same results as 6 months of intravenous pulse cyclophosphamide followed by oral azathioprine in terms of rate of sustained remission at 12 months, time to relapse, improvement of renal function, and rate of adverse events.

Mayo Clinic cohort study

Our group at Mayo Clinic evaluated the safety and effectiveness of rituximab when used repeatedly in order to maintain long-term remission.¹³ The study involved 53 patients who had a long-term (10 years, on average) diagnosis of refractory AAV. The patients received, on average, four courses of rituximab. All of these patients had GPA and all but one were PR3-ANCA–positive.

In this cohort, rituximab was effective and safe for induction and maintenance of remission in patients with relapsing GPA. The study showed that B-cell depletion effectively maintains remission in these patients, supporting the notion that B cells play an important role in GPA. Because rituximab works by depleting B cells and ANCA, timing of re-treatment can be individualized based on B-cell counts and ANCA levels. Thus, rituximab represents a promising alternative to standard therapy and a means for long-term patient management, particularly for those in whom other agents have failed to achieve or maintain remission in the past.

On a cautionary note, rituximab is an immunosuppressive agent. Risk of infection during treatment seems similar to that associated with carefully monitored cyclophosphamide followed by azathioprine. To avoid complications, physicians should also maintain Pneumocystis prophylaxis for at least the duration of B-cell depletion.

CONCLUSION

Enhanced understanding of the mechanism of action of cyclophosphamide has led to investigation of the role of B cells in the development of AAV and, from there, to the potential for treatment with biologics such as rituximab. Rituximab is equivalent in efficacy to cyclophosphamide for remission induction in AAV. It effectively restores remission and prevents relapse, and it is a better option than cyclophosphamide for PR3-ANCA–associated relapsing vasculitis. Future investigations should further address how to best prevent relapses after B-cell reconstitution.

Granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]) is a vasculitis that affects the renal and respiratory systems. Remission can be induced in most patients with the combination of glucocorticoids and cyclophosphamide. Unfortunately, patients often suffer disease relapses requiring re-treatment and exposure to the cumulative toxicities of repeated cyclophosphamide use. In recent years, improved understanding of the mechanisms of action of cyclophosphamide has led to investigation of treatment strategies that target the role of B cells more specifically in the pathogenesis of the disease.

This article reviews the results of recent studies involving the use of biologic therapy in the treatment of GPA, with a brief examination of historic events that influenced the design of recent trials.

HISTORICAL PERSPECTIVE

The natural history of GPA was characterized in 1958¹ in a retrospective study showing that 50% of those afflicted died within 6 months, and 80% died by 18 months. Prednisone and cyclophosphamide changed this dismal outcome. The combination markedly improved the status of 91% to 93% of patients,^2,3 with most achieving complete remission. Treatment came with a price, however. Almost all patients suffered serious morbidity or side effects, including chronic renal insufficiency (11% requiring dialysis), recurrent infections, hearing loss, infertility, and diabetes. In addition, most patients (99 of 155 in one study) suffered relapse and a significant number (19 of 155) died because of the disease or its treatment.

Investigators’ pursuit of treatment alternatives included foregoing cyclophosphamide in patients who had limited or early systemic GPA and reducing the duration of treatment for patients with severe disease.⁴ Studies conducted in the late 1990s defined what eventually became standard therapy for GPA: remission induction with glucocorticoids and methotrexate for limited GPA and with glucocorticoids and cyclophosphamide for severe disease. Following remission induction, after 3 to 6 months cyclophosphamide is replaced by azathioprine or methotrexate for remission maintenance. While helpful, these alternatives still fell short of achieving safe, long-term remission.

THERAPY WITH BIOLOGICS

Targeting tumor necrosis factor

The first randomized placebo-controlled trial of a biologic agent in GPA, the Wegener’s Granulomatosis Etanercept Trial (WGET),⁴ evaluated whether etanercept, a soluble inhibitor of tumor necrosis factor (TNF), would be an effective adjunct to standard therapy. The results showed that etanercept did not confer any beneficial effect and, in fact, if combined with exposure to cyclophosphamide, etanercept increased the risk for solid tumors. Thus, anti-TNF therapy has a limited or no role in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

Targeting B cells

The mechanisms of cyclophosphamide effects on disease activity were not clearly understood. In the late 1970s, however, National Institutes of Health investigators found that cyclophosphamide, at the doses administered for GPA, had a profound effect on B-cell function.⁵ Later investigations showed that disease activity of GPA was clearly related to the frequency of activated B cells detectable in the peripheral blood, while abnormally activated T cells were also detectable in patients in remission.⁶ These findings suggested that activated B cells might be responsible for disease activity, whereas persistently activated T cells might explain the chronically relapsing nature of the disease.⁶

B cells are the precursors of short-lived plasma cells, which are thought to be the primary source of autoantibodies, including ANCA. Based on clinical observations as well as in vitro and some animal model experiments, investigators have ascribed pathogenic roles to ANCA. Consequently, targeting the cells that produce these autoantibodies (short-lived plasma cells of B-cell origin) might form the basis of a novel treatment. Why not target cells of the B-cell lineage, thereby eliminating the short-lived plasma cells that would otherwise produce autoantibodies? This might be achieved with rituximab, a monoclonal antibody directed against the CD20 molecule found on pre-B and mature B cells.⁷ Our group first successfully deployed this strategy in the early 2000s, followed by an open-label pilot study.^8–10

The RAVE trial

The Rituximab in ANCA-Associated Vasculitis (RAVE) trial was a multicenter, randomized, placebo-controlled trial that compared rituximab for remission induction and maintenance with standard therapy consisting of cyclophosphamide followed by azathioprine in patients with severe AAV.¹¹ The results of a pilot trial in 2006¹⁰ set the stage for the RAVE trial, which hypothesized that treatment with rituximab plus glucocorticoids would not be inferior to daily cyclophosphamide plus glucocorticoids. Both would induce remission and permit discontinuation of prednisone after 6 months.

Nine centers enrolled a total of 197 patients with severe GPA or microscopic polyangiitis (MPA), all positive for ANCA, with active disease severe enough to warrant treatment with prednisone and cyclophosphamide. All participants received 1 to 3 g of methyl-prednisolone intravenously followed by prednisone (1 mg/kg per day). The treatment group received rituximab (375 mg/m² once weekly for 4 weeks) and the control group received standard therapy with cyclophosphamide (2 mg/kg per day) followed by azathioprine (2 mg/kg per day) after 3 to 6 months when remission was achieved.

The primary end point was complete remission, defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) of 0 and successful tapering of prednisone by 6 months. Secondary end points included rates of disease flares, cumulative glucocorticoid doses, rates of adverse events, and Medical Outcomes Study 36-item short-form health survey (SF-36, a measure of quality of life) scores. Among patients receiving rituximab, 64% reached the primary end point compared with 53% of patients in the control group. Rituximab was judged not inferior to standard therapy.

Results were similar for the secondary end point of disease remission while taking less than 10 mg/d of prednisone, with 71% of rituximab patients and 62% of control-group patients achieving remission. Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. Most strikingly, rituximab proved superior to the cyclophosphamide-based regimen for inducing remission in patients who entered the trial with relapsing disease (67% rituximab versus 42% cyclophosphamide) (Figure 1). Those who entered the trial with a new diagnosis did not show the same difference in efficacy.

Rituximab also proved significantly more effective than cyclophosphamide for patients who had proteinase-3 (PR3) ANCA, whereas the efficacy of both agents was equivalent among patients who had myeloperoxidase ANCA. Patients in the cyclophosphamide arm experienced more leukopenia compared with the rituximab arm, but this did not lead to more infections.

In summary, the RAVE trial showed that rituximab matched the efficacy of cyclophosphamide (standard therapy) in inducing remission in patients with severe AAV. The results held true for subsets of patients with major renal disease and those with alveolar hemorrhage. Most strikingly, among patients who entered the trial with a severe relapse, those who received rituximab responded better than those treated with cyclophosphamide. There were no significant differences in flare rates by 6 months and no difference in the rate of severe adverse events. However, participants receiving cyclophosphamide experienced more selected adverse events, particularly leukopenias.

Clinically speaking, rituximab represents the first proven alternative to cyclophosphamide for remission induction in this patient population. The treatment presents the preferred option for patients interested in preserving fertility or who need to be re-treated for a severe disease flare. Based on these data, the US Food and Drug Administration recently extended the labeling of rituximab for treatment of GPA and MPA.

The European Vasculitis Study Group (EUVAS) launched another trial comparing the efficacy of rituximab with cyclophosphamide for remission induction.¹² The trial design differed from that of the RAVE trial in that investigators did not discontinue prednisone in all patients, followed patients for 12 months, and assessed sustained remission as the primary end point. In this trial, patients in the rituximab arm also received two single intravenous cyclophosphamide infusions, and cyclophosphamide in the control arm was given intravenously. All 44 patients enrolled in the trial and randomized 3:1 to the rituximab versus the cyclophosphamide control arm were ANCA-positive and had active renal disease. The patient population overall was older and had more severe renal disease than the patients enrolled in the RAVE trial. Overall, one course of rituximab achieved the same results as 6 months of intravenous pulse cyclophosphamide followed by oral azathioprine in terms of rate of sustained remission at 12 months, time to relapse, improvement of renal function, and rate of adverse events.

Mayo Clinic cohort study

Our group at Mayo Clinic evaluated the safety and effectiveness of rituximab when used repeatedly in order to maintain long-term remission.¹³ The study involved 53 patients who had a long-term (10 years, on average) diagnosis of refractory AAV. The patients received, on average, four courses of rituximab. All of these patients had GPA and all but one were PR3-ANCA–positive.

In this cohort, rituximab was effective and safe for induction and maintenance of remission in patients with relapsing GPA. The study showed that B-cell depletion effectively maintains remission in these patients, supporting the notion that B cells play an important role in GPA. Because rituximab works by depleting B cells and ANCA, timing of re-treatment can be individualized based on B-cell counts and ANCA levels. Thus, rituximab represents a promising alternative to standard therapy and a means for long-term patient management, particularly for those in whom other agents have failed to achieve or maintain remission in the past.

On a cautionary note, rituximab is an immunosuppressive agent. Risk of infection during treatment seems similar to that associated with carefully monitored cyclophosphamide followed by azathioprine. To avoid complications, physicians should also maintain Pneumocystis prophylaxis for at least the duration of B-cell depletion.

CONCLUSION

Enhanced understanding of the mechanism of action of cyclophosphamide has led to investigation of the role of B cells in the development of AAV and, from there, to the potential for treatment with biologics such as rituximab. Rituximab is equivalent in efficacy to cyclophosphamide for remission induction in AAV. It effectively restores remission and prevents relapse, and it is a better option than cyclophosphamide for PR3-ANCA–associated relapsing vasculitis. Future investigations should further address how to best prevent relapses after B-cell reconstitution.

Adolf Kussmaul, who lived and practiced medicine in the 19th century, is known for his clinical skills, his scientific acumen, his gift for teaching, and his mastery of diverse areas of knowledge. He was a contemporary of such luminaries as pathologist Rudolf Virchow. In the rheumatology community, he is best known for describing the first case of polyarteritis nodosa (PAN).

FIRST CASE

In the first volume of the first edition of German Archive for Clinical Medicine, Kussmaul, along with his pathology associate Rudolf Maier, reported the case of Carl Seufarth, a 27-year-old tailor’s journeyman. Seufarth arrived at the University of Freiburg internal medicine clinic on May 4, 1865, at 10 am. Kussmaul was at that time head of medicine at Freiburg. Seufarth’s journeyman’s log recorded that he had been healthy when he left his hometown of Gernsbach in southwest Germany on January 30, 1865. His entry indicated that he was 5 feet 2 inches tall, was of strong build, and had healthy facial color.

Kussmaul’s 1866 description of Seufarth upon his arrival at the clinic is among the most memorable passages in medical literature:

Despite his frail appearance, Seufarth was able to walk into the hospital and climb the two flights of stairs to the internal medicine clinic without assistance. He had had a cold followed by a productive cough in the autumn of 1864, but felt well afterward. In the 8 days prior to admission to the University of Freiburg, he developed diarrhea and frequent chills with fevers and sweats. He had felt unwell for the preceding 2 to 3 weeks, during which he was hospitalized briefly for scabies, wandered from one place to another, and eventually arrived in Freiburg. Freiburg police imprisoned him on May 2 for begging and brought him to the internal medicine department on May 4 because of weakness.

Over the next several days, Seufarth experienced rapidly developing weakness, numbness in the left hand and eventually other extremities, and paralysis of the arm and hand muscles. He was closely monitored at the clinic with his temperature recorded every morning and evening. On the 28th day of hospitalization, pea-sized nodules were discovered in the subcutaneous skin of the abdomen and chest. By June 2, the patient was in a state of extreme weakness. He died on June 3, 1865, at 2 am.

Source: Kussmaul A, Maier R. Über eine bisher nicht beschriebene, eigentümliche Arterienerkrankung (Periarteritis nodosa), die mit Morbus Brightii und rapid fortschreitender allgemeiner Muskellähmung einhergeht. Deutsches Arch klin Med 1866; 1:484–518.

This description is what we understand today as typical of vascular involvement in PAN. Maier also examined the tissue microscopically. In his report, he described the aneurysmal dilatations, narrowings, and inflammation occurring at the branches of the arteries. His sketch of involved organs depicted neutrophilic infiltration into the walls of the vessels.

When consulted by Kussmaul for a second opinion, pathologist Rudolf Virchow said he had not observed patients with disease similar to that of Seufarth. In his archives, however, he later found a specimen of an aneurysm in a branch of the superior mesenteric artery.

Kussmaul and Maier published the case under the title “On a previously undescribed peculiar arterial disease (periarteritis nodosa) accompanied by Bright’s disease and rapidly progressive general muscle weakness.” “Periarteritis nodosa” was later termed “polyarteritis nodosa” to better describe the inflammation of multiple medium-and small-vessel arteries rather than inflammation around the arteries as Maier had initially envisioned it.

BIOGRAPHICAL NOTES

The son of a German army surgeon, Kussmaul was born in 1822 in Graben near Karlsruhe, a small town in the Black Forest of southwestern Germany. Kussmaul began his medical studies at the University of Heidelberg in 1840. That same year, he constructed the first ophthalmoscope. The device did not function as intended because he had not discovered the light orientation needed to prevent the iris from contracting. But, as he later said, “It was the best ophthalmoscope of the time. Its only drawback was that it did not work.”

After graduating from the University of Heidelberg, Kussmaul went into private practice in Wiesloch. He returned to the University a year later, after having developed pericarditis, where he served as an assistant in 1846 and 1847 and engaged not only in medicine and medical discovery, but also poetry, publishing, and social movements. He founded a magazine that published short stories, poetry, and spoofs on the government; and he coined the term “Biedermeier,” which refers to a furniture style as well as a German social movement.

With plans to further his medical education, Kussmaul and his friend, Edward Bronner, traveled to Vienna and Prague in 1847 and 1848. In Vienna, they met the anatomic pathologist Karl Rokitansky. Although the young men hoped to study with the renowned scientist, they were soon dissuaded by Rokitansky’s clear dislike of working with students. He also had little use for patients, holding that the best patient was a dead patient because of all that one could learn by doing an autopsy.

Kussmaul and Bronner returned to Germany, Kussmaul having been called to serve as a physician in the Baden battalion during the German-Danish war. There, he contributed significantly to the health of the army by insisting that wounded soldiers not be bled—a common treatment at that time that actually accelerated the deaths of many soldiers in the field.

ACADEMICIAN, SCIENTIST, AND CLINICIAN

Shortly after his 1850 marriage to Luise Amanda Wolf, the daughter of a famous surgeon, Kussmaul developed an ascending polyradiculopathy, which at one time was called Landry-Kussmaul paralysis and later Guillain-Barré syndrome. This condition, along with his previous history of pericarditis, stimulated Kussmaul’s pursuit of medical knowledge for better understanding of his own afflictions as well as medicine in general.

He completed his doctoral dissertation at the University of Würzburg in 1853. There, he worked with pathology professor Virchow, who is known as the father of the theory of coagulation and the cellular theory of disease. It is perhaps less well known that in a treatise on histopathology in 1847, Virchow proposed that vasculitis actually might occur in blood vessels and originate in the adventitia. This profound insight was lost at the time because of inadequate understanding of vasculitic disorders.

Returning to the University of Heidelberg in 1854, Kussmaul earned the rank of assistant professor of medicine and, by 1857, professor of medicine. Two years later, he relocated to the University of Erlangen as a professor of medicine. His inaugural lecture at the University of Erlangen was the presentation of two cases of Landry-Kussmaul paralysis. Kussmaul’s research at Erlangen focused on differentiating the symptoms of mercurialism from syphilis (mercury was used for the treatment of syphilis).

Kussmaul was then called to the University of Freiburg in 1863 as head of the department of medicine. Among Kussmaul’s achievements at the University of Freiburg in the 1860s were the description of paradoxical pulse in obstructive pericarditis that we know as the Kussmaul pulse, and the description of the breathing characteristic of diabetic acidotic coma that we know as Kussmaul respiration. There he also performed the first gastroscopy on a sword-swallowing circus performer using a derivation of a laryngoscope; unfortunately, again his invention was thwarted by lack of an adequate light source. He also studied peptic ulcer disease and described a technique for dilating a stenosed peptic ulcer lesion with a balloon device. He later worked with Czerny and Billroth to develop the surgical procedure used routinely for nearly 100 years to relieve peptic ulcer disease prior to the introduction of drugs such as ranitidine.

RHEUMATOLOGY “WORMS”

Kussmaul and Maier initially published the Seufarth case in abstract form and called it “human worm aneurysm,” because they thought that the vascular pea-shaped or pea-sized structures represented worm and nematode infiltration. When they examined the specimens microscopically, however, they realized that they were viewing an inflammatory disease process.

Source: Eppinger H. Pathogenesis (Histogenesis und Aethiologie) der Aneurysmen einschliesslich des aneurysma equi verminosum. Arch Klin Chir 1887; 35:1–563.

Ironically, vessel disease of the PAN type was described in 1852 by Rokitansky. Rokitansky reported finding mesenteric aneurysms in the branch points of the arteries; however, because he eschewed technology, he did not examine the specimen microscopically and failed to recognize the inflammatory process. His student, Hans Eppinger, revisited the specimen some 30 years later and, under microscopic examination, clearly defined the aneurysmal dilatations and inflammatory infiltrates (Figure 2).

A final rheumatology worm episode occurred late in Kussmaul’s career in Strasburg, where he had become head of the department of medicine in 1878. Kussmaul asked his assistant and biographer, Albert Kahn, to administer naphthalene to a patient to eradicate intestinal worms. Strangely, the worms survived, but the fever resolved. Due to a pharmacy error, acetanilide, an anti-inflammatory marketed by Bayer, had been dispensed rather than naphthalene. Bayer subsequently marketed the product as Antifebrin.

REMEMBERED AND COMMEMORATED

Kussmaul was a much-loved teacher and a well-respected physician. After he retired in 1888, he returned to Heidelberg as emeritus professor of medicine. He died in 1902 at age 80. His desire to understand disease, his clinical observations, his teaching abilities, and his ability to apply medical technology to the bedside all played roles in his contributions to clinical medicine. One of several Kussmaul commemoration sites is a lunette in Lenox Hill Hospital, New York, New York, where his portrait plaque is displayed alongside those of Ismar Boas and Carl Anton Ewald, the founders of modern gastroenterology.

Adolf Kussmaul, who lived and practiced medicine in the 19th century, is known for his clinical skills, his scientific acumen, his gift for teaching, and his mastery of diverse areas of knowledge. He was a contemporary of such luminaries as pathologist Rudolf Virchow. In the rheumatology community, he is best known for describing the first case of polyarteritis nodosa (PAN).

FIRST CASE

In the first volume of the first edition of German Archive for Clinical Medicine, Kussmaul, along with his pathology associate Rudolf Maier, reported the case of Carl Seufarth, a 27-year-old tailor’s journeyman. Seufarth arrived at the University of Freiburg internal medicine clinic on May 4, 1865, at 10 am. Kussmaul was at that time head of medicine at Freiburg. Seufarth’s journeyman’s log recorded that he had been healthy when he left his hometown of Gernsbach in southwest Germany on January 30, 1865. His entry indicated that he was 5 feet 2 inches tall, was of strong build, and had healthy facial color.

Kussmaul’s 1866 description of Seufarth upon his arrival at the clinic is among the most memorable passages in medical literature:

Despite his frail appearance, Seufarth was able to walk into the hospital and climb the two flights of stairs to the internal medicine clinic without assistance. He had had a cold followed by a productive cough in the autumn of 1864, but felt well afterward. In the 8 days prior to admission to the University of Freiburg, he developed diarrhea and frequent chills with fevers and sweats. He had felt unwell for the preceding 2 to 3 weeks, during which he was hospitalized briefly for scabies, wandered from one place to another, and eventually arrived in Freiburg. Freiburg police imprisoned him on May 2 for begging and brought him to the internal medicine department on May 4 because of weakness.

Over the next several days, Seufarth experienced rapidly developing weakness, numbness in the left hand and eventually other extremities, and paralysis of the arm and hand muscles. He was closely monitored at the clinic with his temperature recorded every morning and evening. On the 28th day of hospitalization, pea-sized nodules were discovered in the subcutaneous skin of the abdomen and chest. By June 2, the patient was in a state of extreme weakness. He died on June 3, 1865, at 2 am.

Source: Kussmaul A, Maier R. Über eine bisher nicht beschriebene, eigentümliche Arterienerkrankung (Periarteritis nodosa), die mit Morbus Brightii und rapid fortschreitender allgemeiner Muskellähmung einhergeht. Deutsches Arch klin Med 1866; 1:484–518.

This description is what we understand today as typical of vascular involvement in PAN. Maier also examined the tissue microscopically. In his report, he described the aneurysmal dilatations, narrowings, and inflammation occurring at the branches of the arteries. His sketch of involved organs depicted neutrophilic infiltration into the walls of the vessels.

When consulted by Kussmaul for a second opinion, pathologist Rudolf Virchow said he had not observed patients with disease similar to that of Seufarth. In his archives, however, he later found a specimen of an aneurysm in a branch of the superior mesenteric artery.

Kussmaul and Maier published the case under the title “On a previously undescribed peculiar arterial disease (periarteritis nodosa) accompanied by Bright’s disease and rapidly progressive general muscle weakness.” “Periarteritis nodosa” was later termed “polyarteritis nodosa” to better describe the inflammation of multiple medium-and small-vessel arteries rather than inflammation around the arteries as Maier had initially envisioned it.

BIOGRAPHICAL NOTES

The son of a German army surgeon, Kussmaul was born in 1822 in Graben near Karlsruhe, a small town in the Black Forest of southwestern Germany. Kussmaul began his medical studies at the University of Heidelberg in 1840. That same year, he constructed the first ophthalmoscope. The device did not function as intended because he had not discovered the light orientation needed to prevent the iris from contracting. But, as he later said, “It was the best ophthalmoscope of the time. Its only drawback was that it did not work.”

After graduating from the University of Heidelberg, Kussmaul went into private practice in Wiesloch. He returned to the University a year later, after having developed pericarditis, where he served as an assistant in 1846 and 1847 and engaged not only in medicine and medical discovery, but also poetry, publishing, and social movements. He founded a magazine that published short stories, poetry, and spoofs on the government; and he coined the term “Biedermeier,” which refers to a furniture style as well as a German social movement.

With plans to further his medical education, Kussmaul and his friend, Edward Bronner, traveled to Vienna and Prague in 1847 and 1848. In Vienna, they met the anatomic pathologist Karl Rokitansky. Although the young men hoped to study with the renowned scientist, they were soon dissuaded by Rokitansky’s clear dislike of working with students. He also had little use for patients, holding that the best patient was a dead patient because of all that one could learn by doing an autopsy.

Kussmaul and Bronner returned to Germany, Kussmaul having been called to serve as a physician in the Baden battalion during the German-Danish war. There, he contributed significantly to the health of the army by insisting that wounded soldiers not be bled—a common treatment at that time that actually accelerated the deaths of many soldiers in the field.

ACADEMICIAN, SCIENTIST, AND CLINICIAN

Shortly after his 1850 marriage to Luise Amanda Wolf, the daughter of a famous surgeon, Kussmaul developed an ascending polyradiculopathy, which at one time was called Landry-Kussmaul paralysis and later Guillain-Barré syndrome. This condition, along with his previous history of pericarditis, stimulated Kussmaul’s pursuit of medical knowledge for better understanding of his own afflictions as well as medicine in general.

He completed his doctoral dissertation at the University of Würzburg in 1853. There, he worked with pathology professor Virchow, who is known as the father of the theory of coagulation and the cellular theory of disease. It is perhaps less well known that in a treatise on histopathology in 1847, Virchow proposed that vasculitis actually might occur in blood vessels and originate in the adventitia. This profound insight was lost at the time because of inadequate understanding of vasculitic disorders.

Returning to the University of Heidelberg in 1854, Kussmaul earned the rank of assistant professor of medicine and, by 1857, professor of medicine. Two years later, he relocated to the University of Erlangen as a professor of medicine. His inaugural lecture at the University of Erlangen was the presentation of two cases of Landry-Kussmaul paralysis. Kussmaul’s research at Erlangen focused on differentiating the symptoms of mercurialism from syphilis (mercury was used for the treatment of syphilis).

Kussmaul was then called to the University of Freiburg in 1863 as head of the department of medicine. Among Kussmaul’s achievements at the University of Freiburg in the 1860s were the description of paradoxical pulse in obstructive pericarditis that we know as the Kussmaul pulse, and the description of the breathing characteristic of diabetic acidotic coma that we know as Kussmaul respiration. There he also performed the first gastroscopy on a sword-swallowing circus performer using a derivation of a laryngoscope; unfortunately, again his invention was thwarted by lack of an adequate light source. He also studied peptic ulcer disease and described a technique for dilating a stenosed peptic ulcer lesion with a balloon device. He later worked with Czerny and Billroth to develop the surgical procedure used routinely for nearly 100 years to relieve peptic ulcer disease prior to the introduction of drugs such as ranitidine.

RHEUMATOLOGY “WORMS”

Kussmaul and Maier initially published the Seufarth case in abstract form and called it “human worm aneurysm,” because they thought that the vascular pea-shaped or pea-sized structures represented worm and nematode infiltration. When they examined the specimens microscopically, however, they realized that they were viewing an inflammatory disease process.

Source: Eppinger H. Pathogenesis (Histogenesis und Aethiologie) der Aneurysmen einschliesslich des aneurysma equi verminosum. Arch Klin Chir 1887; 35:1–563.

Ironically, vessel disease of the PAN type was described in 1852 by Rokitansky. Rokitansky reported finding mesenteric aneurysms in the branch points of the arteries; however, because he eschewed technology, he did not examine the specimen microscopically and failed to recognize the inflammatory process. His student, Hans Eppinger, revisited the specimen some 30 years later and, under microscopic examination, clearly defined the aneurysmal dilatations and inflammatory infiltrates (Figure 2).

A final rheumatology worm episode occurred late in Kussmaul’s career in Strasburg, where he had become head of the department of medicine in 1878. Kussmaul asked his assistant and biographer, Albert Kahn, to administer naphthalene to a patient to eradicate intestinal worms. Strangely, the worms survived, but the fever resolved. Due to a pharmacy error, acetanilide, an anti-inflammatory marketed by Bayer, had been dispensed rather than naphthalene. Bayer subsequently marketed the product as Antifebrin.

REMEMBERED AND COMMEMORATED

Kussmaul was a much-loved teacher and a well-respected physician. After he retired in 1888, he returned to Heidelberg as emeritus professor of medicine. He died in 1902 at age 80. His desire to understand disease, his clinical observations, his teaching abilities, and his ability to apply medical technology to the bedside all played roles in his contributions to clinical medicine. One of several Kussmaul commemoration sites is a lunette in Lenox Hill Hospital, New York, New York, where his portrait plaque is displayed alongside those of Ismar Boas and Carl Anton Ewald, the founders of modern gastroenterology.

Adolf Kussmaul, who lived and practiced medicine in the 19th century, is known for his clinical skills, his scientific acumen, his gift for teaching, and his mastery of diverse areas of knowledge. He was a contemporary of such luminaries as pathologist Rudolf Virchow. In the rheumatology community, he is best known for describing the first case of polyarteritis nodosa (PAN).

FIRST CASE

In the first volume of the first edition of German Archive for Clinical Medicine, Kussmaul, along with his pathology associate Rudolf Maier, reported the case of Carl Seufarth, a 27-year-old tailor’s journeyman. Seufarth arrived at the University of Freiburg internal medicine clinic on May 4, 1865, at 10 am. Kussmaul was at that time head of medicine at Freiburg. Seufarth’s journeyman’s log recorded that he had been healthy when he left his hometown of Gernsbach in southwest Germany on January 30, 1865. His entry indicated that he was 5 feet 2 inches tall, was of strong build, and had healthy facial color.

Kussmaul’s 1866 description of Seufarth upon his arrival at the clinic is among the most memorable passages in medical literature:

Despite his frail appearance, Seufarth was able to walk into the hospital and climb the two flights of stairs to the internal medicine clinic without assistance. He had had a cold followed by a productive cough in the autumn of 1864, but felt well afterward. In the 8 days prior to admission to the University of Freiburg, he developed diarrhea and frequent chills with fevers and sweats. He had felt unwell for the preceding 2 to 3 weeks, during which he was hospitalized briefly for scabies, wandered from one place to another, and eventually arrived in Freiburg. Freiburg police imprisoned him on May 2 for begging and brought him to the internal medicine department on May 4 because of weakness.

Over the next several days, Seufarth experienced rapidly developing weakness, numbness in the left hand and eventually other extremities, and paralysis of the arm and hand muscles. He was closely monitored at the clinic with his temperature recorded every morning and evening. On the 28th day of hospitalization, pea-sized nodules were discovered in the subcutaneous skin of the abdomen and chest. By June 2, the patient was in a state of extreme weakness. He died on June 3, 1865, at 2 am.

Source: Kussmaul A, Maier R. Über eine bisher nicht beschriebene, eigentümliche Arterienerkrankung (Periarteritis nodosa), die mit Morbus Brightii und rapid fortschreitender allgemeiner Muskellähmung einhergeht. Deutsches Arch klin Med 1866; 1:484–518.

This description is what we understand today as typical of vascular involvement in PAN. Maier also examined the tissue microscopically. In his report, he described the aneurysmal dilatations, narrowings, and inflammation occurring at the branches of the arteries. His sketch of involved organs depicted neutrophilic infiltration into the walls of the vessels.

When consulted by Kussmaul for a second opinion, pathologist Rudolf Virchow said he had not observed patients with disease similar to that of Seufarth. In his archives, however, he later found a specimen of an aneurysm in a branch of the superior mesenteric artery.

Kussmaul and Maier published the case under the title “On a previously undescribed peculiar arterial disease (periarteritis nodosa) accompanied by Bright’s disease and rapidly progressive general muscle weakness.” “Periarteritis nodosa” was later termed “polyarteritis nodosa” to better describe the inflammation of multiple medium-and small-vessel arteries rather than inflammation around the arteries as Maier had initially envisioned it.

BIOGRAPHICAL NOTES

The son of a German army surgeon, Kussmaul was born in 1822 in Graben near Karlsruhe, a small town in the Black Forest of southwestern Germany. Kussmaul began his medical studies at the University of Heidelberg in 1840. That same year, he constructed the first ophthalmoscope. The device did not function as intended because he had not discovered the light orientation needed to prevent the iris from contracting. But, as he later said, “It was the best ophthalmoscope of the time. Its only drawback was that it did not work.”

After graduating from the University of Heidelberg, Kussmaul went into private practice in Wiesloch. He returned to the University a year later, after having developed pericarditis, where he served as an assistant in 1846 and 1847 and engaged not only in medicine and medical discovery, but also poetry, publishing, and social movements. He founded a magazine that published short stories, poetry, and spoofs on the government; and he coined the term “Biedermeier,” which refers to a furniture style as well as a German social movement.

With plans to further his medical education, Kussmaul and his friend, Edward Bronner, traveled to Vienna and Prague in 1847 and 1848. In Vienna, they met the anatomic pathologist Karl Rokitansky. Although the young men hoped to study with the renowned scientist, they were soon dissuaded by Rokitansky’s clear dislike of working with students. He also had little use for patients, holding that the best patient was a dead patient because of all that one could learn by doing an autopsy.

Kussmaul and Bronner returned to Germany, Kussmaul having been called to serve as a physician in the Baden battalion during the German-Danish war. There, he contributed significantly to the health of the army by insisting that wounded soldiers not be bled—a common treatment at that time that actually accelerated the deaths of many soldiers in the field.

ACADEMICIAN, SCIENTIST, AND CLINICIAN

Shortly after his 1850 marriage to Luise Amanda Wolf, the daughter of a famous surgeon, Kussmaul developed an ascending polyradiculopathy, which at one time was called Landry-Kussmaul paralysis and later Guillain-Barré syndrome. This condition, along with his previous history of pericarditis, stimulated Kussmaul’s pursuit of medical knowledge for better understanding of his own afflictions as well as medicine in general.

He completed his doctoral dissertation at the University of Würzburg in 1853. There, he worked with pathology professor Virchow, who is known as the father of the theory of coagulation and the cellular theory of disease. It is perhaps less well known that in a treatise on histopathology in 1847, Virchow proposed that vasculitis actually might occur in blood vessels and originate in the adventitia. This profound insight was lost at the time because of inadequate understanding of vasculitic disorders.

Returning to the University of Heidelberg in 1854, Kussmaul earned the rank of assistant professor of medicine and, by 1857, professor of medicine. Two years later, he relocated to the University of Erlangen as a professor of medicine. His inaugural lecture at the University of Erlangen was the presentation of two cases of Landry-Kussmaul paralysis. Kussmaul’s research at Erlangen focused on differentiating the symptoms of mercurialism from syphilis (mercury was used for the treatment of syphilis).

Kussmaul was then called to the University of Freiburg in 1863 as head of the department of medicine. Among Kussmaul’s achievements at the University of Freiburg in the 1860s were the description of paradoxical pulse in obstructive pericarditis that we know as the Kussmaul pulse, and the description of the breathing characteristic of diabetic acidotic coma that we know as Kussmaul respiration. There he also performed the first gastroscopy on a sword-swallowing circus performer using a derivation of a laryngoscope; unfortunately, again his invention was thwarted by lack of an adequate light source. He also studied peptic ulcer disease and described a technique for dilating a stenosed peptic ulcer lesion with a balloon device. He later worked with Czerny and Billroth to develop the surgical procedure used routinely for nearly 100 years to relieve peptic ulcer disease prior to the introduction of drugs such as ranitidine.

RHEUMATOLOGY “WORMS”

Kussmaul and Maier initially published the Seufarth case in abstract form and called it “human worm aneurysm,” because they thought that the vascular pea-shaped or pea-sized structures represented worm and nematode infiltration. When they examined the specimens microscopically, however, they realized that they were viewing an inflammatory disease process.

Source: Eppinger H. Pathogenesis (Histogenesis und Aethiologie) der Aneurysmen einschliesslich des aneurysma equi verminosum. Arch Klin Chir 1887; 35:1–563.

Ironically, vessel disease of the PAN type was described in 1852 by Rokitansky. Rokitansky reported finding mesenteric aneurysms in the branch points of the arteries; however, because he eschewed technology, he did not examine the specimen microscopically and failed to recognize the inflammatory process. His student, Hans Eppinger, revisited the specimen some 30 years later and, under microscopic examination, clearly defined the aneurysmal dilatations and inflammatory infiltrates (Figure 2).

A final rheumatology worm episode occurred late in Kussmaul’s career in Strasburg, where he had become head of the department of medicine in 1878. Kussmaul asked his assistant and biographer, Albert Kahn, to administer naphthalene to a patient to eradicate intestinal worms. Strangely, the worms survived, but the fever resolved. Due to a pharmacy error, acetanilide, an anti-inflammatory marketed by Bayer, had been dispensed rather than naphthalene. Bayer subsequently marketed the product as Antifebrin.

REMEMBERED AND COMMEMORATED

Kussmaul was a much-loved teacher and a well-respected physician. After he retired in 1888, he returned to Heidelberg as emeritus professor of medicine. He died in 1902 at age 80. His desire to understand disease, his clinical observations, his teaching abilities, and his ability to apply medical technology to the bedside all played roles in his contributions to clinical medicine. One of several Kussmaul commemoration sites is a lunette in Lenox Hill Hospital, New York, New York, where his portrait plaque is displayed alongside those of Ismar Boas and Carl Anton Ewald, the founders of modern gastroenterology.

Clostridium difficile contributes mightily to the overall burden of gastrointestinal disease in the United States and was associated with a 237% increase in hospitalizations in the last decade.

Researchers who examined the latest data on the nationwide toll of GI and liver disease also found a 314% rise in hospitalizations related to morbid obesity and a continuing national health burden exacted by reflux symptoms, Barrett’s esophagus, and colorectal cancer.

Courtesy CDC/Dr. Gilda Jones

Video from the American Gastroenterological Association (http://www.youtube.com/amergastroassn)

"We compiled the most recently available statistics on GI symptoms, quality of life, outpatient diagnoses, hospitalizations, costs, mortality, and endoscopic utilization from a variety of publicly and privately held databases," Dr. Anne F. Peery of the University of North Carolina, Chapel Hill, and her colleagues reported in the November issue of Gastroenterology (doi:10.1053/j.gastro.2012.08.002).

"Payers, policy makers, clinicians, and others interested in resource utilization may use these statistics to better understand evolving disease trends, and the best way to meet the challenge of these diseases."

The findings are based on data for 2009, the most recent year for which complete information was available, from the National Ambulatory Medical Care Survey, sponsored by the U.S. Centers for Disease Control and Prevention; the United States National Health and Wellness Survey, sponsored by the private company Kantar Health; the Nationwide Inpatient Sample, sponsored by the Agency for Healthcare Research and Quality; the Surveillance, Epidemiology, and End Results database of the National Cancer Institute; the National Vital Statistics System, sponsored by the National Center for Health Statistics and the CDC; and the Thomson Reuters MarketScan’s databases of commercial, Medicare, and Medicaid records.

Among the findings:

• C. difficile hospitalizations have increased 237% since 2000 and were associated with 4% in-hospital mortality. Now the ninth leading GI cause of mortality, with an absolute increase of 230% in the number of C. difficile–related deaths since 2002, the infection also markedly impairs quality of life and the capacity for work and other activities.

• Hospitalizations related to obesity remained relatively stable since 2000, but those associated with morbid obesity rose by 314%, and many were likely caused by the marked increase in bariatric surgery.

• Gastroesophageal reflux remains the most common GI-associated diagnosis in primary care, accounting for 9 million outpatient visits in 2009, and the most common GI-associated discharge diagnosis, with 4.4 million such diagnoses in 2009. Obesity was associated with 1.7 million discharge diagnoses and constipation with 1 million.

• Barrett’s esophagus accounted for almost half a million outpatient visits in 2009, when an estimated 3.3 million Americans had this diagnosis. Given that endoscopic surveillance is recommended every 3-5 years, Barrett’s contributes substantially to resource utilization.

• Colorectal cancer, with an estimated 147,000 patients diagnosed in 2008, accounts for more than half of all GI cancer diagnoses and continues to be the primary cause of GI-associated mortality. Pancreatic and hepatobiliary cancers are the next most frequently diagnosed GI cancers.

• Of the approximately 2.5 million deaths in the United States in 2009, 10% were attributed to an underlying GI cause. Chronic liver disease and cirrhosis are the 12th leading causes of death in the country.

• The total outpatient cost for GI endoscopy in 2009 was estimated to be $32.4 billion, which is higher than previously published estimates. An estimated 6.9 million upper endoscopies, 11.5 million lower endoscopies, and 228,000 biliary endoscopies were performed in the United States in 2009.

• Chronic liver disease and viral hepatitis were associated with 6% mortality and cost an estimated $1.8 billion per year in inpatient cost.

• Hospitalizations for nonalcoholic fatty liver disease increased 97% since 2000.

This study was supported in part by the National Institutes of Health. No financial conflicts of interest were reported.

Clostridium difficile contributes mightily to the overall burden of gastrointestinal disease in the United States and was associated with a 237% increase in hospitalizations in the last decade.

Researchers who examined the latest data on the nationwide toll of GI and liver disease also found a 314% rise in hospitalizations related to morbid obesity and a continuing national health burden exacted by reflux symptoms, Barrett’s esophagus, and colorectal cancer.

Courtesy CDC/Dr. Gilda Jones

Video from the American Gastroenterological Association (http://www.youtube.com/amergastroassn)

"We compiled the most recently available statistics on GI symptoms, quality of life, outpatient diagnoses, hospitalizations, costs, mortality, and endoscopic utilization from a variety of publicly and privately held databases," Dr. Anne F. Peery of the University of North Carolina, Chapel Hill, and her colleagues reported in the November issue of Gastroenterology (doi:10.1053/j.gastro.2012.08.002).

"Payers, policy makers, clinicians, and others interested in resource utilization may use these statistics to better understand evolving disease trends, and the best way to meet the challenge of these diseases."

The findings are based on data for 2009, the most recent year for which complete information was available, from the National Ambulatory Medical Care Survey, sponsored by the U.S. Centers for Disease Control and Prevention; the United States National Health and Wellness Survey, sponsored by the private company Kantar Health; the Nationwide Inpatient Sample, sponsored by the Agency for Healthcare Research and Quality; the Surveillance, Epidemiology, and End Results database of the National Cancer Institute; the National Vital Statistics System, sponsored by the National Center for Health Statistics and the CDC; and the Thomson Reuters MarketScan’s databases of commercial, Medicare, and Medicaid records.

Among the findings:

• C. difficile hospitalizations have increased 237% since 2000 and were associated with 4% in-hospital mortality. Now the ninth leading GI cause of mortality, with an absolute increase of 230% in the number of C. difficile–related deaths since 2002, the infection also markedly impairs quality of life and the capacity for work and other activities.

• Hospitalizations related to obesity remained relatively stable since 2000, but those associated with morbid obesity rose by 314%, and many were likely caused by the marked increase in bariatric surgery.

• Gastroesophageal reflux remains the most common GI-associated diagnosis in primary care, accounting for 9 million outpatient visits in 2009, and the most common GI-associated discharge diagnosis, with 4.4 million such diagnoses in 2009. Obesity was associated with 1.7 million discharge diagnoses and constipation with 1 million.

• Barrett’s esophagus accounted for almost half a million outpatient visits in 2009, when an estimated 3.3 million Americans had this diagnosis. Given that endoscopic surveillance is recommended every 3-5 years, Barrett’s contributes substantially to resource utilization.

• Colorectal cancer, with an estimated 147,000 patients diagnosed in 2008, accounts for more than half of all GI cancer diagnoses and continues to be the primary cause of GI-associated mortality. Pancreatic and hepatobiliary cancers are the next most frequently diagnosed GI cancers.

• Of the approximately 2.5 million deaths in the United States in 2009, 10% were attributed to an underlying GI cause. Chronic liver disease and cirrhosis are the 12th leading causes of death in the country.

• The total outpatient cost for GI endoscopy in 2009 was estimated to be $32.4 billion, which is higher than previously published estimates. An estimated 6.9 million upper endoscopies, 11.5 million lower endoscopies, and 228,000 biliary endoscopies were performed in the United States in 2009.

• Chronic liver disease and viral hepatitis were associated with 6% mortality and cost an estimated $1.8 billion per year in inpatient cost.

• Hospitalizations for nonalcoholic fatty liver disease increased 97% since 2000.

This study was supported in part by the National Institutes of Health. No financial conflicts of interest were reported.

Clostridium difficile contributes mightily to the overall burden of gastrointestinal disease in the United States and was associated with a 237% increase in hospitalizations in the last decade.

Researchers who examined the latest data on the nationwide toll of GI and liver disease also found a 314% rise in hospitalizations related to morbid obesity and a continuing national health burden exacted by reflux symptoms, Barrett’s esophagus, and colorectal cancer.

Courtesy CDC/Dr. Gilda Jones

Video from the American Gastroenterological Association (http://www.youtube.com/amergastroassn)

"We compiled the most recently available statistics on GI symptoms, quality of life, outpatient diagnoses, hospitalizations, costs, mortality, and endoscopic utilization from a variety of publicly and privately held databases," Dr. Anne F. Peery of the University of North Carolina, Chapel Hill, and her colleagues reported in the November issue of Gastroenterology (doi:10.1053/j.gastro.2012.08.002).

"Payers, policy makers, clinicians, and others interested in resource utilization may use these statistics to better understand evolving disease trends, and the best way to meet the challenge of these diseases."

The findings are based on data for 2009, the most recent year for which complete information was available, from the National Ambulatory Medical Care Survey, sponsored by the U.S. Centers for Disease Control and Prevention; the United States National Health and Wellness Survey, sponsored by the private company Kantar Health; the Nationwide Inpatient Sample, sponsored by the Agency for Healthcare Research and Quality; the Surveillance, Epidemiology, and End Results database of the National Cancer Institute; the National Vital Statistics System, sponsored by the National Center for Health Statistics and the CDC; and the Thomson Reuters MarketScan’s databases of commercial, Medicare, and Medicaid records.

Among the findings:

• C. difficile hospitalizations have increased 237% since 2000 and were associated with 4% in-hospital mortality. Now the ninth leading GI cause of mortality, with an absolute increase of 230% in the number of C. difficile–related deaths since 2002, the infection also markedly impairs quality of life and the capacity for work and other activities.

• Hospitalizations related to obesity remained relatively stable since 2000, but those associated with morbid obesity rose by 314%, and many were likely caused by the marked increase in bariatric surgery.

• Gastroesophageal reflux remains the most common GI-associated diagnosis in primary care, accounting for 9 million outpatient visits in 2009, and the most common GI-associated discharge diagnosis, with 4.4 million such diagnoses in 2009. Obesity was associated with 1.7 million discharge diagnoses and constipation with 1 million.

• Barrett’s esophagus accounted for almost half a million outpatient visits in 2009, when an estimated 3.3 million Americans had this diagnosis. Given that endoscopic surveillance is recommended every 3-5 years, Barrett’s contributes substantially to resource utilization.

• Colorectal cancer, with an estimated 147,000 patients diagnosed in 2008, accounts for more than half of all GI cancer diagnoses and continues to be the primary cause of GI-associated mortality. Pancreatic and hepatobiliary cancers are the next most frequently diagnosed GI cancers.

• Of the approximately 2.5 million deaths in the United States in 2009, 10% were attributed to an underlying GI cause. Chronic liver disease and cirrhosis are the 12th leading causes of death in the country.

• The total outpatient cost for GI endoscopy in 2009 was estimated to be $32.4 billion, which is higher than previously published estimates. An estimated 6.9 million upper endoscopies, 11.5 million lower endoscopies, and 228,000 biliary endoscopies were performed in the United States in 2009.

• Chronic liver disease and viral hepatitis were associated with 6% mortality and cost an estimated $1.8 billion per year in inpatient cost.

• Hospitalizations for nonalcoholic fatty liver disease increased 97% since 2000.

This study was supported in part by the National Institutes of Health. No financial conflicts of interest were reported.

Eighty-four percent of candidates on the wait-list for liver transplant who either died or were removed from the list before they were able to undergo transplantation declined at least one offer of a donor liver, Dr. Jennifer Cindy Lai of the University of California, San Francisco, and her colleagues reported in the November issue of Gastroenterology.

Even more surprising, most of these candidates declined "not just one or two but a median of six liver offers during their time on the wait-list."

The "declined" donor organs were then successfully transplanted into lower-priority recipients.

These findings suggest that mortality among wait-listed patients "is not simply a result of not having the opportunity for transplantation, as many of us assume. Rather, wait-list mortality appears to result from opportunities for transplantation that were declined," Dr. Lai and her associates wrote.

The reasons that so many viable donor livers were initially declined are not yet clear. General, somewhat vague reasons were listed but not fully explained in the records the researchers analyzed for this study, which they obtained from the United Network for Organ Sharing/Organ Procurement Transplantation Network database.

The investigators assessed organ offers to 33,389 liver transplant candidates aged 18 years and older who were wait-listed across the United States between 2005 and 2010.

The reasons that proffered organs were declined, as listed in the medical records, fit into six broad categories: unfavorable donor age or quality of organ; unfavorable donor organ size/weight; other unfavorable donor factors, such as ABO blood transfusion incompatibility, "social history," "positive serologic tests," or "organ anatomical damage or defect"; unreadiness of the recipient, usually because he or she was ill, unavailable, refused the organ, or required multiple organ transplants at the same time; problems with the transplant program itself, such as a "heavy workload" or unavailability of a surgeon or operating room at the recipient’s medical center, failure to respond to the offer in a timely way, or excessive distance to ship the organ.

A total of 20% of the study population (6,737 patients) died or were removed from the wait-list because they became too sick before they could undergo transplantation. A total of 5,680 (84%) of those patients had been offered one or more donor livers before they died or were taken off the list.

Offers of donor livers were declined most often (68%) because of "unfavorable donor age or quality of organ," whereas 9% were declined because of unfavorable organ size, 15% because of "other donor factors," 4% because the recipient wasn’t ready, and 4% because of transplant program or miscellaneous other factors.

However, the dominant use of the "donor quality or age" refusal code in the database almost certainly "does not accurately or fully capture the true refusal reason," Dr. Lai and her associates said.

Even livers judged to be of high quality according to standard criteria were declined because of supposed "unfavorable donor age or quality of organ." But the investigators found no difference in the risk of graft failure between such high-quality livers that were declined and other high-quality livers that were accepted on the first offer.

Other reasons must be playing an important role in this high rate refusal, but "the nuances of these refusals cannot be determined" without more individualized data, they said.

Dr. Lai and her colleagues suggested that to cut down on refusals of apparently viable organs, the transplant community should "reduce the stigma associated with non–ideal livers, and set realistic expectations for wait-listed candidates" so that they’re less likely to pass up a suitable donation while assuming that a better offer will come along.

Patients also should be educated about the unpredictability of death or of sudden worsening of liver disease while on the wait-list. They should be advised that there is a survival benefit associated with the transplantation of any graft, compared with continuing on the wait-list.

In addition, the current regulatory environment focuses on transplant centers’ outcomes, which may influence some centers to discourage the acceptance of less than optimal donor organs. "This may be especially relevant for low-volume transplant centers, for whom even a small number of poor outcomes ... may make a relatively large difference in the centers’ perceived performance," the researchers wrote.

Finally, wait-list candidates should be encouraged to complete their transplant work-ups as expeditiously as possible to avoid having to refuse a donor offer simply because they have not yet undergone the necessary cardiac testing or cancer screening.

This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases and the University of California, San Francisco. No financial conflicts of interest were reported.

Eighty-four percent of candidates on the wait-list for liver transplant who either died or were removed from the list before they were able to undergo transplantation declined at least one offer of a donor liver, Dr. Jennifer Cindy Lai of the University of California, San Francisco, and her colleagues reported in the November issue of Gastroenterology.

Even more surprising, most of these candidates declined "not just one or two but a median of six liver offers during their time on the wait-list."

The "declined" donor organs were then successfully transplanted into lower-priority recipients.

These findings suggest that mortality among wait-listed patients "is not simply a result of not having the opportunity for transplantation, as many of us assume. Rather, wait-list mortality appears to result from opportunities for transplantation that were declined," Dr. Lai and her associates wrote.

The reasons that so many viable donor livers were initially declined are not yet clear. General, somewhat vague reasons were listed but not fully explained in the records the researchers analyzed for this study, which they obtained from the United Network for Organ Sharing/Organ Procurement Transplantation Network database.

The investigators assessed organ offers to 33,389 liver transplant candidates aged 18 years and older who were wait-listed across the United States between 2005 and 2010.

The reasons that proffered organs were declined, as listed in the medical records, fit into six broad categories: unfavorable donor age or quality of organ; unfavorable donor organ size/weight; other unfavorable donor factors, such as ABO blood transfusion incompatibility, "social history," "positive serologic tests," or "organ anatomical damage or defect"; unreadiness of the recipient, usually because he or she was ill, unavailable, refused the organ, or required multiple organ transplants at the same time; problems with the transplant program itself, such as a "heavy workload" or unavailability of a surgeon or operating room at the recipient’s medical center, failure to respond to the offer in a timely way, or excessive distance to ship the organ.

A total of 20% of the study population (6,737 patients) died or were removed from the wait-list because they became too sick before they could undergo transplantation. A total of 5,680 (84%) of those patients had been offered one or more donor livers before they died or were taken off the list.

Offers of donor livers were declined most often (68%) because of "unfavorable donor age or quality of organ," whereas 9% were declined because of unfavorable organ size, 15% because of "other donor factors," 4% because the recipient wasn’t ready, and 4% because of transplant program or miscellaneous other factors.

However, the dominant use of the "donor quality or age" refusal code in the database almost certainly "does not accurately or fully capture the true refusal reason," Dr. Lai and her associates said.

Even livers judged to be of high quality according to standard criteria were declined because of supposed "unfavorable donor age or quality of organ." But the investigators found no difference in the risk of graft failure between such high-quality livers that were declined and other high-quality livers that were accepted on the first offer.

Other reasons must be playing an important role in this high rate refusal, but "the nuances of these refusals cannot be determined" without more individualized data, they said.

Dr. Lai and her colleagues suggested that to cut down on refusals of apparently viable organs, the transplant community should "reduce the stigma associated with non–ideal livers, and set realistic expectations for wait-listed candidates" so that they’re less likely to pass up a suitable donation while assuming that a better offer will come along.

Patients also should be educated about the unpredictability of death or of sudden worsening of liver disease while on the wait-list. They should be advised that there is a survival benefit associated with the transplantation of any graft, compared with continuing on the wait-list.

In addition, the current regulatory environment focuses on transplant centers’ outcomes, which may influence some centers to discourage the acceptance of less than optimal donor organs. "This may be especially relevant for low-volume transplant centers, for whom even a small number of poor outcomes ... may make a relatively large difference in the centers’ perceived performance," the researchers wrote.

Finally, wait-list candidates should be encouraged to complete their transplant work-ups as expeditiously as possible to avoid having to refuse a donor offer simply because they have not yet undergone the necessary cardiac testing or cancer screening.

This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases and the University of California, San Francisco. No financial conflicts of interest were reported.

Eighty-four percent of candidates on the wait-list for liver transplant who either died or were removed from the list before they were able to undergo transplantation declined at least one offer of a donor liver, Dr. Jennifer Cindy Lai of the University of California, San Francisco, and her colleagues reported in the November issue of Gastroenterology.

Even more surprising, most of these candidates declined "not just one or two but a median of six liver offers during their time on the wait-list."

The "declined" donor organs were then successfully transplanted into lower-priority recipients.

These findings suggest that mortality among wait-listed patients "is not simply a result of not having the opportunity for transplantation, as many of us assume. Rather, wait-list mortality appears to result from opportunities for transplantation that were declined," Dr. Lai and her associates wrote.

The reasons that so many viable donor livers were initially declined are not yet clear. General, somewhat vague reasons were listed but not fully explained in the records the researchers analyzed for this study, which they obtained from the United Network for Organ Sharing/Organ Procurement Transplantation Network database.

The investigators assessed organ offers to 33,389 liver transplant candidates aged 18 years and older who were wait-listed across the United States between 2005 and 2010.

The reasons that proffered organs were declined, as listed in the medical records, fit into six broad categories: unfavorable donor age or quality of organ; unfavorable donor organ size/weight; other unfavorable donor factors, such as ABO blood transfusion incompatibility, "social history," "positive serologic tests," or "organ anatomical damage or defect"; unreadiness of the recipient, usually because he or she was ill, unavailable, refused the organ, or required multiple organ transplants at the same time; problems with the transplant program itself, such as a "heavy workload" or unavailability of a surgeon or operating room at the recipient’s medical center, failure to respond to the offer in a timely way, or excessive distance to ship the organ.

A total of 20% of the study population (6,737 patients) died or were removed from the wait-list because they became too sick before they could undergo transplantation. A total of 5,680 (84%) of those patients had been offered one or more donor livers before they died or were taken off the list.

Offers of donor livers were declined most often (68%) because of "unfavorable donor age or quality of organ," whereas 9% were declined because of unfavorable organ size, 15% because of "other donor factors," 4% because the recipient wasn’t ready, and 4% because of transplant program or miscellaneous other factors.

However, the dominant use of the "donor quality or age" refusal code in the database almost certainly "does not accurately or fully capture the true refusal reason," Dr. Lai and her associates said.

Even livers judged to be of high quality according to standard criteria were declined because of supposed "unfavorable donor age or quality of organ." But the investigators found no difference in the risk of graft failure between such high-quality livers that were declined and other high-quality livers that were accepted on the first offer.

Other reasons must be playing an important role in this high rate refusal, but "the nuances of these refusals cannot be determined" without more individualized data, they said.

Dr. Lai and her colleagues suggested that to cut down on refusals of apparently viable organs, the transplant community should "reduce the stigma associated with non–ideal livers, and set realistic expectations for wait-listed candidates" so that they’re less likely to pass up a suitable donation while assuming that a better offer will come along.

Patients also should be educated about the unpredictability of death or of sudden worsening of liver disease while on the wait-list. They should be advised that there is a survival benefit associated with the transplantation of any graft, compared with continuing on the wait-list.

In addition, the current regulatory environment focuses on transplant centers’ outcomes, which may influence some centers to discourage the acceptance of less than optimal donor organs. "This may be especially relevant for low-volume transplant centers, for whom even a small number of poor outcomes ... may make a relatively large difference in the centers’ perceived performance," the researchers wrote.

Finally, wait-list candidates should be encouraged to complete their transplant work-ups as expeditiously as possible to avoid having to refuse a donor offer simply because they have not yet undergone the necessary cardiac testing or cancer screening.

This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases and the University of California, San Francisco. No financial conflicts of interest were reported.

Patients with hepatitis C infections are more likely to initiate appropriate antiviral therapy and achieve a sustained virologic response if they receive high quality health care, Dr. Fasiha Kanwal of the Michael E. DeBakey Veterans Affairs Medical Center, Houston, and her colleagues reported in the November issue of Clinical Gastroenterology and Hepatology.

In their study of nearly 35,000 adults with HCV, the odds of initiating antiviral therapy were threefold higher in patients who received optimal care from the moment HCV infection was diagnosed than in those who did not. And among patients who initiated antiviral therapy, the quality of care they received before that therapy even began strongly predicted whether they would complete antiviral therapy and achieve a sustained virologic response, the investigators said.

Courtesy US. Dept of Veterans Affairs

The study showed, however, that only 11% of patients received all of the appropriate initial care.

Process-of-care measures are frequently used to assess the quality of care for HCV, but until now no study has assessed whether these measures actually correlate with better outcomes. To address this issue, Dr. Kanwal and her associates "evaluated the relationship between adherence to a broad set of process-based measures in HCV and 3 subsequent HCV-specific endpoints: receipt of antiviral treatment, completion of antiviral treatment, and the clinical outcome associated with improved survival: sustained virologic response."

The investigators used data from the VA registry on HCV clinical care, which covers patient demographics, lab tests, pharmacy information, and data on inpatient and outpatient care for approximately 300,000 patients across the country. For this study, they included data on 34,749 adults.

The mean subject age was 53 years, and 97% were men. Approximately half the study population was white and 26% was black; ethnicity was not reported for the others.

The researchers assessed seven process-of-care measures: confirmation of HCV viremia, evaluation by HCV specialists, HCV genotype testing, liver biopsy for those found to have genotype 1 HCV, and the ruling out of liver diseases related to hepatitis B, autoimmunity, or iron overload.

They also assessed seven process-of-care measures related to the prevention and management of comorbid conditions: HIV testing; hepatitis A and B serology testing, hepatitis A and B vaccination if serology results proved negative; treatment of depression; and treatment of substance abuse disorder.

Finally, they assessed six process-of-care measures related to monitoring of antiviral therapy’s effects: testing of viral load before antivirals were initiated and again at weeks 12, 24, and 48; reduction of ribavirin dose if anemia developed during treatment; and avoidance of prescribing growth-stimulating factors for leukopenia during antiviral therapy.

Overall, only 11% of the study subjects received all of the appropriate initial care, and 8% received all the appropriate care related to prevention and management of comorbid conditions. Moreover, of the study subjects who received antiviral therapy, just 37% received all the appropriate monitoring of treatment effects Dr. Kanwal and her associates said.

In patients who received optimal care before a definitive diagnosis was made, the odds of receiving antiviral therapy were 3.2 times higher than in patients who did not receive optimal care before diagnosis, they reported.

Similarly, patients who received optimal preventive and comorbid-condition care showed rates of antiviral therapy that were 36% higher than those of patients who received suboptimal preventive and comorbid-condition care.

The strong association between fulfillment of these process-of-care measures and appropriate antiviral therapy remained robust in a series of sensitivity analyses, which means it’s likely that meeting process-of-care goals directly leads to better HCV outcomes, Dr. Kanwal and her colleagues said.

The investigators could not, however, rule out the possibility that meeting these goals is simply a marker of more compliant patients, which in turn produces better outcomes.

The study findings imply that the effectiveness of the two new direct-acting antiviral agents that recently became available for HCV may hinge on the quality of care patients are receiving before they even start taking these drugs, rather than simply on the effectiveness of the drugs alone, Dr. Kanwal and her associates said.

This study was supported by the U.S. Department of Veterans Affairs Health Services Research and Development Service. No financial conflicts of interest were reported.

Patients with hepatitis C infections are more likely to initiate appropriate antiviral therapy and achieve a sustained virologic response if they receive high quality health care, Dr. Fasiha Kanwal of the Michael E. DeBakey Veterans Affairs Medical Center, Houston, and her colleagues reported in the November issue of Clinical Gastroenterology and Hepatology.

In their study of nearly 35,000 adults with HCV, the odds of initiating antiviral therapy were threefold higher in patients who received optimal care from the moment HCV infection was diagnosed than in those who did not. And among patients who initiated antiviral therapy, the quality of care they received before that therapy even began strongly predicted whether they would complete antiviral therapy and achieve a sustained virologic response, the investigators said.

Courtesy US. Dept of Veterans Affairs

The study showed, however, that only 11% of patients received all of the appropriate initial care.

Process-of-care measures are frequently used to assess the quality of care for HCV, but until now no study has assessed whether these measures actually correlate with better outcomes. To address this issue, Dr. Kanwal and her associates "evaluated the relationship between adherence to a broad set of process-based measures in HCV and 3 subsequent HCV-specific endpoints: receipt of antiviral treatment, completion of antiviral treatment, and the clinical outcome associated with improved survival: sustained virologic response."

The investigators used data from the VA registry on HCV clinical care, which covers patient demographics, lab tests, pharmacy information, and data on inpatient and outpatient care for approximately 300,000 patients across the country. For this study, they included data on 34,749 adults.

The mean subject age was 53 years, and 97% were men. Approximately half the study population was white and 26% was black; ethnicity was not reported for the others.

The researchers assessed seven process-of-care measures: confirmation of HCV viremia, evaluation by HCV specialists, HCV genotype testing, liver biopsy for those found to have genotype 1 HCV, and the ruling out of liver diseases related to hepatitis B, autoimmunity, or iron overload.

They also assessed seven process-of-care measures related to the prevention and management of comorbid conditions: HIV testing; hepatitis A and B serology testing, hepatitis A and B vaccination if serology results proved negative; treatment of depression; and treatment of substance abuse disorder.

Finally, they assessed six process-of-care measures related to monitoring of antiviral therapy’s effects: testing of viral load before antivirals were initiated and again at weeks 12, 24, and 48; reduction of ribavirin dose if anemia developed during treatment; and avoidance of prescribing growth-stimulating factors for leukopenia during antiviral therapy.

Overall, only 11% of the study subjects received all of the appropriate initial care, and 8% received all the appropriate care related to prevention and management of comorbid conditions. Moreover, of the study subjects who received antiviral therapy, just 37% received all the appropriate monitoring of treatment effects Dr. Kanwal and her associates said.

In patients who received optimal care before a definitive diagnosis was made, the odds of receiving antiviral therapy were 3.2 times higher than in patients who did not receive optimal care before diagnosis, they reported.

Similarly, patients who received optimal preventive and comorbid-condition care showed rates of antiviral therapy that were 36% higher than those of patients who received suboptimal preventive and comorbid-condition care.

The strong association between fulfillment of these process-of-care measures and appropriate antiviral therapy remained robust in a series of sensitivity analyses, which means it’s likely that meeting process-of-care goals directly leads to better HCV outcomes, Dr. Kanwal and her colleagues said.

The investigators could not, however, rule out the possibility that meeting these goals is simply a marker of more compliant patients, which in turn produces better outcomes.

The study findings imply that the effectiveness of the two new direct-acting antiviral agents that recently became available for HCV may hinge on the quality of care patients are receiving before they even start taking these drugs, rather than simply on the effectiveness of the drugs alone, Dr. Kanwal and her associates said.

This study was supported by the U.S. Department of Veterans Affairs Health Services Research and Development Service. No financial conflicts of interest were reported.

Patients with hepatitis C infections are more likely to initiate appropriate antiviral therapy and achieve a sustained virologic response if they receive high quality health care, Dr. Fasiha Kanwal of the Michael E. DeBakey Veterans Affairs Medical Center, Houston, and her colleagues reported in the November issue of Clinical Gastroenterology and Hepatology.

In their study of nearly 35,000 adults with HCV, the odds of initiating antiviral therapy were threefold higher in patients who received optimal care from the moment HCV infection was diagnosed than in those who did not. And among patients who initiated antiviral therapy, the quality of care they received before that therapy even began strongly predicted whether they would complete antiviral therapy and achieve a sustained virologic response, the investigators said.

Courtesy US. Dept of Veterans Affairs

The study showed, however, that only 11% of patients received all of the appropriate initial care.

Process-of-care measures are frequently used to assess the quality of care for HCV, but until now no study has assessed whether these measures actually correlate with better outcomes. To address this issue, Dr. Kanwal and her associates "evaluated the relationship between adherence to a broad set of process-based measures in HCV and 3 subsequent HCV-specific endpoints: receipt of antiviral treatment, completion of antiviral treatment, and the clinical outcome associated with improved survival: sustained virologic response."

The investigators used data from the VA registry on HCV clinical care, which covers patient demographics, lab tests, pharmacy information, and data on inpatient and outpatient care for approximately 300,000 patients across the country. For this study, they included data on 34,749 adults.

The mean subject age was 53 years, and 97% were men. Approximately half the study population was white and 26% was black; ethnicity was not reported for the others.

The researchers assessed seven process-of-care measures: confirmation of HCV viremia, evaluation by HCV specialists, HCV genotype testing, liver biopsy for those found to have genotype 1 HCV, and the ruling out of liver diseases related to hepatitis B, autoimmunity, or iron overload.

They also assessed seven process-of-care measures related to the prevention and management of comorbid conditions: HIV testing; hepatitis A and B serology testing, hepatitis A and B vaccination if serology results proved negative; treatment of depression; and treatment of substance abuse disorder.

Finally, they assessed six process-of-care measures related to monitoring of antiviral therapy’s effects: testing of viral load before antivirals were initiated and again at weeks 12, 24, and 48; reduction of ribavirin dose if anemia developed during treatment; and avoidance of prescribing growth-stimulating factors for leukopenia during antiviral therapy.

Overall, only 11% of the study subjects received all of the appropriate initial care, and 8% received all the appropriate care related to prevention and management of comorbid conditions. Moreover, of the study subjects who received antiviral therapy, just 37% received all the appropriate monitoring of treatment effects Dr. Kanwal and her associates said.

In patients who received optimal care before a definitive diagnosis was made, the odds of receiving antiviral therapy were 3.2 times higher than in patients who did not receive optimal care before diagnosis, they reported.

Similarly, patients who received optimal preventive and comorbid-condition care showed rates of antiviral therapy that were 36% higher than those of patients who received suboptimal preventive and comorbid-condition care.

The strong association between fulfillment of these process-of-care measures and appropriate antiviral therapy remained robust in a series of sensitivity analyses, which means it’s likely that meeting process-of-care goals directly leads to better HCV outcomes, Dr. Kanwal and her colleagues said.

The investigators could not, however, rule out the possibility that meeting these goals is simply a marker of more compliant patients, which in turn produces better outcomes.

The study findings imply that the effectiveness of the two new direct-acting antiviral agents that recently became available for HCV may hinge on the quality of care patients are receiving before they even start taking these drugs, rather than simply on the effectiveness of the drugs alone, Dr. Kanwal and her associates said.

This study was supported by the U.S. Department of Veterans Affairs Health Services Research and Development Service. No financial conflicts of interest were reported.

Editor’s note: This is the second of two articles on hypogonadism in men and focuses on the appropriate use of testosterone therapy. The first article, published last month, focused in more detail on the differential diagnosis of hypogonadism.

As men age, testosterone production gradually decreases. In our increasingly aged population, clinicians will continue to see an increase in the number of men with seemingly nonspecific symptoms of aging that are possibly due to low serum testosterone (eg, low energy level, depressive symptoms, erectile dysfunction, decreased libido). These clinical symptoms, coupled with low serum testosterone, may adversely affect quality of life and life expectancy. Testosterone replacement therapy (TRT) may improve symptoms and quality of life. Given the nonspecific nature of these symptoms, accurate diagnosis and treatment of clinically significant low testosterone with a goal of symptom and quality of life improvement can prove challenging.

These challenges in diagnosis and treatment result in a lack of standardized nomenclature. The terms male menopause and andropause, although popular, are the least helpful, as they have few correlates with the better-defined female menopause. Late-onset hypogonadism implies a well-defined, later age of decline, which is inaccurate since the decline in serum testosterone in men begins in middle age and is gradual. Testosterone deficiency syndrome implies a set of specific and well-defined symptoms. Androgen deficiency in the aging male (ADAM) and Androgen deficiency in the older male are common terms specifying an age cohort (> 40 years old) and an abnormal laboratory value without mention of symptoms. While all these terms have their limitations, we will primarily use ADAM in this discussion.

PREVALENCE OF LOW TESTOSTERONE

Serum testosterone levels begin to decline in men in their mid-40s, with an approximately 1% to 2% decline annually and a marked decline after age 60.¹

Araujo and colleagues² studied the prevalence of androgen-deficient men, with androgen deficiency defined as at least three signs or symptoms and either a total testosterone less than 200 ng/dL or a total testosterone 200 ng/dL to 400 ng/dL with a free testosterone less than 8.91 ng/dL. The overall prevalence of low testosterone on initial measurement was 6%, which doubled to 12% with repeat measurement.

Serial measures are important: one study that followed untreated men over 15 years found normal testosterone on serial measures in 50%.³ In a multicenter cross-sectional study, 11.8% of men had low testosterone and low or normal luteinizing hormone (LH) levels (secondary hypogonadism/hypothalamic-pituitary failure), with 2% of patients with low testosterone and elevated LH (primary hypogonadism/testicular failure).⁴

CLINICAL PRESENTATION AND DIAGNOSIS

A biochemical diagnosis of low testosterone is dependent on accurate measurement. Testosterone release is diurnal, with the highest levels in the early morning, and often has week-to-week variability. Thus, it is important to collect blood in the early morning and to confirm a diagnosis of low testosterone with at least one repeat measurement several days later, including LH assessment. LH levels will help differentiate primary hypogonadism from secondary hypogonadism, which may alter diagnosis and treatment in certain patients, with secondary hypogonadism associated with pituitary dysfunction, and primary hypogonadism associated with aging.⁴

Testosterone binds in the bloodstream to sex hormone-binding globulin (SHBG), and this bound form is generally considered biologically inactive, although there are in vitro and animal studies suggesting SHBG-bound androgen may indeed have biological activity. ^5,6 “Bioavailable” testosterone is active and includes both free testosterone and testosterone bound to albumin.

There is no general agreement on the acceptable normal range of testosterone, with variability within the literature and between laboratories. “Normal” total testosterone levels have ranged from more than 280 ng/dL to more than 350 ng/dL (12 nmol/L).^7,8 Similarly, there is no generally accepted lower limit of normal, although some studies report a threshold level of testosterone less than 230 ng/dL (8 nmol/L) as “abnormal.” Values between these two upper and lower limits are considered “borderline.”^7,8 These intermediate or borderline values coupled with clinical symptoms of testosterone deficiency syndrome or ADAM should be considered abnormal.

When total testosterone is borderline, measurement of free or bioavailable testosterone (free plus albumin-bound) should be considered. Total testosterone is typically measured using automated immunoassay platforms, with method-related differences leading to significant variability in measurement accuracy and precision. This variability is seen most dramatically in those with low total testosterone.⁹ However, the variability of total testosterone measurements is substantially smaller among mass spectrometry assays than among immunoassays. ¹⁰

The gold standards for free testosterone measurement are centrifugal ultrafiltration and equilibrium dialysis.⁹ However, these techniques are laborious and usually unavailable in local laboratories. Calculated free testosterone values using total testosterone and SHBG are most commonly used and are sufficiently accurate for clinical practice.¹¹

Free testosterone levels can be diagnostic when total testosterone levels do not correspond with clinical presentation. However, the clinical utility of free testosterone is difficult to assess due to the variability among laboratory assays and a lack of consensus on threshold parameters. A threshold free testosterone level of more than 225 pmol/L (65 pg/mL) is generally considered normal.^7,8 Before starting a patient on TRT, measurement of hemoglobin and prostate-specific antigen (PSA) and digital rectal examination of the prostate (if age is > 39) are essential.

Prolactin levels are recommended when low testosterone is confirmed, especially in patients at high clinical risk for hyperprolactinemia. Once hyperprolactinemia is identified, Endocrine Society guidelines recommend excluding medication use, renal failure, hypothyroidism, and parasellar tumors as possible causes of elevated prolactin levels.¹²

Low testosterone values should be treated only in patients with clinically significant symptoms that are likely to be caused by the low testosterone itself. Symptoms associated with age-related decline in testosterone that may improve with TRT include low libido,^13,14 low energy,¹⁴ depressed mood,^15–17 low muscle mass, osteoporosis, and hot flashes. Men with erectile dysfunction have also shown a significant improvement with TRT compared with placebo, but with a variable overall response independent of normalization of testosterone. ^18,19 This is likely due to the multifactorial nature of erectile dysfunction, including vascular, neurologic, psychogenic, and endocrinologic causes.

Screening questionnaires have been developed for symptoms of low testosterone, but their clinical utility is unclear. The ADAM questionnaire is used as a screening tool for low testosterone but not to monitor response to TRT, and it is highly nonspecific.²⁰ The Aging Male Symptom Scale questionnaire includes psychological, somatovegetative, and sexual components and is used both to screen for low testosterone and to measure outcomes.²¹ However, a recent observational study comparing the ability of these questionnaires to assess clinical symptoms revealed a low sensitivity and a low specificity to detect androgen deficiency in men with a total testosterone level less than 300 ng/dL.²² Overall, the current data do not conclusively support the use of hypogonadism questionnaires for screening.

The patient history when evaluating for ADAM should include evaluation of sexual and constitutional symptoms as described above and in Table 1. In addition, a history of traumatic, medical, or surgical events that could affect testosterone production should be obtained, including cryptorchidism, scrotal, inguinal, or abdominal surgery, pituitary surgery or radiation, prior issues with infertility, timing of puberty, history of renal or hepatic failure, chemotherapy (for cancer or autoimmune diseases), and prior use of anabolic steroids or opiates.

A complete physical examination should include assessment of virilization, gynecomastia, and the genitalia, including the size, position, and volume of the testes. The size and consistency of the prostate should be assessed on digital rectal examination.

LOW TESTOSTERONE AND ASSOCIATED COMORBIDITIES

Low testosterone is associated with many comorbidities, including metabolic syndrome, depression, type 2 diabetes mellitus, and cardiovascular disease, as discussed later in this section. Low testosterone has also shown associations with osteoporosis, cognitive impairment, hypertension, hyperlipidemia, decreased physical performance, end-stage renal disease, and treatment with steroids or opiates.^23–26 However, the studies that found these associations included men younger than 40 years and may not be fully applicable to the ADAM population.

The association of metabolic syndrome and type 2 diabetes mellitus with low testosterone is well established in multiple studies. Grossman and colleagues²⁷ investigated the association of type 2 diabetes mellitus and low testosterone, with low total testosterone defined as below 10 nmol/L and low calculated free testosterone less than 0.23 nmol/L. The prevalence of low total testosterone was 43%, and the prevalence of low free testosterone was 57%. In addition, a recent meta-analysis comparing total testosterone of men with and without metabolic syndrome revealed an association between a baseline decrease in mean total and free testosterone levels in men with metabolic syndrome compared with controls. This study found a total testosterone mean difference of –2.64 nmol/L (95% confidence interval [CI] –2.95 to –2.32) and a free testosterone mean difference of –0.26 pmol/L (95% CI –0.39 to –0.13), respectively, when comparing men with metabolic syndrome against those without.²⁸

Testosterone has also been suggested to be protective against type 2 diabetes mellitus, with 42% lower risk of type 2 diabetes mellitus in men with testosterone levels ranging from 450 ng/dL to 605 ng/dL.²⁹

Obesity has been specifically linked with secondary hypogonadism.^4,23,24 A prospective cohort of 58 men with an average age of 46 years and a body mass index ranging from 30 to 45 kg/m² were monitored on a low-calorie diet for 9 weeks. Afterward, biochemical analysis revealed an increase in free testosterone from 185 pmol/L ± 66 to 208 ± 70 pmol/L (P = .002) with a mean weight loss of 16.3 kg ± 4.5 kg.³⁰ This emphasizes the importance of lifestyle changes in the management of hypogonadal men.

LOW TESTOSTERONE AND THE OVERALL MORTALITY RATE

Low testosterone is associated unfavorably with the rate of all-cause mortality. A retrospective study in male veterans over age 40 with repeated testosterone levels over a 5-year period found that the risk of death from all causes in men with normal testosterone (> 250 ng/dL or free testosterone > 0.75 ng/dL) was 20% (95% CI 16.2%–241%) vs 35% (95% CI 28.5%–41.4%) in men with low testosterone (< 250 ng/dL or free testosterone < 0.75 ng/dL). In multivariate analysis, men with testosterone less than 250 ng/dL (< 8.7 nmol/L) or free testosterone less than 0.75 ng/dL (< 0.03 nmol/L) had up to an 88% higher death rate than men with normal testosterone levels.³¹

Low testosterone has also been associated with other end-organ, disease-specific mortality. In men with end-stage renal disease, low testosterone was an independent predictor of death from all causes and from cardiovascular disease.³² A prospective European health study revealed an association between low testosterone and increased risk of death from cardiovascular disease and cancer.³³ A recent meta-analysis of population-based studies confirmed this association, despite significant interstudy heterogeneity. ³⁴ Although multiple studies show an independent association of low testosterone and increased mortality rate, causality remains unconfirmed. This may be difficult to prove, given the available study designs and the nonspecific nature of symptoms related to low testosterone and potentially associated comorbidities.

TRT: INDICATIONS AND CONTRAINDICATIONS

The indications, benefits, and risks of TRT are controversial, with current data lacking long-term follow-up and consistent biochemical target values. Treatment of low testosterone is not indicated at the present time in the absence of clinical symptoms.

According to recently published guidelines, TRT is recommended for symptomatic men with low or borderline total testosterone or free testosterone (< 350 ng/dL or < 65 pg/mL).^7,8 Patients with borderline biochemical values (total testosterone 200–350 ng/dL, free testosterone 40–65 pg/mL) and possible related symptoms should be treated with TRT for at least 3 months and then reevaluated to verify improved testosterone levels and to assess for symptom amelioration or resolution.³⁵ Dose escalation is recommended in patients with subtherapeutic testosterone levels and limited clinical improvement after 3 months of treatment.

Target maintenance testosterone levels have not been defined, with mid to lower young adult male serum testosterone levels recommended at this time.⁸ Given that the current literature does not specify a target testosterone replacement range, we recommend monitoring the clinical response along with total testosterone to decide adjustments in TRT. Ultimately, treatment goals of TRT should be the resolution of signs and symptoms, including improvement of sexual function, libido, and preservation of bone mineral density.^7,8

Contraindications

TRT is not recommended in men with the following:

• Breast cancer
• Polycythemia (hematocrit > 50%)
• Untreated obstructive sleep apnea
• Lower urinary tract symptoms caused by an enlarged prostate; International Prostate Symptom Score > 19
• Poorly controlled heart failure
• Desire for fertility.

The role of TRT in prostate cancer remains controversial (see below) and remains contraindicated in recent Endocrine Society clinical practice guidelines.⁷ Guidelines recommend urologic consultation prior to initiation of TRT in patients at increased risk of prostate cancer,⁷ based on age, race, family history, PSA, PSA velocity, and history of prostate biopsy.

One prominent historic concern about androgen replacement therapy regards the potential for de novo development of prostate cancer. Numerous studies have failed to find elevated risk of new diagnosis, progression, or recurrence of prostate cancer in patients on TRT.^36,37 Nevertheless, patients who develop elevated PSA, increased PSA velocity, or an abnormal digital rectal examination while on TRT should undergo prostate biopsy.

TRT FORMULATIONS AND TREATMENT OPTIONS

A number of effective formulations of TRT are available (Table 2). Transdermal and parenteral formulations are most commonly used. Enteric testosterone formulations are not available in the United States and are associated with hepatotoxicity. While buccal testosterone therapy is available, it often leads to local gingival irritation and has not gained widespread popularity.

Parenteral TRT can be administered intramuscularly (IM) or subcutaneously (SQ). Testosterone cypionate (Depo-Testosterone) is the only IM form available in the United States and is given every 2 to 3 weeks. It is the least expensive form of TRT, but it requires frequent administration (by either the clinical practitioner or the patient himself). Testosterone cypionate injections lead to markedly wide swings of testosterone levels, ranging from supraphysiologic levels for a few days after administration to hypogonadal levels before the next injection. This may be mitigated by more-frequent injections. The longer-acting form testosterone undecanoate is available outside the United States and is given every 12 weeks when stable levels are reached.

The other parenteral option is SQ slow-release pellets (Testopel). These pellets have 75 mg of testosterone. Typically 8 to 14 pellets are placed subcutaneously in the buttock area, which will provide coverage for 3 to 6 months.³⁸ The insertion procedure is simple with a short learning curve, limited compliance issues, and elimination of risk of transdermal transmission of drug to others. Disadvantages include wound infection and pellet extrusion, seen in 0.3% to 12% of patients in various studies.³⁸

Another route of TRT is transdermal, including patches, liquids, and gels. Patches are applied daily and are rotated to different sites with minimal risk for skin transmission to others, although use may be limited by site dermatitis. Three hydro-alcoholic gel formulations are currently available in the United States: Androgel (1% or 1.62%), which is applied to the chest or the shoulders; Testim 1%, which is applied to the shoulders; and Fortesta (2%), which is applied to the thighs. A liquid preparation, Axiron, is applied to the axillae. Because secondary transfer to women and children is possible, it is important to thoroughly wash hands after application and to cover the treated skin with clothing. In 3 to 4 hours, all the medication is absorbed, and the area should then be washed before direct skin contact with others (Table 2).

MONITORING PATIENTS ON TRT

Patients starting TRT will require clinical and biochemical monitoring to evaluate response to therapy as well as possible side effects. The first set of laboratory values should be obtained 6 to 12 weeks after initiation of therapy and then typically quarterly for 1 year, every 6 months for the second year, and annually thereafter. Laboratory values monitored should include total testosterone, PSA, and hematocrit.

Men on daily therapy (patch, gel, liquid) should have testosterone drawn approximately 2 hours after application. Current TRT regimen data lack an appropriate target testosterone value, and guidelines suggest a mid to lower young adult male testosterone level.⁸ Since this is not clearly delineated in the current literature, the authors recommend monitoring clinical symptoms along with testosterone levels when adjusting TRT. It is important to document that serum testosterone was actually increased to the normal range in treated men without clinical improvement.

A rise in PSA of up to 24% would be an acceptable response in a benign prostate gland, but a higher increase or increase above 4.0 ng/dL should prompt consideration of prostate biopsy. ³⁹ Similarly, hemoglobin and hematocrit typically increase, but a hematocrit greater than 55% should prompt dose reduction or cessation.⁷ Transaminases do not need routine monitoring during parenteral or transdermal therapy. Bone mineral density should be monitored every 1 to 2 years.^7,8

CLINICAL BENEFITS OF TRT

There are promising data regarding the clinical benefits of TRT in patients with metabolic syndrome and type 2 diabetes mellitus. A recent meta-analysis investigating the effect of TRT on metabolic syndrome revealed an improvement in fasting plasma glucose, homeostatic model assessment index, triglycerides, treadmill duration, high-density lipoprotein cholesterol, and waist circumference.^40,41 TRT also decreased insulin resistance and improved glycemic control in type 2 diabetic hypogonadal men.⁴² Results from a randomized controlled trial comparing 12 weeks of intramuscular testosterone treatment vs placebo in men with metabolic syndrome revealed an improvement in mean waist circumference from 108 cm ± 8 cm to 105.5 cm ± 7.7 cm. Sixty percent of men initially diagnosed with metabolic syndrome and treated with testosterone no longer met diagnostic criteria for metabolic syndrome according to the National Cholesterol Education Program–Third Adult Treatment Panel (NCEP-ATP III) and the International Diabetes Federation (IDF) guidelines.⁴³

Depression has also been associated with low testosterone, with free testosterone levels below 170 pmol/L associated with frank depressive symptoms and levels below 220 pmol/L predictive of future onset of depressive symptoms.¹⁵ Testosterone replacement therapy has been shown to improve depressive symptoms in hypogonadal men.^16,17 Shores et al¹⁶ conducted a randomized placebo-controlled study of testosterone replacement in men older than 50 years with dysthymia or minor depression. Men treated with testosterone gel for 12 weeks showed an improvement of baseline total testosterone levels from 291 ng/dL to 449 ng/dL. Men treated with testosterone also had a 53% rate of depression remission compared with 19% in the placebo group.¹⁶

The evidence supporting improved sexual function with TRT is variable. Some studies indicate limited or transient improvement of sexual function after TRT in men with erectile dysfunction,^18,19 while others report an improvement in sexual function after 3 months of TRT.⁴⁴ Because of the multifactorial nature of erectile dysfunction, men with erectile dysfunction and ADAM may require TRT and a phosphodiesterase type 5 (PDE5) inhibitor, as TRT alone may be insufficient. In a prospective observational study of men with erectile dysfunction and an initial testosterone lower than 300 ng/dL, testosterone gel was administered for at least 1 year, and improvement in sexual function was seen. Results revealed a correlation between improvement in sexual function and concurrent therapy with a PDE5 inhibitor.⁴⁵ In a recent multicenter placebo-controlled study of PDE5 inhibitor nonresponders, the addition of a testosterone gel to tadalafil (Cialis) improved sexual function, again suggesting a synergistic effect when treating erectile dysfunction with both TRT and a PDE5 inhibitor.⁴⁶

ADVERSE EVENTS RELATED TO TRT

Despite the aforementioned benefits, it must be emphasized that TRT should be used for specific target symptoms related to hypogonadism in older men and that the general health benefits and safety of TRT in an asymptomatic man with a low measured testosterone alone remains unproven.

Cardiovascular events. In a recent study of 209 elderly men with low testosterone and limited mobility associated with other chronic illnesses, 6 months of TRT resulted in the development of cardiovascular-related adverse events in 23 patients compared with 5 men in the placebo group.⁴⁷ This may have been related to how adverse events were reported, with cumulative adverse events reviewed every 6 months, ranging from peripheral edema, hypertension, arrhythmias, and electrocardiographic changes. Serious adverse events were reviewed as they occurred, including stroke and acute myocardial events.

Other studies^41,43 have revealed a favorable effect of TRT on cardiovascular disease and its surrogate markers but have lacked detailed reports and close monitoring of adverse events. Thus, variation of outcome measurement and reporting may obfuscate the detection of adverse cardiovascular events. Outcomes may also depend on the testosterone formulation and the target serum concentration.⁴³

Larger, long-term placebo-controlled trials are needed to elucidate cardiovascular risk as a primary outcome in older androgen-deficient men undergoing TRT.

Other adverse effects related to TRT include erythrocytosis, seen in 3% to 18% of patients with transdermal administration,^48,49 and up to 44% of patients undergoing IM therapy.⁴⁸ Gynecomastia can occur and is more likely to resolve after treatment cessation of transdermal testosterone treatment than IM injections.⁴⁸ Other potential clinical side effects that should prompt dose-reduction or discontinuation are irritability, bothersome acne, fluid retention, testicular atrophy, worsening of lower urinary tract symptoms from an enlarged prostate, and new or worsening heart failure. Infrequently, obstructive sleep apnea may be worsened by TRT, although currently the data linking sleep apnea and TRT are limited.⁵⁰

TRT AND PROSTATE CANCER

The relationship between prostate cancer growth and testosterone is well established, with androgen ablation remaining the cornerstone of treatment for metastatic disease. Since androgen deprivation leads to the regression of prostate cancer, there has been concern that TRT may lead to growth or de novo development of prostate cancer. TRT has thus been strongly prohibited in patients with prostate cancer.⁷ However, recent data challenge this paradigm.

In a retrospective study of 81 men (mean age 56.8 years) treated with TRT, only 4 men (4.9%) developed prostate cancer over a 5-year period.⁵¹ This is less than the estimated 16.7% probability of developing prostate cancer in the general US population.⁵²

Recent accumulating data support the concept of testosterone reaching a saturation level when binding androgen receptors within the prostate at extremely low levels. Increases above this level with TRT as with ADAM do not increase the risk of development or progression of prostate cancer.⁵³ In addition, large doses of dihydrotestosterone do not seem to alter PSA, prostate volume, or International Prostate Symptom Score.⁵⁴ These findings may have implications in future androgen therapies in hypogonadal older men.

Pathologic studies suggest low testosterone is associated with a higher Gleason grade of prostate cancer,⁵⁵ although this association remains unconfirmed.⁵⁶

In men with erectile dysfunction after prostate cancer treatment, TRT appears safe after brachytherapy⁵⁷ or radical prostatectomy.⁵⁸ A small study of 15 hypogonadal men with castrate-resistant prostate cancer and minimal or no metastatic disease showed only 1 patient had symptomatic progression.⁵⁹ Moreover, a recent small study of 13 men with known prostate cancer on active surveillance showed that TRT did not lead to local progression or metastatic disease in any of the patients.⁶⁰

While these data are provocative, it should still be emphasized that the standard of care for prostate cancer screening should be followed in age-appropriate men with ADAM. In addition, hypogonadal men with prostate cancer should only be treated with testosterone in conjunction with careful counseling and ongoing monitoring.

TRT SHOULD NOT REPLACE HEALTHY LIFESTYLE CHANGES

There has been a dramatic increase in TRT initiation for nonspecific symptoms of low testosterone in older androgen-deficient men. With this increase in initiation of TRT, there is a significant risk of overtreating. While there are many encouraging associations between treatment of androgen deficiency and improvement in rates of of morbidity and mortality, much remains unknown about the overall long-term risks and benefits of TRT. It is important to emphasize that TRT should not replace healthy lifestyle changes including regular exercise, weight loss, and diet modifications, which may provide the patient symptom resolution. Thoughtful dialogue with the patient is critical prior to TRT initiation, including thorough disclosure of the risks and benefits of treatment, and the limitations of the data as it evolves.

Editor’s note: This is the second of two articles on hypogonadism in men and focuses on the appropriate use of testosterone therapy. The first article, published last month, focused in more detail on the differential diagnosis of hypogonadism.

As men age, testosterone production gradually decreases. In our increasingly aged population, clinicians will continue to see an increase in the number of men with seemingly nonspecific symptoms of aging that are possibly due to low serum testosterone (eg, low energy level, depressive symptoms, erectile dysfunction, decreased libido). These clinical symptoms, coupled with low serum testosterone, may adversely affect quality of life and life expectancy. Testosterone replacement therapy (TRT) may improve symptoms and quality of life. Given the nonspecific nature of these symptoms, accurate diagnosis and treatment of clinically significant low testosterone with a goal of symptom and quality of life improvement can prove challenging.

These challenges in diagnosis and treatment result in a lack of standardized nomenclature. The terms male menopause and andropause, although popular, are the least helpful, as they have few correlates with the better-defined female menopause. Late-onset hypogonadism implies a well-defined, later age of decline, which is inaccurate since the decline in serum testosterone in men begins in middle age and is gradual. Testosterone deficiency syndrome implies a set of specific and well-defined symptoms. Androgen deficiency in the aging male (ADAM) and Androgen deficiency in the older male are common terms specifying an age cohort (> 40 years old) and an abnormal laboratory value without mention of symptoms. While all these terms have their limitations, we will primarily use ADAM in this discussion.

PREVALENCE OF LOW TESTOSTERONE

Serum testosterone levels begin to decline in men in their mid-40s, with an approximately 1% to 2% decline annually and a marked decline after age 60.¹

Araujo and colleagues² studied the prevalence of androgen-deficient men, with androgen deficiency defined as at least three signs or symptoms and either a total testosterone less than 200 ng/dL or a total testosterone 200 ng/dL to 400 ng/dL with a free testosterone less than 8.91 ng/dL. The overall prevalence of low testosterone on initial measurement was 6%, which doubled to 12% with repeat measurement.

Serial measures are important: one study that followed untreated men over 15 years found normal testosterone on serial measures in 50%.³ In a multicenter cross-sectional study, 11.8% of men had low testosterone and low or normal luteinizing hormone (LH) levels (secondary hypogonadism/hypothalamic-pituitary failure), with 2% of patients with low testosterone and elevated LH (primary hypogonadism/testicular failure).⁴

CLINICAL PRESENTATION AND DIAGNOSIS

A biochemical diagnosis of low testosterone is dependent on accurate measurement. Testosterone release is diurnal, with the highest levels in the early morning, and often has week-to-week variability. Thus, it is important to collect blood in the early morning and to confirm a diagnosis of low testosterone with at least one repeat measurement several days later, including LH assessment. LH levels will help differentiate primary hypogonadism from secondary hypogonadism, which may alter diagnosis and treatment in certain patients, with secondary hypogonadism associated with pituitary dysfunction, and primary hypogonadism associated with aging.⁴

Testosterone binds in the bloodstream to sex hormone-binding globulin (SHBG), and this bound form is generally considered biologically inactive, although there are in vitro and animal studies suggesting SHBG-bound androgen may indeed have biological activity. ^5,6 “Bioavailable” testosterone is active and includes both free testosterone and testosterone bound to albumin.

There is no general agreement on the acceptable normal range of testosterone, with variability within the literature and between laboratories. “Normal” total testosterone levels have ranged from more than 280 ng/dL to more than 350 ng/dL (12 nmol/L).^7,8 Similarly, there is no generally accepted lower limit of normal, although some studies report a threshold level of testosterone less than 230 ng/dL (8 nmol/L) as “abnormal.” Values between these two upper and lower limits are considered “borderline.”^7,8 These intermediate or borderline values coupled with clinical symptoms of testosterone deficiency syndrome or ADAM should be considered abnormal.

When total testosterone is borderline, measurement of free or bioavailable testosterone (free plus albumin-bound) should be considered. Total testosterone is typically measured using automated immunoassay platforms, with method-related differences leading to significant variability in measurement accuracy and precision. This variability is seen most dramatically in those with low total testosterone.⁹ However, the variability of total testosterone measurements is substantially smaller among mass spectrometry assays than among immunoassays. ¹⁰

The gold standards for free testosterone measurement are centrifugal ultrafiltration and equilibrium dialysis.⁹ However, these techniques are laborious and usually unavailable in local laboratories. Calculated free testosterone values using total testosterone and SHBG are most commonly used and are sufficiently accurate for clinical practice.¹¹

Free testosterone levels can be diagnostic when total testosterone levels do not correspond with clinical presentation. However, the clinical utility of free testosterone is difficult to assess due to the variability among laboratory assays and a lack of consensus on threshold parameters. A threshold free testosterone level of more than 225 pmol/L (65 pg/mL) is generally considered normal.^7,8 Before starting a patient on TRT, measurement of hemoglobin and prostate-specific antigen (PSA) and digital rectal examination of the prostate (if age is > 39) are essential.

Prolactin levels are recommended when low testosterone is confirmed, especially in patients at high clinical risk for hyperprolactinemia. Once hyperprolactinemia is identified, Endocrine Society guidelines recommend excluding medication use, renal failure, hypothyroidism, and parasellar tumors as possible causes of elevated prolactin levels.¹²

Low testosterone values should be treated only in patients with clinically significant symptoms that are likely to be caused by the low testosterone itself. Symptoms associated with age-related decline in testosterone that may improve with TRT include low libido,^13,14 low energy,¹⁴ depressed mood,^15–17 low muscle mass, osteoporosis, and hot flashes. Men with erectile dysfunction have also shown a significant improvement with TRT compared with placebo, but with a variable overall response independent of normalization of testosterone. ^18,19 This is likely due to the multifactorial nature of erectile dysfunction, including vascular, neurologic, psychogenic, and endocrinologic causes.

Screening questionnaires have been developed for symptoms of low testosterone, but their clinical utility is unclear. The ADAM questionnaire is used as a screening tool for low testosterone but not to monitor response to TRT, and it is highly nonspecific.²⁰ The Aging Male Symptom Scale questionnaire includes psychological, somatovegetative, and sexual components and is used both to screen for low testosterone and to measure outcomes.²¹ However, a recent observational study comparing the ability of these questionnaires to assess clinical symptoms revealed a low sensitivity and a low specificity to detect androgen deficiency in men with a total testosterone level less than 300 ng/dL.²² Overall, the current data do not conclusively support the use of hypogonadism questionnaires for screening.

The patient history when evaluating for ADAM should include evaluation of sexual and constitutional symptoms as described above and in Table 1. In addition, a history of traumatic, medical, or surgical events that could affect testosterone production should be obtained, including cryptorchidism, scrotal, inguinal, or abdominal surgery, pituitary surgery or radiation, prior issues with infertility, timing of puberty, history of renal or hepatic failure, chemotherapy (for cancer or autoimmune diseases), and prior use of anabolic steroids or opiates.

A complete physical examination should include assessment of virilization, gynecomastia, and the genitalia, including the size, position, and volume of the testes. The size and consistency of the prostate should be assessed on digital rectal examination.

LOW TESTOSTERONE AND ASSOCIATED COMORBIDITIES

Low testosterone is associated with many comorbidities, including metabolic syndrome, depression, type 2 diabetes mellitus, and cardiovascular disease, as discussed later in this section. Low testosterone has also shown associations with osteoporosis, cognitive impairment, hypertension, hyperlipidemia, decreased physical performance, end-stage renal disease, and treatment with steroids or opiates.^23–26 However, the studies that found these associations included men younger than 40 years and may not be fully applicable to the ADAM population.

The association of metabolic syndrome and type 2 diabetes mellitus with low testosterone is well established in multiple studies. Grossman and colleagues²⁷ investigated the association of type 2 diabetes mellitus and low testosterone, with low total testosterone defined as below 10 nmol/L and low calculated free testosterone less than 0.23 nmol/L. The prevalence of low total testosterone was 43%, and the prevalence of low free testosterone was 57%. In addition, a recent meta-analysis comparing total testosterone of men with and without metabolic syndrome revealed an association between a baseline decrease in mean total and free testosterone levels in men with metabolic syndrome compared with controls. This study found a total testosterone mean difference of –2.64 nmol/L (95% confidence interval [CI] –2.95 to –2.32) and a free testosterone mean difference of –0.26 pmol/L (95% CI –0.39 to –0.13), respectively, when comparing men with metabolic syndrome against those without.²⁸

Testosterone has also been suggested to be protective against type 2 diabetes mellitus, with 42% lower risk of type 2 diabetes mellitus in men with testosterone levels ranging from 450 ng/dL to 605 ng/dL.²⁹

Obesity has been specifically linked with secondary hypogonadism.^4,23,24 A prospective cohort of 58 men with an average age of 46 years and a body mass index ranging from 30 to 45 kg/m² were monitored on a low-calorie diet for 9 weeks. Afterward, biochemical analysis revealed an increase in free testosterone from 185 pmol/L ± 66 to 208 ± 70 pmol/L (P = .002) with a mean weight loss of 16.3 kg ± 4.5 kg.³⁰ This emphasizes the importance of lifestyle changes in the management of hypogonadal men.

LOW TESTOSTERONE AND THE OVERALL MORTALITY RATE

Low testosterone is associated unfavorably with the rate of all-cause mortality. A retrospective study in male veterans over age 40 with repeated testosterone levels over a 5-year period found that the risk of death from all causes in men with normal testosterone (> 250 ng/dL or free testosterone > 0.75 ng/dL) was 20% (95% CI 16.2%–241%) vs 35% (95% CI 28.5%–41.4%) in men with low testosterone (< 250 ng/dL or free testosterone < 0.75 ng/dL). In multivariate analysis, men with testosterone less than 250 ng/dL (< 8.7 nmol/L) or free testosterone less than 0.75 ng/dL (< 0.03 nmol/L) had up to an 88% higher death rate than men with normal testosterone levels.³¹

Low testosterone has also been associated with other end-organ, disease-specific mortality. In men with end-stage renal disease, low testosterone was an independent predictor of death from all causes and from cardiovascular disease.³² A prospective European health study revealed an association between low testosterone and increased risk of death from cardiovascular disease and cancer.³³ A recent meta-analysis of population-based studies confirmed this association, despite significant interstudy heterogeneity. ³⁴ Although multiple studies show an independent association of low testosterone and increased mortality rate, causality remains unconfirmed. This may be difficult to prove, given the available study designs and the nonspecific nature of symptoms related to low testosterone and potentially associated comorbidities.

TRT: INDICATIONS AND CONTRAINDICATIONS

The indications, benefits, and risks of TRT are controversial, with current data lacking long-term follow-up and consistent biochemical target values. Treatment of low testosterone is not indicated at the present time in the absence of clinical symptoms.

According to recently published guidelines, TRT is recommended for symptomatic men with low or borderline total testosterone or free testosterone (< 350 ng/dL or < 65 pg/mL).^7,8 Patients with borderline biochemical values (total testosterone 200–350 ng/dL, free testosterone 40–65 pg/mL) and possible related symptoms should be treated with TRT for at least 3 months and then reevaluated to verify improved testosterone levels and to assess for symptom amelioration or resolution.³⁵ Dose escalation is recommended in patients with subtherapeutic testosterone levels and limited clinical improvement after 3 months of treatment.

Target maintenance testosterone levels have not been defined, with mid to lower young adult male serum testosterone levels recommended at this time.⁸ Given that the current literature does not specify a target testosterone replacement range, we recommend monitoring the clinical response along with total testosterone to decide adjustments in TRT. Ultimately, treatment goals of TRT should be the resolution of signs and symptoms, including improvement of sexual function, libido, and preservation of bone mineral density.^7,8

Contraindications

TRT is not recommended in men with the following:

• Breast cancer
• Polycythemia (hematocrit > 50%)
• Untreated obstructive sleep apnea
• Lower urinary tract symptoms caused by an enlarged prostate; International Prostate Symptom Score > 19
• Poorly controlled heart failure
• Desire for fertility.

The role of TRT in prostate cancer remains controversial (see below) and remains contraindicated in recent Endocrine Society clinical practice guidelines.⁷ Guidelines recommend urologic consultation prior to initiation of TRT in patients at increased risk of prostate cancer,⁷ based on age, race, family history, PSA, PSA velocity, and history of prostate biopsy.

One prominent historic concern about androgen replacement therapy regards the potential for de novo development of prostate cancer. Numerous studies have failed to find elevated risk of new diagnosis, progression, or recurrence of prostate cancer in patients on TRT.^36,37 Nevertheless, patients who develop elevated PSA, increased PSA velocity, or an abnormal digital rectal examination while on TRT should undergo prostate biopsy.

TRT FORMULATIONS AND TREATMENT OPTIONS

A number of effective formulations of TRT are available (Table 2). Transdermal and parenteral formulations are most commonly used. Enteric testosterone formulations are not available in the United States and are associated with hepatotoxicity. While buccal testosterone therapy is available, it often leads to local gingival irritation and has not gained widespread popularity.

Parenteral TRT can be administered intramuscularly (IM) or subcutaneously (SQ). Testosterone cypionate (Depo-Testosterone) is the only IM form available in the United States and is given every 2 to 3 weeks. It is the least expensive form of TRT, but it requires frequent administration (by either the clinical practitioner or the patient himself). Testosterone cypionate injections lead to markedly wide swings of testosterone levels, ranging from supraphysiologic levels for a few days after administration to hypogonadal levels before the next injection. This may be mitigated by more-frequent injections. The longer-acting form testosterone undecanoate is available outside the United States and is given every 12 weeks when stable levels are reached.

The other parenteral option is SQ slow-release pellets (Testopel). These pellets have 75 mg of testosterone. Typically 8 to 14 pellets are placed subcutaneously in the buttock area, which will provide coverage for 3 to 6 months.³⁸ The insertion procedure is simple with a short learning curve, limited compliance issues, and elimination of risk of transdermal transmission of drug to others. Disadvantages include wound infection and pellet extrusion, seen in 0.3% to 12% of patients in various studies.³⁸

Another route of TRT is transdermal, including patches, liquids, and gels. Patches are applied daily and are rotated to different sites with minimal risk for skin transmission to others, although use may be limited by site dermatitis. Three hydro-alcoholic gel formulations are currently available in the United States: Androgel (1% or 1.62%), which is applied to the chest or the shoulders; Testim 1%, which is applied to the shoulders; and Fortesta (2%), which is applied to the thighs. A liquid preparation, Axiron, is applied to the axillae. Because secondary transfer to women and children is possible, it is important to thoroughly wash hands after application and to cover the treated skin with clothing. In 3 to 4 hours, all the medication is absorbed, and the area should then be washed before direct skin contact with others (Table 2).

MONITORING PATIENTS ON TRT

Patients starting TRT will require clinical and biochemical monitoring to evaluate response to therapy as well as possible side effects. The first set of laboratory values should be obtained 6 to 12 weeks after initiation of therapy and then typically quarterly for 1 year, every 6 months for the second year, and annually thereafter. Laboratory values monitored should include total testosterone, PSA, and hematocrit.

Men on daily therapy (patch, gel, liquid) should have testosterone drawn approximately 2 hours after application. Current TRT regimen data lack an appropriate target testosterone value, and guidelines suggest a mid to lower young adult male testosterone level.⁸ Since this is not clearly delineated in the current literature, the authors recommend monitoring clinical symptoms along with testosterone levels when adjusting TRT. It is important to document that serum testosterone was actually increased to the normal range in treated men without clinical improvement.

A rise in PSA of up to 24% would be an acceptable response in a benign prostate gland, but a higher increase or increase above 4.0 ng/dL should prompt consideration of prostate biopsy. ³⁹ Similarly, hemoglobin and hematocrit typically increase, but a hematocrit greater than 55% should prompt dose reduction or cessation.⁷ Transaminases do not need routine monitoring during parenteral or transdermal therapy. Bone mineral density should be monitored every 1 to 2 years.^7,8

CLINICAL BENEFITS OF TRT

There are promising data regarding the clinical benefits of TRT in patients with metabolic syndrome and type 2 diabetes mellitus. A recent meta-analysis investigating the effect of TRT on metabolic syndrome revealed an improvement in fasting plasma glucose, homeostatic model assessment index, triglycerides, treadmill duration, high-density lipoprotein cholesterol, and waist circumference.^40,41 TRT also decreased insulin resistance and improved glycemic control in type 2 diabetic hypogonadal men.⁴² Results from a randomized controlled trial comparing 12 weeks of intramuscular testosterone treatment vs placebo in men with metabolic syndrome revealed an improvement in mean waist circumference from 108 cm ± 8 cm to 105.5 cm ± 7.7 cm. Sixty percent of men initially diagnosed with metabolic syndrome and treated with testosterone no longer met diagnostic criteria for metabolic syndrome according to the National Cholesterol Education Program–Third Adult Treatment Panel (NCEP-ATP III) and the International Diabetes Federation (IDF) guidelines.⁴³

Depression has also been associated with low testosterone, with free testosterone levels below 170 pmol/L associated with frank depressive symptoms and levels below 220 pmol/L predictive of future onset of depressive symptoms.¹⁵ Testosterone replacement therapy has been shown to improve depressive symptoms in hypogonadal men.^16,17 Shores et al¹⁶ conducted a randomized placebo-controlled study of testosterone replacement in men older than 50 years with dysthymia or minor depression. Men treated with testosterone gel for 12 weeks showed an improvement of baseline total testosterone levels from 291 ng/dL to 449 ng/dL. Men treated with testosterone also had a 53% rate of depression remission compared with 19% in the placebo group.¹⁶

The evidence supporting improved sexual function with TRT is variable. Some studies indicate limited or transient improvement of sexual function after TRT in men with erectile dysfunction,^18,19 while others report an improvement in sexual function after 3 months of TRT.⁴⁴ Because of the multifactorial nature of erectile dysfunction, men with erectile dysfunction and ADAM may require TRT and a phosphodiesterase type 5 (PDE5) inhibitor, as TRT alone may be insufficient. In a prospective observational study of men with erectile dysfunction and an initial testosterone lower than 300 ng/dL, testosterone gel was administered for at least 1 year, and improvement in sexual function was seen. Results revealed a correlation between improvement in sexual function and concurrent therapy with a PDE5 inhibitor.⁴⁵ In a recent multicenter placebo-controlled study of PDE5 inhibitor nonresponders, the addition of a testosterone gel to tadalafil (Cialis) improved sexual function, again suggesting a synergistic effect when treating erectile dysfunction with both TRT and a PDE5 inhibitor.⁴⁶

ADVERSE EVENTS RELATED TO TRT

Despite the aforementioned benefits, it must be emphasized that TRT should be used for specific target symptoms related to hypogonadism in older men and that the general health benefits and safety of TRT in an asymptomatic man with a low measured testosterone alone remains unproven.

Cardiovascular events. In a recent study of 209 elderly men with low testosterone and limited mobility associated with other chronic illnesses, 6 months of TRT resulted in the development of cardiovascular-related adverse events in 23 patients compared with 5 men in the placebo group.⁴⁷ This may have been related to how adverse events were reported, with cumulative adverse events reviewed every 6 months, ranging from peripheral edema, hypertension, arrhythmias, and electrocardiographic changes. Serious adverse events were reviewed as they occurred, including stroke and acute myocardial events.

Other studies^41,43 have revealed a favorable effect of TRT on cardiovascular disease and its surrogate markers but have lacked detailed reports and close monitoring of adverse events. Thus, variation of outcome measurement and reporting may obfuscate the detection of adverse cardiovascular events. Outcomes may also depend on the testosterone formulation and the target serum concentration.⁴³

Larger, long-term placebo-controlled trials are needed to elucidate cardiovascular risk as a primary outcome in older androgen-deficient men undergoing TRT.

Other adverse effects related to TRT include erythrocytosis, seen in 3% to 18% of patients with transdermal administration,^48,49 and up to 44% of patients undergoing IM therapy.⁴⁸ Gynecomastia can occur and is more likely to resolve after treatment cessation of transdermal testosterone treatment than IM injections.⁴⁸ Other potential clinical side effects that should prompt dose-reduction or discontinuation are irritability, bothersome acne, fluid retention, testicular atrophy, worsening of lower urinary tract symptoms from an enlarged prostate, and new or worsening heart failure. Infrequently, obstructive sleep apnea may be worsened by TRT, although currently the data linking sleep apnea and TRT are limited.⁵⁰

TRT AND PROSTATE CANCER

The relationship between prostate cancer growth and testosterone is well established, with androgen ablation remaining the cornerstone of treatment for metastatic disease. Since androgen deprivation leads to the regression of prostate cancer, there has been concern that TRT may lead to growth or de novo development of prostate cancer. TRT has thus been strongly prohibited in patients with prostate cancer.⁷ However, recent data challenge this paradigm.

In a retrospective study of 81 men (mean age 56.8 years) treated with TRT, only 4 men (4.9%) developed prostate cancer over a 5-year period.⁵¹ This is less than the estimated 16.7% probability of developing prostate cancer in the general US population.⁵²

Recent accumulating data support the concept of testosterone reaching a saturation level when binding androgen receptors within the prostate at extremely low levels. Increases above this level with TRT as with ADAM do not increase the risk of development or progression of prostate cancer.⁵³ In addition, large doses of dihydrotestosterone do not seem to alter PSA, prostate volume, or International Prostate Symptom Score.⁵⁴ These findings may have implications in future androgen therapies in hypogonadal older men.

Pathologic studies suggest low testosterone is associated with a higher Gleason grade of prostate cancer,⁵⁵ although this association remains unconfirmed.⁵⁶

In men with erectile dysfunction after prostate cancer treatment, TRT appears safe after brachytherapy⁵⁷ or radical prostatectomy.⁵⁸ A small study of 15 hypogonadal men with castrate-resistant prostate cancer and minimal or no metastatic disease showed only 1 patient had symptomatic progression.⁵⁹ Moreover, a recent small study of 13 men with known prostate cancer on active surveillance showed that TRT did not lead to local progression or metastatic disease in any of the patients.⁶⁰

While these data are provocative, it should still be emphasized that the standard of care for prostate cancer screening should be followed in age-appropriate men with ADAM. In addition, hypogonadal men with prostate cancer should only be treated with testosterone in conjunction with careful counseling and ongoing monitoring.

TRT SHOULD NOT REPLACE HEALTHY LIFESTYLE CHANGES

There has been a dramatic increase in TRT initiation for nonspecific symptoms of low testosterone in older androgen-deficient men. With this increase in initiation of TRT, there is a significant risk of overtreating. While there are many encouraging associations between treatment of androgen deficiency and improvement in rates of of morbidity and mortality, much remains unknown about the overall long-term risks and benefits of TRT. It is important to emphasize that TRT should not replace healthy lifestyle changes including regular exercise, weight loss, and diet modifications, which may provide the patient symptom resolution. Thoughtful dialogue with the patient is critical prior to TRT initiation, including thorough disclosure of the risks and benefits of treatment, and the limitations of the data as it evolves.

Editor’s note: This is the second of two articles on hypogonadism in men and focuses on the appropriate use of testosterone therapy. The first article, published last month, focused in more detail on the differential diagnosis of hypogonadism.

As men age, testosterone production gradually decreases. In our increasingly aged population, clinicians will continue to see an increase in the number of men with seemingly nonspecific symptoms of aging that are possibly due to low serum testosterone (eg, low energy level, depressive symptoms, erectile dysfunction, decreased libido). These clinical symptoms, coupled with low serum testosterone, may adversely affect quality of life and life expectancy. Testosterone replacement therapy (TRT) may improve symptoms and quality of life. Given the nonspecific nature of these symptoms, accurate diagnosis and treatment of clinically significant low testosterone with a goal of symptom and quality of life improvement can prove challenging.

These challenges in diagnosis and treatment result in a lack of standardized nomenclature. The terms male menopause and andropause, although popular, are the least helpful, as they have few correlates with the better-defined female menopause. Late-onset hypogonadism implies a well-defined, later age of decline, which is inaccurate since the decline in serum testosterone in men begins in middle age and is gradual. Testosterone deficiency syndrome implies a set of specific and well-defined symptoms. Androgen deficiency in the aging male (ADAM) and Androgen deficiency in the older male are common terms specifying an age cohort (> 40 years old) and an abnormal laboratory value without mention of symptoms. While all these terms have their limitations, we will primarily use ADAM in this discussion.

PREVALENCE OF LOW TESTOSTERONE

Serum testosterone levels begin to decline in men in their mid-40s, with an approximately 1% to 2% decline annually and a marked decline after age 60.¹

Araujo and colleagues² studied the prevalence of androgen-deficient men, with androgen deficiency defined as at least three signs or symptoms and either a total testosterone less than 200 ng/dL or a total testosterone 200 ng/dL to 400 ng/dL with a free testosterone less than 8.91 ng/dL. The overall prevalence of low testosterone on initial measurement was 6%, which doubled to 12% with repeat measurement.

Serial measures are important: one study that followed untreated men over 15 years found normal testosterone on serial measures in 50%.³ In a multicenter cross-sectional study, 11.8% of men had low testosterone and low or normal luteinizing hormone (LH) levels (secondary hypogonadism/hypothalamic-pituitary failure), with 2% of patients with low testosterone and elevated LH (primary hypogonadism/testicular failure).⁴

CLINICAL PRESENTATION AND DIAGNOSIS

A biochemical diagnosis of low testosterone is dependent on accurate measurement. Testosterone release is diurnal, with the highest levels in the early morning, and often has week-to-week variability. Thus, it is important to collect blood in the early morning and to confirm a diagnosis of low testosterone with at least one repeat measurement several days later, including LH assessment. LH levels will help differentiate primary hypogonadism from secondary hypogonadism, which may alter diagnosis and treatment in certain patients, with secondary hypogonadism associated with pituitary dysfunction, and primary hypogonadism associated with aging.⁴

Testosterone binds in the bloodstream to sex hormone-binding globulin (SHBG), and this bound form is generally considered biologically inactive, although there are in vitro and animal studies suggesting SHBG-bound androgen may indeed have biological activity. ^5,6 “Bioavailable” testosterone is active and includes both free testosterone and testosterone bound to albumin.

There is no general agreement on the acceptable normal range of testosterone, with variability within the literature and between laboratories. “Normal” total testosterone levels have ranged from more than 280 ng/dL to more than 350 ng/dL (12 nmol/L).^7,8 Similarly, there is no generally accepted lower limit of normal, although some studies report a threshold level of testosterone less than 230 ng/dL (8 nmol/L) as “abnormal.” Values between these two upper and lower limits are considered “borderline.”^7,8 These intermediate or borderline values coupled with clinical symptoms of testosterone deficiency syndrome or ADAM should be considered abnormal.

When total testosterone is borderline, measurement of free or bioavailable testosterone (free plus albumin-bound) should be considered. Total testosterone is typically measured using automated immunoassay platforms, with method-related differences leading to significant variability in measurement accuracy and precision. This variability is seen most dramatically in those with low total testosterone.⁹ However, the variability of total testosterone measurements is substantially smaller among mass spectrometry assays than among immunoassays. ¹⁰

The gold standards for free testosterone measurement are centrifugal ultrafiltration and equilibrium dialysis.⁹ However, these techniques are laborious and usually unavailable in local laboratories. Calculated free testosterone values using total testosterone and SHBG are most commonly used and are sufficiently accurate for clinical practice.¹¹

Free testosterone levels can be diagnostic when total testosterone levels do not correspond with clinical presentation. However, the clinical utility of free testosterone is difficult to assess due to the variability among laboratory assays and a lack of consensus on threshold parameters. A threshold free testosterone level of more than 225 pmol/L (65 pg/mL) is generally considered normal.^7,8 Before starting a patient on TRT, measurement of hemoglobin and prostate-specific antigen (PSA) and digital rectal examination of the prostate (if age is > 39) are essential.

Prolactin levels are recommended when low testosterone is confirmed, especially in patients at high clinical risk for hyperprolactinemia. Once hyperprolactinemia is identified, Endocrine Society guidelines recommend excluding medication use, renal failure, hypothyroidism, and parasellar tumors as possible causes of elevated prolactin levels.¹²

Low testosterone values should be treated only in patients with clinically significant symptoms that are likely to be caused by the low testosterone itself. Symptoms associated with age-related decline in testosterone that may improve with TRT include low libido,^13,14 low energy,¹⁴ depressed mood,^15–17 low muscle mass, osteoporosis, and hot flashes. Men with erectile dysfunction have also shown a significant improvement with TRT compared with placebo, but with a variable overall response independent of normalization of testosterone. ^18,19 This is likely due to the multifactorial nature of erectile dysfunction, including vascular, neurologic, psychogenic, and endocrinologic causes.

Screening questionnaires have been developed for symptoms of low testosterone, but their clinical utility is unclear. The ADAM questionnaire is used as a screening tool for low testosterone but not to monitor response to TRT, and it is highly nonspecific.²⁰ The Aging Male Symptom Scale questionnaire includes psychological, somatovegetative, and sexual components and is used both to screen for low testosterone and to measure outcomes.²¹ However, a recent observational study comparing the ability of these questionnaires to assess clinical symptoms revealed a low sensitivity and a low specificity to detect androgen deficiency in men with a total testosterone level less than 300 ng/dL.²² Overall, the current data do not conclusively support the use of hypogonadism questionnaires for screening.

The patient history when evaluating for ADAM should include evaluation of sexual and constitutional symptoms as described above and in Table 1. In addition, a history of traumatic, medical, or surgical events that could affect testosterone production should be obtained, including cryptorchidism, scrotal, inguinal, or abdominal surgery, pituitary surgery or radiation, prior issues with infertility, timing of puberty, history of renal or hepatic failure, chemotherapy (for cancer or autoimmune diseases), and prior use of anabolic steroids or opiates.

A complete physical examination should include assessment of virilization, gynecomastia, and the genitalia, including the size, position, and volume of the testes. The size and consistency of the prostate should be assessed on digital rectal examination.

LOW TESTOSTERONE AND ASSOCIATED COMORBIDITIES

Low testosterone is associated with many comorbidities, including metabolic syndrome, depression, type 2 diabetes mellitus, and cardiovascular disease, as discussed later in this section. Low testosterone has also shown associations with osteoporosis, cognitive impairment, hypertension, hyperlipidemia, decreased physical performance, end-stage renal disease, and treatment with steroids or opiates.^23–26 However, the studies that found these associations included men younger than 40 years and may not be fully applicable to the ADAM population.

The association of metabolic syndrome and type 2 diabetes mellitus with low testosterone is well established in multiple studies. Grossman and colleagues²⁷ investigated the association of type 2 diabetes mellitus and low testosterone, with low total testosterone defined as below 10 nmol/L and low calculated free testosterone less than 0.23 nmol/L. The prevalence of low total testosterone was 43%, and the prevalence of low free testosterone was 57%. In addition, a recent meta-analysis comparing total testosterone of men with and without metabolic syndrome revealed an association between a baseline decrease in mean total and free testosterone levels in men with metabolic syndrome compared with controls. This study found a total testosterone mean difference of –2.64 nmol/L (95% confidence interval [CI] –2.95 to –2.32) and a free testosterone mean difference of –0.26 pmol/L (95% CI –0.39 to –0.13), respectively, when comparing men with metabolic syndrome against those without.²⁸

Testosterone has also been suggested to be protective against type 2 diabetes mellitus, with 42% lower risk of type 2 diabetes mellitus in men with testosterone levels ranging from 450 ng/dL to 605 ng/dL.²⁹

Obesity has been specifically linked with secondary hypogonadism.^4,23,24 A prospective cohort of 58 men with an average age of 46 years and a body mass index ranging from 30 to 45 kg/m² were monitored on a low-calorie diet for 9 weeks. Afterward, biochemical analysis revealed an increase in free testosterone from 185 pmol/L ± 66 to 208 ± 70 pmol/L (P = .002) with a mean weight loss of 16.3 kg ± 4.5 kg.³⁰ This emphasizes the importance of lifestyle changes in the management of hypogonadal men.

LOW TESTOSTERONE AND THE OVERALL MORTALITY RATE

Low testosterone is associated unfavorably with the rate of all-cause mortality. A retrospective study in male veterans over age 40 with repeated testosterone levels over a 5-year period found that the risk of death from all causes in men with normal testosterone (> 250 ng/dL or free testosterone > 0.75 ng/dL) was 20% (95% CI 16.2%–241%) vs 35% (95% CI 28.5%–41.4%) in men with low testosterone (< 250 ng/dL or free testosterone < 0.75 ng/dL). In multivariate analysis, men with testosterone less than 250 ng/dL (< 8.7 nmol/L) or free testosterone less than 0.75 ng/dL (< 0.03 nmol/L) had up to an 88% higher death rate than men with normal testosterone levels.³¹

Low testosterone has also been associated with other end-organ, disease-specific mortality. In men with end-stage renal disease, low testosterone was an independent predictor of death from all causes and from cardiovascular disease.³² A prospective European health study revealed an association between low testosterone and increased risk of death from cardiovascular disease and cancer.³³ A recent meta-analysis of population-based studies confirmed this association, despite significant interstudy heterogeneity. ³⁴ Although multiple studies show an independent association of low testosterone and increased mortality rate, causality remains unconfirmed. This may be difficult to prove, given the available study designs and the nonspecific nature of symptoms related to low testosterone and potentially associated comorbidities.

TRT: INDICATIONS AND CONTRAINDICATIONS

The indications, benefits, and risks of TRT are controversial, with current data lacking long-term follow-up and consistent biochemical target values. Treatment of low testosterone is not indicated at the present time in the absence of clinical symptoms.

According to recently published guidelines, TRT is recommended for symptomatic men with low or borderline total testosterone or free testosterone (< 350 ng/dL or < 65 pg/mL).^7,8 Patients with borderline biochemical values (total testosterone 200–350 ng/dL, free testosterone 40–65 pg/mL) and possible related symptoms should be treated with TRT for at least 3 months and then reevaluated to verify improved testosterone levels and to assess for symptom amelioration or resolution.³⁵ Dose escalation is recommended in patients with subtherapeutic testosterone levels and limited clinical improvement after 3 months of treatment.

Target maintenance testosterone levels have not been defined, with mid to lower young adult male serum testosterone levels recommended at this time.⁸ Given that the current literature does not specify a target testosterone replacement range, we recommend monitoring the clinical response along with total testosterone to decide adjustments in TRT. Ultimately, treatment goals of TRT should be the resolution of signs and symptoms, including improvement of sexual function, libido, and preservation of bone mineral density.^7,8

Contraindications

TRT is not recommended in men with the following:

• Breast cancer
• Polycythemia (hematocrit > 50%)
• Untreated obstructive sleep apnea
• Lower urinary tract symptoms caused by an enlarged prostate; International Prostate Symptom Score > 19
• Poorly controlled heart failure
• Desire for fertility.

The role of TRT in prostate cancer remains controversial (see below) and remains contraindicated in recent Endocrine Society clinical practice guidelines.⁷ Guidelines recommend urologic consultation prior to initiation of TRT in patients at increased risk of prostate cancer,⁷ based on age, race, family history, PSA, PSA velocity, and history of prostate biopsy.

One prominent historic concern about androgen replacement therapy regards the potential for de novo development of prostate cancer. Numerous studies have failed to find elevated risk of new diagnosis, progression, or recurrence of prostate cancer in patients on TRT.^36,37 Nevertheless, patients who develop elevated PSA, increased PSA velocity, or an abnormal digital rectal examination while on TRT should undergo prostate biopsy.

TRT FORMULATIONS AND TREATMENT OPTIONS

A number of effective formulations of TRT are available (Table 2). Transdermal and parenteral formulations are most commonly used. Enteric testosterone formulations are not available in the United States and are associated with hepatotoxicity. While buccal testosterone therapy is available, it often leads to local gingival irritation and has not gained widespread popularity.

Parenteral TRT can be administered intramuscularly (IM) or subcutaneously (SQ). Testosterone cypionate (Depo-Testosterone) is the only IM form available in the United States and is given every 2 to 3 weeks. It is the least expensive form of TRT, but it requires frequent administration (by either the clinical practitioner or the patient himself). Testosterone cypionate injections lead to markedly wide swings of testosterone levels, ranging from supraphysiologic levels for a few days after administration to hypogonadal levels before the next injection. This may be mitigated by more-frequent injections. The longer-acting form testosterone undecanoate is available outside the United States and is given every 12 weeks when stable levels are reached.

The other parenteral option is SQ slow-release pellets (Testopel). These pellets have 75 mg of testosterone. Typically 8 to 14 pellets are placed subcutaneously in the buttock area, which will provide coverage for 3 to 6 months.³⁸ The insertion procedure is simple with a short learning curve, limited compliance issues, and elimination of risk of transdermal transmission of drug to others. Disadvantages include wound infection and pellet extrusion, seen in 0.3% to 12% of patients in various studies.³⁸

Another route of TRT is transdermal, including patches, liquids, and gels. Patches are applied daily and are rotated to different sites with minimal risk for skin transmission to others, although use may be limited by site dermatitis. Three hydro-alcoholic gel formulations are currently available in the United States: Androgel (1% or 1.62%), which is applied to the chest or the shoulders; Testim 1%, which is applied to the shoulders; and Fortesta (2%), which is applied to the thighs. A liquid preparation, Axiron, is applied to the axillae. Because secondary transfer to women and children is possible, it is important to thoroughly wash hands after application and to cover the treated skin with clothing. In 3 to 4 hours, all the medication is absorbed, and the area should then be washed before direct skin contact with others (Table 2).

MONITORING PATIENTS ON TRT

Patients starting TRT will require clinical and biochemical monitoring to evaluate response to therapy as well as possible side effects. The first set of laboratory values should be obtained 6 to 12 weeks after initiation of therapy and then typically quarterly for 1 year, every 6 months for the second year, and annually thereafter. Laboratory values monitored should include total testosterone, PSA, and hematocrit.

Men on daily therapy (patch, gel, liquid) should have testosterone drawn approximately 2 hours after application. Current TRT regimen data lack an appropriate target testosterone value, and guidelines suggest a mid to lower young adult male testosterone level.⁸ Since this is not clearly delineated in the current literature, the authors recommend monitoring clinical symptoms along with testosterone levels when adjusting TRT. It is important to document that serum testosterone was actually increased to the normal range in treated men without clinical improvement.

A rise in PSA of up to 24% would be an acceptable response in a benign prostate gland, but a higher increase or increase above 4.0 ng/dL should prompt consideration of prostate biopsy. ³⁹ Similarly, hemoglobin and hematocrit typically increase, but a hematocrit greater than 55% should prompt dose reduction or cessation.⁷ Transaminases do not need routine monitoring during parenteral or transdermal therapy. Bone mineral density should be monitored every 1 to 2 years.^7,8

CLINICAL BENEFITS OF TRT

There are promising data regarding the clinical benefits of TRT in patients with metabolic syndrome and type 2 diabetes mellitus. A recent meta-analysis investigating the effect of TRT on metabolic syndrome revealed an improvement in fasting plasma glucose, homeostatic model assessment index, triglycerides, treadmill duration, high-density lipoprotein cholesterol, and waist circumference.^40,41 TRT also decreased insulin resistance and improved glycemic control in type 2 diabetic hypogonadal men.⁴² Results from a randomized controlled trial comparing 12 weeks of intramuscular testosterone treatment vs placebo in men with metabolic syndrome revealed an improvement in mean waist circumference from 108 cm ± 8 cm to 105.5 cm ± 7.7 cm. Sixty percent of men initially diagnosed with metabolic syndrome and treated with testosterone no longer met diagnostic criteria for metabolic syndrome according to the National Cholesterol Education Program–Third Adult Treatment Panel (NCEP-ATP III) and the International Diabetes Federation (IDF) guidelines.⁴³

Depression has also been associated with low testosterone, with free testosterone levels below 170 pmol/L associated with frank depressive symptoms and levels below 220 pmol/L predictive of future onset of depressive symptoms.¹⁵ Testosterone replacement therapy has been shown to improve depressive symptoms in hypogonadal men.^16,17 Shores et al¹⁶ conducted a randomized placebo-controlled study of testosterone replacement in men older than 50 years with dysthymia or minor depression. Men treated with testosterone gel for 12 weeks showed an improvement of baseline total testosterone levels from 291 ng/dL to 449 ng/dL. Men treated with testosterone also had a 53% rate of depression remission compared with 19% in the placebo group.¹⁶

The evidence supporting improved sexual function with TRT is variable. Some studies indicate limited or transient improvement of sexual function after TRT in men with erectile dysfunction,^18,19 while others report an improvement in sexual function after 3 months of TRT.⁴⁴ Because of the multifactorial nature of erectile dysfunction, men with erectile dysfunction and ADAM may require TRT and a phosphodiesterase type 5 (PDE5) inhibitor, as TRT alone may be insufficient. In a prospective observational study of men with erectile dysfunction and an initial testosterone lower than 300 ng/dL, testosterone gel was administered for at least 1 year, and improvement in sexual function was seen. Results revealed a correlation between improvement in sexual function and concurrent therapy with a PDE5 inhibitor.⁴⁵ In a recent multicenter placebo-controlled study of PDE5 inhibitor nonresponders, the addition of a testosterone gel to tadalafil (Cialis) improved sexual function, again suggesting a synergistic effect when treating erectile dysfunction with both TRT and a PDE5 inhibitor.⁴⁶

ADVERSE EVENTS RELATED TO TRT

Despite the aforementioned benefits, it must be emphasized that TRT should be used for specific target symptoms related to hypogonadism in older men and that the general health benefits and safety of TRT in an asymptomatic man with a low measured testosterone alone remains unproven.

Cardiovascular events. In a recent study of 209 elderly men with low testosterone and limited mobility associated with other chronic illnesses, 6 months of TRT resulted in the development of cardiovascular-related adverse events in 23 patients compared with 5 men in the placebo group.⁴⁷ This may have been related to how adverse events were reported, with cumulative adverse events reviewed every 6 months, ranging from peripheral edema, hypertension, arrhythmias, and electrocardiographic changes. Serious adverse events were reviewed as they occurred, including stroke and acute myocardial events.

Other studies^41,43 have revealed a favorable effect of TRT on cardiovascular disease and its surrogate markers but have lacked detailed reports and close monitoring of adverse events. Thus, variation of outcome measurement and reporting may obfuscate the detection of adverse cardiovascular events. Outcomes may also depend on the testosterone formulation and the target serum concentration.⁴³

Larger, long-term placebo-controlled trials are needed to elucidate cardiovascular risk as a primary outcome in older androgen-deficient men undergoing TRT.

Other adverse effects related to TRT include erythrocytosis, seen in 3% to 18% of patients with transdermal administration,^48,49 and up to 44% of patients undergoing IM therapy.⁴⁸ Gynecomastia can occur and is more likely to resolve after treatment cessation of transdermal testosterone treatment than IM injections.⁴⁸ Other potential clinical side effects that should prompt dose-reduction or discontinuation are irritability, bothersome acne, fluid retention, testicular atrophy, worsening of lower urinary tract symptoms from an enlarged prostate, and new or worsening heart failure. Infrequently, obstructive sleep apnea may be worsened by TRT, although currently the data linking sleep apnea and TRT are limited.⁵⁰

TRT AND PROSTATE CANCER

The relationship between prostate cancer growth and testosterone is well established, with androgen ablation remaining the cornerstone of treatment for metastatic disease. Since androgen deprivation leads to the regression of prostate cancer, there has been concern that TRT may lead to growth or de novo development of prostate cancer. TRT has thus been strongly prohibited in patients with prostate cancer.⁷ However, recent data challenge this paradigm.

In a retrospective study of 81 men (mean age 56.8 years) treated with TRT, only 4 men (4.9%) developed prostate cancer over a 5-year period.⁵¹ This is less than the estimated 16.7% probability of developing prostate cancer in the general US population.⁵²

Recent accumulating data support the concept of testosterone reaching a saturation level when binding androgen receptors within the prostate at extremely low levels. Increases above this level with TRT as with ADAM do not increase the risk of development or progression of prostate cancer.⁵³ In addition, large doses of dihydrotestosterone do not seem to alter PSA, prostate volume, or International Prostate Symptom Score.⁵⁴ These findings may have implications in future androgen therapies in hypogonadal older men.

Pathologic studies suggest low testosterone is associated with a higher Gleason grade of prostate cancer,⁵⁵ although this association remains unconfirmed.⁵⁶

In men with erectile dysfunction after prostate cancer treatment, TRT appears safe after brachytherapy⁵⁷ or radical prostatectomy.⁵⁸ A small study of 15 hypogonadal men with castrate-resistant prostate cancer and minimal or no metastatic disease showed only 1 patient had symptomatic progression.⁵⁹ Moreover, a recent small study of 13 men with known prostate cancer on active surveillance showed that TRT did not lead to local progression or metastatic disease in any of the patients.⁶⁰

While these data are provocative, it should still be emphasized that the standard of care for prostate cancer screening should be followed in age-appropriate men with ADAM. In addition, hypogonadal men with prostate cancer should only be treated with testosterone in conjunction with careful counseling and ongoing monitoring.

TRT SHOULD NOT REPLACE HEALTHY LIFESTYLE CHANGES

There has been a dramatic increase in TRT initiation for nonspecific symptoms of low testosterone in older androgen-deficient men. With this increase in initiation of TRT, there is a significant risk of overtreating. While there are many encouraging associations between treatment of androgen deficiency and improvement in rates of of morbidity and mortality, much remains unknown about the overall long-term risks and benefits of TRT. It is important to emphasize that TRT should not replace healthy lifestyle changes including regular exercise, weight loss, and diet modifications, which may provide the patient symptom resolution. Thoughtful dialogue with the patient is critical prior to TRT initiation, including thorough disclosure of the risks and benefits of treatment, and the limitations of the data as it evolves.

Hereditary colorectal cancer syndromes account for 5% to 10% of cases of colorectal cancer.

Identifying these patients in clinical practice begins by assessing a patient’s personal and family health history. An accurate and comprehensive family history should cover three generations and include ethnic background, ages and causes of death of relatives, and any diagnosis of cancer, including age at onset and history of polyps.

Red flags for a hereditary colorectal cancer syndrome in the personal or family history are:

• Early age of onset of cancer (eg, colorectal cancer before age 50)
• More than 10 colorectal adenomas
• Synchronous (ie, occurring at the same time) or metachronous (occurring at different times) primary cancers
• Multiple relatives in successive generations with the same or related cancers (eg, colon or endometrial cancer)
• A family member with a known hereditary colorectal cancer syndrome (Table 1).

Any of these red flags should prompt a referral for genetic counseling.

SYNDROMES ARE CLASSIFIED AS WITH OR WITHOUT POLYPOSIS

Many hereditary syndromes are associated with a higher risk of colorectal cancer. Generally, they can be divided into two categories (Table 2): polyposis syndromes (in which patients have numerous colorectal polyps) and nonpolyposis syndromes (with few or no polyps).

These two main types are subclassified on the basis of the histology of most of the polyps detected: adenomatous, hamartomatous, serrated, or mixed types.

In this review, we will address the three most common of these syndromes: Lynch syndrome (hereditary nonpolyposis colorectal cancer), familial adenomatous polyposis, and MYH-associated polyposis. However, as noted in Table 2, other hereditary colorectal cancer syndromes exist, and suspicion of these conditions should prompt a referral for further evaluation.

LYNCH SYNDROME (HEREDITARY NONPOLYPOSIS COLORECTAL CANCER)

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, predisposes people to a variety of cancers.

Colorectal cancer is the most common type of cancer associated with Lynch syndrome. Recent research suggests that the cumulative risk of developing colorectal cancer by age 80 is 42% for all patients with Lynch syndrome.¹ The median age at onset is 45 years.¹ For patients who undergo segmental resection of their initial cancer, the cumulative risk of metachronous colorectal cancer (ie, a new tumor arising later) is 16% at 10 years, 41% at 20 years, and up to 62% after 30 years.²

Endometrial cancer occurs in 17% to 57% of women with Lynch syndrome by age 70, with a median age at onset of 49 years.¹

Other extracolonic cancers in Lynch syndrome include cancers of the:

• Stomach (1%–10% risk by age 70 years)
• Ovaries (1%–20% risk)
• Hepatobiliary tract (1%–2% risk)
• Urinary tract (1%–12% risk)
• Small bowel (1%–2% risk)
• Brain (1%–8% risk)
• Skin (sebaceous adenomas, adenocarcinomas, and keratoacanthomas).^1,3,4

Earlier studies reported higher rates of associated cancer than those shown here. However, their data were largely derived from registries and may be overestimates. The numbers shown above are from population-based studies.

Genetics of Lynch syndrome

Lynch syndrome is caused by a germline mutation in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes.⁵ These genes code for proteins that are responsible DNA mismatch repair—one of the cell’s proofreading mechanisms during DNA replication.

These mutations are inherited in an autosomal dominant manner. Though de novo mutations in these genes have been reported, they are rare and the exact frequency with which they occur is unknown.⁶

In whom should Lynch syndrome be suspected?

Lynch syndrome can be suspected on the basis of family history and clinical criteria.

In 1991, the same group of experts who coined the term “hereditary nonpolyposis colorectal cancer” developed family history criteria for it¹:

• At least three relatives with histologically confirmed colorectal cancer, one of whom is a first-degree relative of the other two
• At least two successive generations involved
• At least one of the cancers diagnosed before age 50
• Familial adenomatous polyposis is excluded.

Known as the Amsterdam criteria, these were to be used in collaborative studies of families with hereditary colorectal cancer.⁷ In 1999, these criteria were broadened to include extracolonic cancers and became known as the Amsterdam II criteria (Table 3).⁸

Patients whose families meet the Amsterdam II criteria or who have molecular pathologic evidence of Lynch syndrome (see below) are appropriate candidates for genetic counseling and testing.

The diagnosis of Lynch syndrome is based on molecular pathologic analysis (performed on tumor samples) and confirmed by genetic testing.

Molecular pathologic evidence of Lynch syndrome includes microsatellite instability and loss of expression of one or more of the DNA mismatch repair proteins (detected using immunohistochemistry) (more on these below). The revised Bethesda guidelines (TABLE 3) were intended to identify individuals whose tumors should be tested for one or both of these phenomena.⁹

In 2009, the Evaluation of Genomic Applications in Practice and Prevention working group recommended that all patients with newly diagnosed colorectal cancer undergo microsatellite instability analysis, immunohistochemistry testing, or both, regardless of whether they meet the Amsterdam II or the Bethesda guideline criteria.¹⁰

Microsatellite instability analysis. Microsatellites are short sequences of repeated DNA. The tumor cells of patients who carry defective mismatch repair genes have microsatellites that are longer or shorter than in normal cells, a condition called microsatellite instability (ie, “MSI-high”).

Microsatellite instability testing, using a standardized panel of five DNA markers, is performed on normal and tumor tissue. If more than two of the five microsatellite markers in the tumor show instability, the lesion is considered to have a high level of microsatellite instability. About 15% of colorectal cancers have this high level, although most are not associated with Lynch syndrome and lose MLH1 expression by promoter methylation.^11,12

While only 2% of patients with colorectal cancer have Lynch syndrome, from 90% to 95% of colorectal cancers from patients with Lynch syndrome have high levels of microsatellite instability.¹⁰ The presence of MLH1 promoter hypermethylation, the BRAF mutation V600E, or both within the tumor suggests that the cancer is not associated with Lynch syndrome.

Some families that meet the Amsterdam I criteria have microsatellite-stable tumors: their condition has been called familial colorectal cancer type X.¹³ This condition is associated with a higher risk of colorectal cancer but not the other malignancies observed in Lynch syndrome.

Immunohistochemistry is performed to assess for expression of the mismatch repair proteins MSH2, MSH6, MLH1, and PMS2. Absence of expression of the specific protein within tumor cells compared with normal cells within the specimen suggests dysfunction of the specific gene and guides germline mutation testing (Figure 1). For example, a patient who lacks expression of the MSH2 protein in his or her colon cancer most likely has a mutation in the MSH2 gene. Therefore, germ-line genetic testing should initially target the MSH2 gene. Approximately 88% of Lynch syndrome-associated colorectal cancers have abnormal immunohistochemical staining.¹⁰

Testing for microsatellite instability and mismatch repair gene expression ideally precedes germline genetic testing and helps to guide which gene or genes should be tested.^9,14

Genetic testing for Lynch syndrome is routinely performed on a blood or saliva sample, using DNA from white blood cells and sequencing the gene or genes involved to look for mutations. Positive results from a germline genetic test confirm the diagnosis of Lynch syndrome and allow for predictive testing for relatives at risk. The term Lynch syndrome is used exclusively to describe individuals with evidence of a mutation in one of the mismatch repair genes.¹⁵

If a patient’s results are positive, genetic counseling and genetic testing should be offered to at-risk relatives age 18 and over.

Management of Lynch syndrome

Aggressive cancer surveillance is essential for people with Lynch syndrome and for those who are considered at risk but have not pursued genetic testing, such as a sibling of a person with Lynch syndrome.

Colorectal cancer. Colonoscopy is recommended every 1 to 2 years beginning at the age of 20 to 25 years, or 2 to 5 years earlier than the age of the youngest relative affected with colorectal cancer if the initial diagnosis was before age 25. When patients turn 40 years old, colonoscopy is done annually.^16–18 A significant reduction in cancer incidence and in the mortality rate has been shown with colonoscopic surveillance.^19–21

Chemoprevention may also have a role. Patients with Lynch syndrome who took aspirin 600 mg per day for an average of 25 months had a significantly lower incidence of colorectal cancer during a 55-month follow-up period compared with patients randomized to placebo.²²

For patients with Lynch syndrome who are diagnosed with colorectal cancer, the high risk of metachronous cancers after standard segmental colectomy calls for a more extended resection. Retrospective analysis of 382 Lynch syndrome patients found that none of the 50 who underwent total or subtotal colectomy were diagnosed with metachronous colorectal cancer, whereas a metachronous cancer developed in 74 (22%) of the 332 patients who had had segmented resection.² Annual surveillance of the remaining colon, rectum, or both is indicated postoperatively.

Gynecologic cancers. Women with Lynch syndrome should also consider gynecologic surveillance and risk-reducing surgery. This includes annual gynecologic examination, transvaginal ultrasonography, and endometrial aspiration, beginning at age 30 to 35 years. Although this surveillance does detect premalignant lesions and early symptomatic cancers, its effect on the mortality rate is unknown. Hysterectomy with bilateral salpingo-oophorectomy has been shown to significantly reduce endometrial and ovarian cancers in women with Lynch syndrome.^23,24

Urothelial cancers. Carriers of MSH2 mutations have a significantly higher risk of urothelial cancers.⁴ Therefore, MSH2 carriers should consider ultrasonography of the urinary tract, urinary cytology, and urinalysis every 1 to 2 years beginning at age 40.⁴

Other extracolonic cancers. Poor evidence exists for systematic screening for the other extracolonic tumors associated with Lynch syndrome. However, the National Comprehensive Cancer Network advises considering esophagogastroduodenoscopy with extended duodenoscopy as well as capsule endoscopy every 2 to 3 years beginning at age 30 to 35.¹⁴

ADENOMATOUS POLYPOSIS SYNDROMES

Familial adenomatous polyposis and MYH-associated polyposis are the next most common hereditary colorectal cancer syndromes. Each of these accounts for about 1% of cases of colorectal cancer. Clinically, these two syndromes can be challenging to distinguish because they overlap phenotypically to a significant degree.

FAMILIAL ADENOMATOUS POLYPOSIS

Familial adenomatous polyposis is caused by mutations in the APC gene. Its prevalence is 2.29 to 3.2 per 100,000 individuals.^25,26

Genetics of familial adenomatous polyposis

APC is the only gene known to cause familial adenomatous polyposis. Mutations in APC are inherited in an autosomal dominant manner. Approximately 25% of cases of familial adenomatous polyposis are due to a de novo mutation in APC.²⁷

Clinical presentation of familial adenomatous polyposis

Familial adenomatous polyposis is classified by the burden of colorectal adenomas.

Patients who have fewer than 100 adenomas have an attenuated form of the disease. In this group, polyps usually begin to form in the late teenage years or early 20s and tend to develop in the proximal colon. The attenuated form is associated with an approximately 70% lifetime risk of colorectal cancer.²⁸

Patients who have more than 100 polyps are considered to have the classic form of the disease, and those with more than 1,000 polyps have profuse familial adenomatous polyposis (Figure 2). In these groups, polyps typically begin to develop in the preteenage to mid-teenage years. Without surgery, there is nearly a 100% risk of colorectal cancer. The average age at diagnosis of colorectal cancer is 39 years for patients with classic disease.

Upper gastrointestinal polyps are common in familial adenomatous polyposis. Nearly 90% of patients develop duodenal adenomas by a mean age of 44, with a cumulative lifetime risk of nearly 100%.²⁹ Fundic gland polyposis occurs in nearly 90% of patients,³⁰ while gastric adenomas are reported in fewer than 15% of patients.

Duodenal and periampullary cancer is the second most common malignancy in familial adenomatous polyposis. The lifetime risk ranges from 2% to 36%, depending on the Spigelman stage. People with Spigelman stage I, II, or III have a 2.5% risk of duodenal cancer, while those with stage IV disease have up to a 36% lifetime risk.

Gastric cancer, arising from fundic gland polyps, has been reported but is rare in Western populations.

In familial adenomatous polyposis, the incidence of jejunal adenomas and cancer is less than 10%, and the risk of ileal adenomas and cancer is less than 1%.³¹

Familial adenomatous polyposis is also associated with a higher risk of other malignancies, including:

• Pancreatic cancer (2% lifetime risk)
• Thyroid cancer (2% to 3% lifetime risk, typically papillary carcinoma)³²
• Hepatoblastoma (1% to 2% lifetime risk)
• Brain tumors (< 1% lifetime risk)
• Biliary cancer (higher risk than in the general population).³³

Benign extracolonic manifestations that have been observed include osteomas, dental abnormalities (supernumerary teeth, unerupted or absent teeth, odontomas), congenital hypertrophy of the retinal pigment epithelium, benign cutaneous lesions (epidermoid cysts and fibromas), and desmoid tumors.³³ The term “Gardner syndrome” has been used to describe patients who have familial adenomatous polyposis but also have osteomas and soft-tissue tumors.³⁴ These patients carry the same risk of colorectal cancer as other patients with familial adenomatous polyposis.

Diagnosing familial adenomatous polyposis

The diagnosis of familial adenomatous polyposis is suspected when a patient has more than 10 adenomatous polyps.

Seventy-five percent of patients with familial adenomatous polyposis have a family history of the condition. Therefore, most cases are identified at a young age on screening sigmoidoscopy or colonoscopy or by predictive gene testing. Patients rarely have cancer at the time of diagnosis.

The other 25% of patients typically are diagnosed when symptoms develop from the polyps or cancer. Over 50% of these symptomatic patients have cancer at the time of diagnosis.

It is recommended that people who have more than 10 adenomas detected on a single colonoscopy or who are first-degree relatives of patients with familial adenomatous polyposis undergo a genetic evaluation and testing for mutations in the APC gene.¹⁴ Once an APC mutation is identified in the family, at-risk relatives should be offered testing around age 10 years for families with classic familial adenomatous polyposis or in the mid to late teenage years for those with the attenuated form. It also appropriate to refer patients with desmoid tumors, duodenal adenomas, and bilateral or multifocal congenital hypertrophy of the retinal pigment epithelium for a genetic evaluation.

Management of familial adenomatous polyposis

Flexible sigmoidoscopy every 1 to 2 years beginning at age 10 to 12 years is recommended for individuals and families who have been phenotypically or genetically diagnosed with familial adenomatous polyposis.^35–37 If colorectal adenomas are found, surgical options should be discussed and annual colonoscopic surveillance should commence.

For people with the attenuated form, because of the later age of disease onset and the tendency for right-sided disease, colonoscopy every 1 to 2 years should commence at about age 18.^35–37 If polyps are found, colonoscopy should be performed every year.

The decision of when to offer colectomy is based on polyp burden (taking into account the number, pathologic appearance, and size of the polyps) and psychosocial factors such as patient maturity. Surgical options include total colectomy and ileorectal anastomosis or total proctocolectomy and ileal pouch anal anastomosis.³⁸ Colonic and extracolonic phenotype as well as genotype should factor into the type of operation recommended. After colectomy, annual endoscopic surveillance of the rectum or ileal pouch is indicated to screen for recurrent polyposis and cancer.

Chemoprevention with sulindac (Clinoril) 150 mg or celecoxib (Celebrex) 400 mg twice a day causes regression of colorectal adenomas in familial adenomatous polyposis and may be useful as an adjunct to endoscopy in managing the colorectal polyp burden.^39,40

Forward and side-viewing upper endoscopy should commence at age 20. This should include visualization and biopsy of the papilla and periampulllary region.²⁹ The frequency of endoscopic surveillance depends on the Spigelman stage, which reflects the duodenal polyp burden. It is recommended that patients with Spigelman stage IV duodenal polyposis be seen in consultation with an experienced gastrointestinal surgeon for consideration of a prophylactic, pylorus-preserving, pancreas-sparing duodenectomy. This procedure has been shown to be more effective in polyp control and cancer prevention than endoscopic polyp ablation and local surgical resection.⁴¹

Some evidence for the utility of celecoxib 400 mg twice daily for the regression of duodenal polyposis was noted in a 6-month placebo-controlled trial.⁴² Some experts recommend removal of large duodenal adenomas, with adjunctive celecoxib therapy to control polyposis burden.³⁰

People with familial adenomatous polyposis have been shown to have a 2.6% risk of thyroid cancer, and ultrasonography of the neck with attention to the thyroid is recommended for them.³²

MYH-ASSOCIATED POLYPOSIS

Biallelic mutations in the MYH gene result in an adenomatous polyposis syndrome that may be indistinguishable from the attenuated or classic forms of familial adenomatous polyposis. A characteristic autosomal recessive pattern of inheritance in the family can be useful for identifying these patients in the clinic.

Genetics of MYH-associated polyposis

MYH-associated polyposis is the only known autosomal recessive hereditary colorectal cancer syndrome. In white populations, the most commonly reported mutations in MYH are Y179C (previously called Y165C) and G396D (previously called G382D), which account for up to 80% of cases.⁴³ These two mutations are estimated to occur in 1% to 2% of the general population.⁴⁴

Clinical presentation of MYH-associated polyposis

MYH-associated polyposis typically presents as multiple adenomatous polyps and is diagnosed at a mean age of 47 years. Eleven percent to 42% of affected individuals are reported to have fewer than 100 adenomas, while a minority (7.5% to 29%) of patients present with classic polyposis.^45–47 In one study, an estimated 19% of patients presented with colorectal cancer and reported no history of colorectal polyps.⁴⁸ Synchronous colorectal cancer is seen in more than 60% of patients with biallelic MYH mutations.⁴⁹ Patients with monoallelic (heterozygous) MYH mutations appear to have the same risk of developing colorectal adenomas and cancer as the general population.⁴⁹

Upper-gastrointestinal polyps have been reported in MYH-associated polyposis; as many as 17% to 25% of patients have duodenal adenomas.^50,51

Diagnosis of MYH-associated polyposis

Genetic testing for biallelic MYH mutations should be performed in patients who test negative for an APC mutation but who have clinical features of familial adenomatous polyposis, a personal history of more than 10 colorectal adenomas, or a recessive family history of polyposis. ¹⁴ It has been shown that up to 29% of patients with familial adenomatous polyposis who are APC-negative will have biallelic mutations in the MYH gene.⁵² The siblings of a patient with biallelic MYH mutations should be offered genetic counseling and testing in their late teens or early 20s. All children of an individual with MYH-associated polyposis will carry one MYH mutation and are only at risk of having the syndrome if the other parent is also a MYH carrier and passed on his or her mutation.

Management of MYH-associated polyposis

The management of patients with MYH-associated polyposis is similar to that recommended for attenuated and classic familial adenomatous polyposis.¹⁴ Genetic counseling and testing and colonic and extracolonic surveillance are warranted. There are no data on the use of chemoprevention in MYH-associated polyposis. Surgery should be considered early because of the high risk of colorectal cancer, even in individuals with very few adenomas. Patients with monoallelic MYH mutations should follow the general population screening guidelines for colorectal cancer.⁴⁹

GENETIC COUNSELING AND GENETIC TESTING

The American College of Gastroenterology advises that patients suspected of having hereditary colorectal cancer syndromes be advised to pursue genetic counseling and, if appropriate, genetic testing.¹⁶ They further recommend genetic counseling and informed consent before genetic testing.¹⁶

Genetic counseling is a process of working with patients and families whereby:

• A detailed medical and family history is obtained
• A formal risk assessment is performed
• Education about the disease in question and about genetic testing is provided
• Psychosocial concerns are assessed
• Informed consent is obtained when genetic testing is recommended.⁵³

This process is important for helping patients better understand their cancer risks, the benefits and limitations of genetic testing, and the protections that are in place for people who undergo genetic testing, including the Genetic Information Non-Discrimination Act.

In 1996 the American Society of Clinical Oncology issued a policy statement highlighting the essential elements of informed consent for genetic testing for cancer susceptibility, and this was updated in 2003.⁵⁴ In particular, it notes that patients should be informed of the implications of positive and negative results and of the possibility that the test may be uninformative.

When a hereditary colorectal cancer syndrome is suspected, a positive genetic test result confirms the diagnosis and allows for predictive testing of the patient’s relatives. However, no genetic test for a hereditary colorectal cancer syndrome is 100% sensitive. Therefore, a negative result does not rule out the syndrome in question.

Further, all cancer susceptibility genes have variants of uncertain significance, which are genetic alterations for which there are insufficient data to determine if the mutation is disease-causing or polymorphic (benign). Both negative and uninformative results can be confusing for patients and providers and can lead to false reassurance or undue worry when patients are not properly educated about these potential outcomes of testing.

Genetic testing is an evolving field, and with additional research and improved testing technologies, appropriate diagnoses can be made over time. That is why it is important for the genetic counseling relationship to continue over time.

Hereditary colorectal cancer syndromes account for 5% to 10% of cases of colorectal cancer.

Identifying these patients in clinical practice begins by assessing a patient’s personal and family health history. An accurate and comprehensive family history should cover three generations and include ethnic background, ages and causes of death of relatives, and any diagnosis of cancer, including age at onset and history of polyps.

Red flags for a hereditary colorectal cancer syndrome in the personal or family history are:

• Early age of onset of cancer (eg, colorectal cancer before age 50)
• More than 10 colorectal adenomas
• Synchronous (ie, occurring at the same time) or metachronous (occurring at different times) primary cancers
• Multiple relatives in successive generations with the same or related cancers (eg, colon or endometrial cancer)
• A family member with a known hereditary colorectal cancer syndrome (Table 1).

Any of these red flags should prompt a referral for genetic counseling.

SYNDROMES ARE CLASSIFIED AS WITH OR WITHOUT POLYPOSIS

Many hereditary syndromes are associated with a higher risk of colorectal cancer. Generally, they can be divided into two categories (Table 2): polyposis syndromes (in which patients have numerous colorectal polyps) and nonpolyposis syndromes (with few or no polyps).

These two main types are subclassified on the basis of the histology of most of the polyps detected: adenomatous, hamartomatous, serrated, or mixed types.

In this review, we will address the three most common of these syndromes: Lynch syndrome (hereditary nonpolyposis colorectal cancer), familial adenomatous polyposis, and MYH-associated polyposis. However, as noted in Table 2, other hereditary colorectal cancer syndromes exist, and suspicion of these conditions should prompt a referral for further evaluation.

LYNCH SYNDROME (HEREDITARY NONPOLYPOSIS COLORECTAL CANCER)

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, predisposes people to a variety of cancers.

Colorectal cancer is the most common type of cancer associated with Lynch syndrome. Recent research suggests that the cumulative risk of developing colorectal cancer by age 80 is 42% for all patients with Lynch syndrome.¹ The median age at onset is 45 years.¹ For patients who undergo segmental resection of their initial cancer, the cumulative risk of metachronous colorectal cancer (ie, a new tumor arising later) is 16% at 10 years, 41% at 20 years, and up to 62% after 30 years.²

Endometrial cancer occurs in 17% to 57% of women with Lynch syndrome by age 70, with a median age at onset of 49 years.¹

Other extracolonic cancers in Lynch syndrome include cancers of the:

• Stomach (1%–10% risk by age 70 years)
• Ovaries (1%–20% risk)
• Hepatobiliary tract (1%–2% risk)
• Urinary tract (1%–12% risk)
• Small bowel (1%–2% risk)
• Brain (1%–8% risk)
• Skin (sebaceous adenomas, adenocarcinomas, and keratoacanthomas).^1,3,4

Earlier studies reported higher rates of associated cancer than those shown here. However, their data were largely derived from registries and may be overestimates. The numbers shown above are from population-based studies.

Genetics of Lynch syndrome

Lynch syndrome is caused by a germline mutation in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes.⁵ These genes code for proteins that are responsible DNA mismatch repair—one of the cell’s proofreading mechanisms during DNA replication.

These mutations are inherited in an autosomal dominant manner. Though de novo mutations in these genes have been reported, they are rare and the exact frequency with which they occur is unknown.⁶

In whom should Lynch syndrome be suspected?

Lynch syndrome can be suspected on the basis of family history and clinical criteria.

In 1991, the same group of experts who coined the term “hereditary nonpolyposis colorectal cancer” developed family history criteria for it¹:

• At least three relatives with histologically confirmed colorectal cancer, one of whom is a first-degree relative of the other two
• At least two successive generations involved
• At least one of the cancers diagnosed before age 50
• Familial adenomatous polyposis is excluded.

Known as the Amsterdam criteria, these were to be used in collaborative studies of families with hereditary colorectal cancer.⁷ In 1999, these criteria were broadened to include extracolonic cancers and became known as the Amsterdam II criteria (Table 3).⁸

Patients whose families meet the Amsterdam II criteria or who have molecular pathologic evidence of Lynch syndrome (see below) are appropriate candidates for genetic counseling and testing.

The diagnosis of Lynch syndrome is based on molecular pathologic analysis (performed on tumor samples) and confirmed by genetic testing.

Molecular pathologic evidence of Lynch syndrome includes microsatellite instability and loss of expression of one or more of the DNA mismatch repair proteins (detected using immunohistochemistry) (more on these below). The revised Bethesda guidelines (TABLE 3) were intended to identify individuals whose tumors should be tested for one or both of these phenomena.⁹

In 2009, the Evaluation of Genomic Applications in Practice and Prevention working group recommended that all patients with newly diagnosed colorectal cancer undergo microsatellite instability analysis, immunohistochemistry testing, or both, regardless of whether they meet the Amsterdam II or the Bethesda guideline criteria.¹⁰

Microsatellite instability analysis. Microsatellites are short sequences of repeated DNA. The tumor cells of patients who carry defective mismatch repair genes have microsatellites that are longer or shorter than in normal cells, a condition called microsatellite instability (ie, “MSI-high”).

Microsatellite instability testing, using a standardized panel of five DNA markers, is performed on normal and tumor tissue. If more than two of the five microsatellite markers in the tumor show instability, the lesion is considered to have a high level of microsatellite instability. About 15% of colorectal cancers have this high level, although most are not associated with Lynch syndrome and lose MLH1 expression by promoter methylation.^11,12

While only 2% of patients with colorectal cancer have Lynch syndrome, from 90% to 95% of colorectal cancers from patients with Lynch syndrome have high levels of microsatellite instability.¹⁰ The presence of MLH1 promoter hypermethylation, the BRAF mutation V600E, or both within the tumor suggests that the cancer is not associated with Lynch syndrome.

Some families that meet the Amsterdam I criteria have microsatellite-stable tumors: their condition has been called familial colorectal cancer type X.¹³ This condition is associated with a higher risk of colorectal cancer but not the other malignancies observed in Lynch syndrome.

Immunohistochemistry is performed to assess for expression of the mismatch repair proteins MSH2, MSH6, MLH1, and PMS2. Absence of expression of the specific protein within tumor cells compared with normal cells within the specimen suggests dysfunction of the specific gene and guides germline mutation testing (Figure 1). For example, a patient who lacks expression of the MSH2 protein in his or her colon cancer most likely has a mutation in the MSH2 gene. Therefore, germ-line genetic testing should initially target the MSH2 gene. Approximately 88% of Lynch syndrome-associated colorectal cancers have abnormal immunohistochemical staining.¹⁰

Testing for microsatellite instability and mismatch repair gene expression ideally precedes germline genetic testing and helps to guide which gene or genes should be tested.^9,14

Genetic testing for Lynch syndrome is routinely performed on a blood or saliva sample, using DNA from white blood cells and sequencing the gene or genes involved to look for mutations. Positive results from a germline genetic test confirm the diagnosis of Lynch syndrome and allow for predictive testing for relatives at risk. The term Lynch syndrome is used exclusively to describe individuals with evidence of a mutation in one of the mismatch repair genes.¹⁵

If a patient’s results are positive, genetic counseling and genetic testing should be offered to at-risk relatives age 18 and over.

Management of Lynch syndrome

Aggressive cancer surveillance is essential for people with Lynch syndrome and for those who are considered at risk but have not pursued genetic testing, such as a sibling of a person with Lynch syndrome.

Colorectal cancer. Colonoscopy is recommended every 1 to 2 years beginning at the age of 20 to 25 years, or 2 to 5 years earlier than the age of the youngest relative affected with colorectal cancer if the initial diagnosis was before age 25. When patients turn 40 years old, colonoscopy is done annually.^16–18 A significant reduction in cancer incidence and in the mortality rate has been shown with colonoscopic surveillance.^19–21

Chemoprevention may also have a role. Patients with Lynch syndrome who took aspirin 600 mg per day for an average of 25 months had a significantly lower incidence of colorectal cancer during a 55-month follow-up period compared with patients randomized to placebo.²²

For patients with Lynch syndrome who are diagnosed with colorectal cancer, the high risk of metachronous cancers after standard segmental colectomy calls for a more extended resection. Retrospective analysis of 382 Lynch syndrome patients found that none of the 50 who underwent total or subtotal colectomy were diagnosed with metachronous colorectal cancer, whereas a metachronous cancer developed in 74 (22%) of the 332 patients who had had segmented resection.² Annual surveillance of the remaining colon, rectum, or both is indicated postoperatively.

Gynecologic cancers. Women with Lynch syndrome should also consider gynecologic surveillance and risk-reducing surgery. This includes annual gynecologic examination, transvaginal ultrasonography, and endometrial aspiration, beginning at age 30 to 35 years. Although this surveillance does detect premalignant lesions and early symptomatic cancers, its effect on the mortality rate is unknown. Hysterectomy with bilateral salpingo-oophorectomy has been shown to significantly reduce endometrial and ovarian cancers in women with Lynch syndrome.^23,24

Urothelial cancers. Carriers of MSH2 mutations have a significantly higher risk of urothelial cancers.⁴ Therefore, MSH2 carriers should consider ultrasonography of the urinary tract, urinary cytology, and urinalysis every 1 to 2 years beginning at age 40.⁴

Other extracolonic cancers. Poor evidence exists for systematic screening for the other extracolonic tumors associated with Lynch syndrome. However, the National Comprehensive Cancer Network advises considering esophagogastroduodenoscopy with extended duodenoscopy as well as capsule endoscopy every 2 to 3 years beginning at age 30 to 35.¹⁴

ADENOMATOUS POLYPOSIS SYNDROMES

Familial adenomatous polyposis and MYH-associated polyposis are the next most common hereditary colorectal cancer syndromes. Each of these accounts for about 1% of cases of colorectal cancer. Clinically, these two syndromes can be challenging to distinguish because they overlap phenotypically to a significant degree.

FAMILIAL ADENOMATOUS POLYPOSIS

Familial adenomatous polyposis is caused by mutations in the APC gene. Its prevalence is 2.29 to 3.2 per 100,000 individuals.^25,26

Genetics of familial adenomatous polyposis

APC is the only gene known to cause familial adenomatous polyposis. Mutations in APC are inherited in an autosomal dominant manner. Approximately 25% of cases of familial adenomatous polyposis are due to a de novo mutation in APC.²⁷

Clinical presentation of familial adenomatous polyposis

Familial adenomatous polyposis is classified by the burden of colorectal adenomas.

Patients who have fewer than 100 adenomas have an attenuated form of the disease. In this group, polyps usually begin to form in the late teenage years or early 20s and tend to develop in the proximal colon. The attenuated form is associated with an approximately 70% lifetime risk of colorectal cancer.²⁸

Patients who have more than 100 polyps are considered to have the classic form of the disease, and those with more than 1,000 polyps have profuse familial adenomatous polyposis (Figure 2). In these groups, polyps typically begin to develop in the preteenage to mid-teenage years. Without surgery, there is nearly a 100% risk of colorectal cancer. The average age at diagnosis of colorectal cancer is 39 years for patients with classic disease.

Upper gastrointestinal polyps are common in familial adenomatous polyposis. Nearly 90% of patients develop duodenal adenomas by a mean age of 44, with a cumulative lifetime risk of nearly 100%.²⁹ Fundic gland polyposis occurs in nearly 90% of patients,³⁰ while gastric adenomas are reported in fewer than 15% of patients.

Duodenal and periampullary cancer is the second most common malignancy in familial adenomatous polyposis. The lifetime risk ranges from 2% to 36%, depending on the Spigelman stage. People with Spigelman stage I, II, or III have a 2.5% risk of duodenal cancer, while those with stage IV disease have up to a 36% lifetime risk.

Gastric cancer, arising from fundic gland polyps, has been reported but is rare in Western populations.

In familial adenomatous polyposis, the incidence of jejunal adenomas and cancer is less than 10%, and the risk of ileal adenomas and cancer is less than 1%.³¹

Familial adenomatous polyposis is also associated with a higher risk of other malignancies, including:

• Pancreatic cancer (2% lifetime risk)
• Thyroid cancer (2% to 3% lifetime risk, typically papillary carcinoma)³²
• Hepatoblastoma (1% to 2% lifetime risk)
• Brain tumors (< 1% lifetime risk)
• Biliary cancer (higher risk than in the general population).³³

Benign extracolonic manifestations that have been observed include osteomas, dental abnormalities (supernumerary teeth, unerupted or absent teeth, odontomas), congenital hypertrophy of the retinal pigment epithelium, benign cutaneous lesions (epidermoid cysts and fibromas), and desmoid tumors.³³ The term “Gardner syndrome” has been used to describe patients who have familial adenomatous polyposis but also have osteomas and soft-tissue tumors.³⁴ These patients carry the same risk of colorectal cancer as other patients with familial adenomatous polyposis.

Diagnosing familial adenomatous polyposis

The diagnosis of familial adenomatous polyposis is suspected when a patient has more than 10 adenomatous polyps.

Seventy-five percent of patients with familial adenomatous polyposis have a family history of the condition. Therefore, most cases are identified at a young age on screening sigmoidoscopy or colonoscopy or by predictive gene testing. Patients rarely have cancer at the time of diagnosis.

The other 25% of patients typically are diagnosed when symptoms develop from the polyps or cancer. Over 50% of these symptomatic patients have cancer at the time of diagnosis.

It is recommended that people who have more than 10 adenomas detected on a single colonoscopy or who are first-degree relatives of patients with familial adenomatous polyposis undergo a genetic evaluation and testing for mutations in the APC gene.¹⁴ Once an APC mutation is identified in the family, at-risk relatives should be offered testing around age 10 years for families with classic familial adenomatous polyposis or in the mid to late teenage years for those with the attenuated form. It also appropriate to refer patients with desmoid tumors, duodenal adenomas, and bilateral or multifocal congenital hypertrophy of the retinal pigment epithelium for a genetic evaluation.

Management of familial adenomatous polyposis

Flexible sigmoidoscopy every 1 to 2 years beginning at age 10 to 12 years is recommended for individuals and families who have been phenotypically or genetically diagnosed with familial adenomatous polyposis.^35–37 If colorectal adenomas are found, surgical options should be discussed and annual colonoscopic surveillance should commence.

For people with the attenuated form, because of the later age of disease onset and the tendency for right-sided disease, colonoscopy every 1 to 2 years should commence at about age 18.^35–37 If polyps are found, colonoscopy should be performed every year.

The decision of when to offer colectomy is based on polyp burden (taking into account the number, pathologic appearance, and size of the polyps) and psychosocial factors such as patient maturity. Surgical options include total colectomy and ileorectal anastomosis or total proctocolectomy and ileal pouch anal anastomosis.³⁸ Colonic and extracolonic phenotype as well as genotype should factor into the type of operation recommended. After colectomy, annual endoscopic surveillance of the rectum or ileal pouch is indicated to screen for recurrent polyposis and cancer.

Chemoprevention with sulindac (Clinoril) 150 mg or celecoxib (Celebrex) 400 mg twice a day causes regression of colorectal adenomas in familial adenomatous polyposis and may be useful as an adjunct to endoscopy in managing the colorectal polyp burden.^39,40

Forward and side-viewing upper endoscopy should commence at age 20. This should include visualization and biopsy of the papilla and periampulllary region.²⁹ The frequency of endoscopic surveillance depends on the Spigelman stage, which reflects the duodenal polyp burden. It is recommended that patients with Spigelman stage IV duodenal polyposis be seen in consultation with an experienced gastrointestinal surgeon for consideration of a prophylactic, pylorus-preserving, pancreas-sparing duodenectomy. This procedure has been shown to be more effective in polyp control and cancer prevention than endoscopic polyp ablation and local surgical resection.⁴¹

Some evidence for the utility of celecoxib 400 mg twice daily for the regression of duodenal polyposis was noted in a 6-month placebo-controlled trial.⁴² Some experts recommend removal of large duodenal adenomas, with adjunctive celecoxib therapy to control polyposis burden.³⁰

People with familial adenomatous polyposis have been shown to have a 2.6% risk of thyroid cancer, and ultrasonography of the neck with attention to the thyroid is recommended for them.³²

MYH-ASSOCIATED POLYPOSIS

Biallelic mutations in the MYH gene result in an adenomatous polyposis syndrome that may be indistinguishable from the attenuated or classic forms of familial adenomatous polyposis. A characteristic autosomal recessive pattern of inheritance in the family can be useful for identifying these patients in the clinic.

Genetics of MYH-associated polyposis

MYH-associated polyposis is the only known autosomal recessive hereditary colorectal cancer syndrome. In white populations, the most commonly reported mutations in MYH are Y179C (previously called Y165C) and G396D (previously called G382D), which account for up to 80% of cases.⁴³ These two mutations are estimated to occur in 1% to 2% of the general population.⁴⁴

Clinical presentation of MYH-associated polyposis

MYH-associated polyposis typically presents as multiple adenomatous polyps and is diagnosed at a mean age of 47 years. Eleven percent to 42% of affected individuals are reported to have fewer than 100 adenomas, while a minority (7.5% to 29%) of patients present with classic polyposis.^45–47 In one study, an estimated 19% of patients presented with colorectal cancer and reported no history of colorectal polyps.⁴⁸ Synchronous colorectal cancer is seen in more than 60% of patients with biallelic MYH mutations.⁴⁹ Patients with monoallelic (heterozygous) MYH mutations appear to have the same risk of developing colorectal adenomas and cancer as the general population.⁴⁹

Upper-gastrointestinal polyps have been reported in MYH-associated polyposis; as many as 17% to 25% of patients have duodenal adenomas.^50,51

Diagnosis of MYH-associated polyposis

Genetic testing for biallelic MYH mutations should be performed in patients who test negative for an APC mutation but who have clinical features of familial adenomatous polyposis, a personal history of more than 10 colorectal adenomas, or a recessive family history of polyposis. ¹⁴ It has been shown that up to 29% of patients with familial adenomatous polyposis who are APC-negative will have biallelic mutations in the MYH gene.⁵² The siblings of a patient with biallelic MYH mutations should be offered genetic counseling and testing in their late teens or early 20s. All children of an individual with MYH-associated polyposis will carry one MYH mutation and are only at risk of having the syndrome if the other parent is also a MYH carrier and passed on his or her mutation.

Management of MYH-associated polyposis

The management of patients with MYH-associated polyposis is similar to that recommended for attenuated and classic familial adenomatous polyposis.¹⁴ Genetic counseling and testing and colonic and extracolonic surveillance are warranted. There are no data on the use of chemoprevention in MYH-associated polyposis. Surgery should be considered early because of the high risk of colorectal cancer, even in individuals with very few adenomas. Patients with monoallelic MYH mutations should follow the general population screening guidelines for colorectal cancer.⁴⁹

GENETIC COUNSELING AND GENETIC TESTING

The American College of Gastroenterology advises that patients suspected of having hereditary colorectal cancer syndromes be advised to pursue genetic counseling and, if appropriate, genetic testing.¹⁶ They further recommend genetic counseling and informed consent before genetic testing.¹⁶

Genetic counseling is a process of working with patients and families whereby:

• A detailed medical and family history is obtained
• A formal risk assessment is performed
• Education about the disease in question and about genetic testing is provided
• Psychosocial concerns are assessed
• Informed consent is obtained when genetic testing is recommended.⁵³

This process is important for helping patients better understand their cancer risks, the benefits and limitations of genetic testing, and the protections that are in place for people who undergo genetic testing, including the Genetic Information Non-Discrimination Act.

In 1996 the American Society of Clinical Oncology issued a policy statement highlighting the essential elements of informed consent for genetic testing for cancer susceptibility, and this was updated in 2003.⁵⁴ In particular, it notes that patients should be informed of the implications of positive and negative results and of the possibility that the test may be uninformative.

When a hereditary colorectal cancer syndrome is suspected, a positive genetic test result confirms the diagnosis and allows for predictive testing of the patient’s relatives. However, no genetic test for a hereditary colorectal cancer syndrome is 100% sensitive. Therefore, a negative result does not rule out the syndrome in question.

Further, all cancer susceptibility genes have variants of uncertain significance, which are genetic alterations for which there are insufficient data to determine if the mutation is disease-causing or polymorphic (benign). Both negative and uninformative results can be confusing for patients and providers and can lead to false reassurance or undue worry when patients are not properly educated about these potential outcomes of testing.

Genetic testing is an evolving field, and with additional research and improved testing technologies, appropriate diagnoses can be made over time. That is why it is important for the genetic counseling relationship to continue over time.

Hereditary colorectal cancer syndromes account for 5% to 10% of cases of colorectal cancer.

Identifying these patients in clinical practice begins by assessing a patient’s personal and family health history. An accurate and comprehensive family history should cover three generations and include ethnic background, ages and causes of death of relatives, and any diagnosis of cancer, including age at onset and history of polyps.

Red flags for a hereditary colorectal cancer syndrome in the personal or family history are:

• Early age of onset of cancer (eg, colorectal cancer before age 50)
• More than 10 colorectal adenomas
• Synchronous (ie, occurring at the same time) or metachronous (occurring at different times) primary cancers
• Multiple relatives in successive generations with the same or related cancers (eg, colon or endometrial cancer)
• A family member with a known hereditary colorectal cancer syndrome (Table 1).

Any of these red flags should prompt a referral for genetic counseling.

SYNDROMES ARE CLASSIFIED AS WITH OR WITHOUT POLYPOSIS

Many hereditary syndromes are associated with a higher risk of colorectal cancer. Generally, they can be divided into two categories (Table 2): polyposis syndromes (in which patients have numerous colorectal polyps) and nonpolyposis syndromes (with few or no polyps).

These two main types are subclassified on the basis of the histology of most of the polyps detected: adenomatous, hamartomatous, serrated, or mixed types.

In this review, we will address the three most common of these syndromes: Lynch syndrome (hereditary nonpolyposis colorectal cancer), familial adenomatous polyposis, and MYH-associated polyposis. However, as noted in Table 2, other hereditary colorectal cancer syndromes exist, and suspicion of these conditions should prompt a referral for further evaluation.

LYNCH SYNDROME (HEREDITARY NONPOLYPOSIS COLORECTAL CANCER)

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, predisposes people to a variety of cancers.

Colorectal cancer is the most common type of cancer associated with Lynch syndrome. Recent research suggests that the cumulative risk of developing colorectal cancer by age 80 is 42% for all patients with Lynch syndrome.¹ The median age at onset is 45 years.¹ For patients who undergo segmental resection of their initial cancer, the cumulative risk of metachronous colorectal cancer (ie, a new tumor arising later) is 16% at 10 years, 41% at 20 years, and up to 62% after 30 years.²

Endometrial cancer occurs in 17% to 57% of women with Lynch syndrome by age 70, with a median age at onset of 49 years.¹

Other extracolonic cancers in Lynch syndrome include cancers of the:

• Stomach (1%–10% risk by age 70 years)
• Ovaries (1%–20% risk)
• Hepatobiliary tract (1%–2% risk)
• Urinary tract (1%–12% risk)
• Small bowel (1%–2% risk)
• Brain (1%–8% risk)
• Skin (sebaceous adenomas, adenocarcinomas, and keratoacanthomas).^1,3,4

Earlier studies reported higher rates of associated cancer than those shown here. However, their data were largely derived from registries and may be overestimates. The numbers shown above are from population-based studies.

Genetics of Lynch syndrome

Lynch syndrome is caused by a germline mutation in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes.⁵ These genes code for proteins that are responsible DNA mismatch repair—one of the cell’s proofreading mechanisms during DNA replication.

These mutations are inherited in an autosomal dominant manner. Though de novo mutations in these genes have been reported, they are rare and the exact frequency with which they occur is unknown.⁶

In whom should Lynch syndrome be suspected?

Lynch syndrome can be suspected on the basis of family history and clinical criteria.

In 1991, the same group of experts who coined the term “hereditary nonpolyposis colorectal cancer” developed family history criteria for it¹:

• At least three relatives with histologically confirmed colorectal cancer, one of whom is a first-degree relative of the other two
• At least two successive generations involved
• At least one of the cancers diagnosed before age 50
• Familial adenomatous polyposis is excluded.

Known as the Amsterdam criteria, these were to be used in collaborative studies of families with hereditary colorectal cancer.⁷ In 1999, these criteria were broadened to include extracolonic cancers and became known as the Amsterdam II criteria (Table 3).⁸

Patients whose families meet the Amsterdam II criteria or who have molecular pathologic evidence of Lynch syndrome (see below) are appropriate candidates for genetic counseling and testing.

The diagnosis of Lynch syndrome is based on molecular pathologic analysis (performed on tumor samples) and confirmed by genetic testing.

Molecular pathologic evidence of Lynch syndrome includes microsatellite instability and loss of expression of one or more of the DNA mismatch repair proteins (detected using immunohistochemistry) (more on these below). The revised Bethesda guidelines (TABLE 3) were intended to identify individuals whose tumors should be tested for one or both of these phenomena.⁹

In 2009, the Evaluation of Genomic Applications in Practice and Prevention working group recommended that all patients with newly diagnosed colorectal cancer undergo microsatellite instability analysis, immunohistochemistry testing, or both, regardless of whether they meet the Amsterdam II or the Bethesda guideline criteria.¹⁰

Microsatellite instability analysis. Microsatellites are short sequences of repeated DNA. The tumor cells of patients who carry defective mismatch repair genes have microsatellites that are longer or shorter than in normal cells, a condition called microsatellite instability (ie, “MSI-high”).

Microsatellite instability testing, using a standardized panel of five DNA markers, is performed on normal and tumor tissue. If more than two of the five microsatellite markers in the tumor show instability, the lesion is considered to have a high level of microsatellite instability. About 15% of colorectal cancers have this high level, although most are not associated with Lynch syndrome and lose MLH1 expression by promoter methylation.^11,12

While only 2% of patients with colorectal cancer have Lynch syndrome, from 90% to 95% of colorectal cancers from patients with Lynch syndrome have high levels of microsatellite instability.¹⁰ The presence of MLH1 promoter hypermethylation, the BRAF mutation V600E, or both within the tumor suggests that the cancer is not associated with Lynch syndrome.

Some families that meet the Amsterdam I criteria have microsatellite-stable tumors: their condition has been called familial colorectal cancer type X.¹³ This condition is associated with a higher risk of colorectal cancer but not the other malignancies observed in Lynch syndrome.

Immunohistochemistry is performed to assess for expression of the mismatch repair proteins MSH2, MSH6, MLH1, and PMS2. Absence of expression of the specific protein within tumor cells compared with normal cells within the specimen suggests dysfunction of the specific gene and guides germline mutation testing (Figure 1). For example, a patient who lacks expression of the MSH2 protein in his or her colon cancer most likely has a mutation in the MSH2 gene. Therefore, germ-line genetic testing should initially target the MSH2 gene. Approximately 88% of Lynch syndrome-associated colorectal cancers have abnormal immunohistochemical staining.¹⁰

Testing for microsatellite instability and mismatch repair gene expression ideally precedes germline genetic testing and helps to guide which gene or genes should be tested.^9,14

Genetic testing for Lynch syndrome is routinely performed on a blood or saliva sample, using DNA from white blood cells and sequencing the gene or genes involved to look for mutations. Positive results from a germline genetic test confirm the diagnosis of Lynch syndrome and allow for predictive testing for relatives at risk. The term Lynch syndrome is used exclusively to describe individuals with evidence of a mutation in one of the mismatch repair genes.¹⁵

If a patient’s results are positive, genetic counseling and genetic testing should be offered to at-risk relatives age 18 and over.

Management of Lynch syndrome

Aggressive cancer surveillance is essential for people with Lynch syndrome and for those who are considered at risk but have not pursued genetic testing, such as a sibling of a person with Lynch syndrome.

Colorectal cancer. Colonoscopy is recommended every 1 to 2 years beginning at the age of 20 to 25 years, or 2 to 5 years earlier than the age of the youngest relative affected with colorectal cancer if the initial diagnosis was before age 25. When patients turn 40 years old, colonoscopy is done annually.^16–18 A significant reduction in cancer incidence and in the mortality rate has been shown with colonoscopic surveillance.^19–21

Chemoprevention may also have a role. Patients with Lynch syndrome who took aspirin 600 mg per day for an average of 25 months had a significantly lower incidence of colorectal cancer during a 55-month follow-up period compared with patients randomized to placebo.²²

For patients with Lynch syndrome who are diagnosed with colorectal cancer, the high risk of metachronous cancers after standard segmental colectomy calls for a more extended resection. Retrospective analysis of 382 Lynch syndrome patients found that none of the 50 who underwent total or subtotal colectomy were diagnosed with metachronous colorectal cancer, whereas a metachronous cancer developed in 74 (22%) of the 332 patients who had had segmented resection.² Annual surveillance of the remaining colon, rectum, or both is indicated postoperatively.

Gynecologic cancers. Women with Lynch syndrome should also consider gynecologic surveillance and risk-reducing surgery. This includes annual gynecologic examination, transvaginal ultrasonography, and endometrial aspiration, beginning at age 30 to 35 years. Although this surveillance does detect premalignant lesions and early symptomatic cancers, its effect on the mortality rate is unknown. Hysterectomy with bilateral salpingo-oophorectomy has been shown to significantly reduce endometrial and ovarian cancers in women with Lynch syndrome.^23,24

Urothelial cancers. Carriers of MSH2 mutations have a significantly higher risk of urothelial cancers.⁴ Therefore, MSH2 carriers should consider ultrasonography of the urinary tract, urinary cytology, and urinalysis every 1 to 2 years beginning at age 40.⁴

Other extracolonic cancers. Poor evidence exists for systematic screening for the other extracolonic tumors associated with Lynch syndrome. However, the National Comprehensive Cancer Network advises considering esophagogastroduodenoscopy with extended duodenoscopy as well as capsule endoscopy every 2 to 3 years beginning at age 30 to 35.¹⁴

ADENOMATOUS POLYPOSIS SYNDROMES

Familial adenomatous polyposis and MYH-associated polyposis are the next most common hereditary colorectal cancer syndromes. Each of these accounts for about 1% of cases of colorectal cancer. Clinically, these two syndromes can be challenging to distinguish because they overlap phenotypically to a significant degree.

FAMILIAL ADENOMATOUS POLYPOSIS

Familial adenomatous polyposis is caused by mutations in the APC gene. Its prevalence is 2.29 to 3.2 per 100,000 individuals.^25,26

Genetics of familial adenomatous polyposis

APC is the only gene known to cause familial adenomatous polyposis. Mutations in APC are inherited in an autosomal dominant manner. Approximately 25% of cases of familial adenomatous polyposis are due to a de novo mutation in APC.²⁷

Clinical presentation of familial adenomatous polyposis

Familial adenomatous polyposis is classified by the burden of colorectal adenomas.

Patients who have fewer than 100 adenomas have an attenuated form of the disease. In this group, polyps usually begin to form in the late teenage years or early 20s and tend to develop in the proximal colon. The attenuated form is associated with an approximately 70% lifetime risk of colorectal cancer.²⁸

Patients who have more than 100 polyps are considered to have the classic form of the disease, and those with more than 1,000 polyps have profuse familial adenomatous polyposis (Figure 2). In these groups, polyps typically begin to develop in the preteenage to mid-teenage years. Without surgery, there is nearly a 100% risk of colorectal cancer. The average age at diagnosis of colorectal cancer is 39 years for patients with classic disease.

Upper gastrointestinal polyps are common in familial adenomatous polyposis. Nearly 90% of patients develop duodenal adenomas by a mean age of 44, with a cumulative lifetime risk of nearly 100%.²⁹ Fundic gland polyposis occurs in nearly 90% of patients,³⁰ while gastric adenomas are reported in fewer than 15% of patients.

Duodenal and periampullary cancer is the second most common malignancy in familial adenomatous polyposis. The lifetime risk ranges from 2% to 36%, depending on the Spigelman stage. People with Spigelman stage I, II, or III have a 2.5% risk of duodenal cancer, while those with stage IV disease have up to a 36% lifetime risk.

Gastric cancer, arising from fundic gland polyps, has been reported but is rare in Western populations.

In familial adenomatous polyposis, the incidence of jejunal adenomas and cancer is less than 10%, and the risk of ileal adenomas and cancer is less than 1%.³¹

Familial adenomatous polyposis is also associated with a higher risk of other malignancies, including:

• Pancreatic cancer (2% lifetime risk)
• Thyroid cancer (2% to 3% lifetime risk, typically papillary carcinoma)³²
• Hepatoblastoma (1% to 2% lifetime risk)
• Brain tumors (< 1% lifetime risk)
• Biliary cancer (higher risk than in the general population).³³

Benign extracolonic manifestations that have been observed include osteomas, dental abnormalities (supernumerary teeth, unerupted or absent teeth, odontomas), congenital hypertrophy of the retinal pigment epithelium, benign cutaneous lesions (epidermoid cysts and fibromas), and desmoid tumors.³³ The term “Gardner syndrome” has been used to describe patients who have familial adenomatous polyposis but also have osteomas and soft-tissue tumors.³⁴ These patients carry the same risk of colorectal cancer as other patients with familial adenomatous polyposis.

Diagnosing familial adenomatous polyposis

The diagnosis of familial adenomatous polyposis is suspected when a patient has more than 10 adenomatous polyps.

Seventy-five percent of patients with familial adenomatous polyposis have a family history of the condition. Therefore, most cases are identified at a young age on screening sigmoidoscopy or colonoscopy or by predictive gene testing. Patients rarely have cancer at the time of diagnosis.

The other 25% of patients typically are diagnosed when symptoms develop from the polyps or cancer. Over 50% of these symptomatic patients have cancer at the time of diagnosis.

It is recommended that people who have more than 10 adenomas detected on a single colonoscopy or who are first-degree relatives of patients with familial adenomatous polyposis undergo a genetic evaluation and testing for mutations in the APC gene.¹⁴ Once an APC mutation is identified in the family, at-risk relatives should be offered testing around age 10 years for families with classic familial adenomatous polyposis or in the mid to late teenage years for those with the attenuated form. It also appropriate to refer patients with desmoid tumors, duodenal adenomas, and bilateral or multifocal congenital hypertrophy of the retinal pigment epithelium for a genetic evaluation.

Management of familial adenomatous polyposis

Flexible sigmoidoscopy every 1 to 2 years beginning at age 10 to 12 years is recommended for individuals and families who have been phenotypically or genetically diagnosed with familial adenomatous polyposis.^35–37 If colorectal adenomas are found, surgical options should be discussed and annual colonoscopic surveillance should commence.

For people with the attenuated form, because of the later age of disease onset and the tendency for right-sided disease, colonoscopy every 1 to 2 years should commence at about age 18.^35–37 If polyps are found, colonoscopy should be performed every year.

The decision of when to offer colectomy is based on polyp burden (taking into account the number, pathologic appearance, and size of the polyps) and psychosocial factors such as patient maturity. Surgical options include total colectomy and ileorectal anastomosis or total proctocolectomy and ileal pouch anal anastomosis.³⁸ Colonic and extracolonic phenotype as well as genotype should factor into the type of operation recommended. After colectomy, annual endoscopic surveillance of the rectum or ileal pouch is indicated to screen for recurrent polyposis and cancer.

Chemoprevention with sulindac (Clinoril) 150 mg or celecoxib (Celebrex) 400 mg twice a day causes regression of colorectal adenomas in familial adenomatous polyposis and may be useful as an adjunct to endoscopy in managing the colorectal polyp burden.^39,40

Forward and side-viewing upper endoscopy should commence at age 20. This should include visualization and biopsy of the papilla and periampulllary region.²⁹ The frequency of endoscopic surveillance depends on the Spigelman stage, which reflects the duodenal polyp burden. It is recommended that patients with Spigelman stage IV duodenal polyposis be seen in consultation with an experienced gastrointestinal surgeon for consideration of a prophylactic, pylorus-preserving, pancreas-sparing duodenectomy. This procedure has been shown to be more effective in polyp control and cancer prevention than endoscopic polyp ablation and local surgical resection.⁴¹

Some evidence for the utility of celecoxib 400 mg twice daily for the regression of duodenal polyposis was noted in a 6-month placebo-controlled trial.⁴² Some experts recommend removal of large duodenal adenomas, with adjunctive celecoxib therapy to control polyposis burden.³⁰

People with familial adenomatous polyposis have been shown to have a 2.6% risk of thyroid cancer, and ultrasonography of the neck with attention to the thyroid is recommended for them.³²

MYH-ASSOCIATED POLYPOSIS

Biallelic mutations in the MYH gene result in an adenomatous polyposis syndrome that may be indistinguishable from the attenuated or classic forms of familial adenomatous polyposis. A characteristic autosomal recessive pattern of inheritance in the family can be useful for identifying these patients in the clinic.

Genetics of MYH-associated polyposis

MYH-associated polyposis is the only known autosomal recessive hereditary colorectal cancer syndrome. In white populations, the most commonly reported mutations in MYH are Y179C (previously called Y165C) and G396D (previously called G382D), which account for up to 80% of cases.⁴³ These two mutations are estimated to occur in 1% to 2% of the general population.⁴⁴

Clinical presentation of MYH-associated polyposis

MYH-associated polyposis typically presents as multiple adenomatous polyps and is diagnosed at a mean age of 47 years. Eleven percent to 42% of affected individuals are reported to have fewer than 100 adenomas, while a minority (7.5% to 29%) of patients present with classic polyposis.^45–47 In one study, an estimated 19% of patients presented with colorectal cancer and reported no history of colorectal polyps.⁴⁸ Synchronous colorectal cancer is seen in more than 60% of patients with biallelic MYH mutations.⁴⁹ Patients with monoallelic (heterozygous) MYH mutations appear to have the same risk of developing colorectal adenomas and cancer as the general population.⁴⁹

Upper-gastrointestinal polyps have been reported in MYH-associated polyposis; as many as 17% to 25% of patients have duodenal adenomas.^50,51

Diagnosis of MYH-associated polyposis

Genetic testing for biallelic MYH mutations should be performed in patients who test negative for an APC mutation but who have clinical features of familial adenomatous polyposis, a personal history of more than 10 colorectal adenomas, or a recessive family history of polyposis. ¹⁴ It has been shown that up to 29% of patients with familial adenomatous polyposis who are APC-negative will have biallelic mutations in the MYH gene.⁵² The siblings of a patient with biallelic MYH mutations should be offered genetic counseling and testing in their late teens or early 20s. All children of an individual with MYH-associated polyposis will carry one MYH mutation and are only at risk of having the syndrome if the other parent is also a MYH carrier and passed on his or her mutation.

Management of MYH-associated polyposis

The management of patients with MYH-associated polyposis is similar to that recommended for attenuated and classic familial adenomatous polyposis.¹⁴ Genetic counseling and testing and colonic and extracolonic surveillance are warranted. There are no data on the use of chemoprevention in MYH-associated polyposis. Surgery should be considered early because of the high risk of colorectal cancer, even in individuals with very few adenomas. Patients with monoallelic MYH mutations should follow the general population screening guidelines for colorectal cancer.⁴⁹

GENETIC COUNSELING AND GENETIC TESTING

The American College of Gastroenterology advises that patients suspected of having hereditary colorectal cancer syndromes be advised to pursue genetic counseling and, if appropriate, genetic testing.¹⁶ They further recommend genetic counseling and informed consent before genetic testing.¹⁶

Genetic counseling is a process of working with patients and families whereby:

• A detailed medical and family history is obtained
• A formal risk assessment is performed
• Education about the disease in question and about genetic testing is provided
• Psychosocial concerns are assessed
• Informed consent is obtained when genetic testing is recommended.⁵³

This process is important for helping patients better understand their cancer risks, the benefits and limitations of genetic testing, and the protections that are in place for people who undergo genetic testing, including the Genetic Information Non-Discrimination Act.

In 1996 the American Society of Clinical Oncology issued a policy statement highlighting the essential elements of informed consent for genetic testing for cancer susceptibility, and this was updated in 2003.⁵⁴ In particular, it notes that patients should be informed of the implications of positive and negative results and of the possibility that the test may be uninformative.

When a hereditary colorectal cancer syndrome is suspected, a positive genetic test result confirms the diagnosis and allows for predictive testing of the patient’s relatives. However, no genetic test for a hereditary colorectal cancer syndrome is 100% sensitive. Therefore, a negative result does not rule out the syndrome in question.

Further, all cancer susceptibility genes have variants of uncertain significance, which are genetic alterations for which there are insufficient data to determine if the mutation is disease-causing or polymorphic (benign). Both negative and uninformative results can be confusing for patients and providers and can lead to false reassurance or undue worry when patients are not properly educated about these potential outcomes of testing.

Genetic testing is an evolving field, and with additional research and improved testing technologies, appropriate diagnoses can be made over time. That is why it is important for the genetic counseling relationship to continue over time.