If you get up more than once every night to empty your bladder, you should tell your doctor. He or she may be able to do something about it.

Many people get this problem as they get older. It even has a medical name: nocturia (noct = night, uria = urination). However, it is not something you just have to put up with.

What causes nocturia?

Potential causes are many, and most people have a combination of them.

A large urine output can be a sign of a number of diseases. Diabetes, for example, is high on the list and not something you should ignore.

Less room in the bladder, overactive bladder, or an enlarged prostate gland can also make you have to go to the bathroom more often. There are drugs that can help with this. Another common cause is urinary tract infection.

Poor sleep. If you keep waking up for other reasons, you may be getting up just because you are awake. Your doctor may be able to suggest treatments to help you sleep better.

Dear Diary…

To help figure out what is causing the problem, your doctor may ask you to keep a “voiding diary” (a urination diary) for a few days to a week. This means you’ll have to measure everything that comes out—every time—and write down the amount and time. Some people use a special plastic measuring container that fits in the toilet.

Some common-sense advice

• Don’t drink a lot before you go to bed, especially alcoholic or caffeinated drinks.
• If you take a diuretic (water pill) for your blood pressure or heart, don’t take it right before you go to bed.
• If your feet and ankles swell, try wearing compression stockings during the day, and sitting with your legs up in the afternoon.
• Get some moderate exercise every day, such as walking.
• Bed is for sleeping. Avoid reading or watching TV when you’re in bed. Keep the bedroom dark and quiet, if possible. And if it’s cold, put another blanket on the bed.

Be safe

To avoid the risk of tripping and falling down on the way to and from the bathroom, make sure that the path is clear before you go to bed. Clean up the clutter. Get rid of throw rugs. Keep a nightlight on so you can see where you are going. Try to discourage your dog or cat from sleeping in the path you’re going to take. Wear slippers that don’t slip.

It may not be possible to make the problem go away completely, but you may be able to improve it. And if you can sleep better, you’ll probably feel better in the daytime too.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.

For patient information on hundreds of health topics, see the Web site, www.clevelandclinic.org/health.

If you get up more than once every night to empty your bladder, you should tell your doctor. He or she may be able to do something about it.

Many people get this problem as they get older. It even has a medical name: nocturia (noct = night, uria = urination). However, it is not something you just have to put up with.

What causes nocturia?

Potential causes are many, and most people have a combination of them.

A large urine output can be a sign of a number of diseases. Diabetes, for example, is high on the list and not something you should ignore.

Less room in the bladder, overactive bladder, or an enlarged prostate gland can also make you have to go to the bathroom more often. There are drugs that can help with this. Another common cause is urinary tract infection.

Poor sleep. If you keep waking up for other reasons, you may be getting up just because you are awake. Your doctor may be able to suggest treatments to help you sleep better.

Dear Diary…

To help figure out what is causing the problem, your doctor may ask you to keep a “voiding diary” (a urination diary) for a few days to a week. This means you’ll have to measure everything that comes out—every time—and write down the amount and time. Some people use a special plastic measuring container that fits in the toilet.

Some common-sense advice

• Don’t drink a lot before you go to bed, especially alcoholic or caffeinated drinks.
• If you take a diuretic (water pill) for your blood pressure or heart, don’t take it right before you go to bed.
• If your feet and ankles swell, try wearing compression stockings during the day, and sitting with your legs up in the afternoon.
• Get some moderate exercise every day, such as walking.
• Bed is for sleeping. Avoid reading or watching TV when you’re in bed. Keep the bedroom dark and quiet, if possible. And if it’s cold, put another blanket on the bed.

Be safe

To avoid the risk of tripping and falling down on the way to and from the bathroom, make sure that the path is clear before you go to bed. Clean up the clutter. Get rid of throw rugs. Keep a nightlight on so you can see where you are going. Try to discourage your dog or cat from sleeping in the path you’re going to take. Wear slippers that don’t slip.

It may not be possible to make the problem go away completely, but you may be able to improve it. And if you can sleep better, you’ll probably feel better in the daytime too.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.

For patient information on hundreds of health topics, see the Web site, www.clevelandclinic.org/health.

If you get up more than once every night to empty your bladder, you should tell your doctor. He or she may be able to do something about it.

Many people get this problem as they get older. It even has a medical name: nocturia (noct = night, uria = urination). However, it is not something you just have to put up with.

What causes nocturia?

Potential causes are many, and most people have a combination of them.

A large urine output can be a sign of a number of diseases. Diabetes, for example, is high on the list and not something you should ignore.

Less room in the bladder, overactive bladder, or an enlarged prostate gland can also make you have to go to the bathroom more often. There are drugs that can help with this. Another common cause is urinary tract infection.

Poor sleep. If you keep waking up for other reasons, you may be getting up just because you are awake. Your doctor may be able to suggest treatments to help you sleep better.

Dear Diary…

To help figure out what is causing the problem, your doctor may ask you to keep a “voiding diary” (a urination diary) for a few days to a week. This means you’ll have to measure everything that comes out—every time—and write down the amount and time. Some people use a special plastic measuring container that fits in the toilet.

Some common-sense advice

• Don’t drink a lot before you go to bed, especially alcoholic or caffeinated drinks.
• If you take a diuretic (water pill) for your blood pressure or heart, don’t take it right before you go to bed.
• If your feet and ankles swell, try wearing compression stockings during the day, and sitting with your legs up in the afternoon.
• Get some moderate exercise every day, such as walking.
• Bed is for sleeping. Avoid reading or watching TV when you’re in bed. Keep the bedroom dark and quiet, if possible. And if it’s cold, put another blanket on the bed.

Be safe

To avoid the risk of tripping and falling down on the way to and from the bathroom, make sure that the path is clear before you go to bed. Clean up the clutter. Get rid of throw rugs. Keep a nightlight on so you can see where you are going. Try to discourage your dog or cat from sleeping in the path you’re going to take. Wear slippers that don’t slip.

It may not be possible to make the problem go away completely, but you may be able to improve it. And if you can sleep better, you’ll probably feel better in the daytime too.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.

For patient information on hundreds of health topics, see the Web site, www.clevelandclinic.org/health.

Cervical cancer screening and prevention have evolved rapidly in the last decade, especially in the 5 years since the introduction of the first cancer prevention vaccine, human papillomavirus (HPV) recombinant vaccine.¹

Providers need to understand the rationale for the recommendations so that they can explain them to patients. In particular, patients may wonder why we now begin screening for cervical cancer later than we used to, and why some women do not need to be screened as often. Both of these changes result from our enhanced understanding of the role of HPV in cervical cancer genesis.

In this article we will briefly review:

• The current understanding of the natural history of cervical cancer
• Advantages and disadvantages of cervical cytology, ie, the Papanicolaou (Pap) test
• The role of HPV testing in cervical cancer screening
• The latest screening guidelines (the new standard of care)
• A possible future screening strategy
• The impact of HPV vaccination on screening.

500,000 NEW CASES EVERY YEAR

The incidence of cervical cancer and its mortality rate have decreased more than 50% in the United States over the past 3 decades, largely as a result of screening with the Pap test.² In 2010, there were an estimated 12,200 new cases of invasive cervical cancer in the United States and 4,210 deaths from it,³ which are lower than the historical rates.

However, because most developing countries lack effective screening programs, cervical cancer remains the second-leading cause of death from cancer in women worldwide. According to a recent estimate, there are almost 500,000 new cases and 240,000 deaths from this disease worldwide every year.⁴ If effective global screening programs could be set up, they would markedly reduce the incidence of cervical cancer and deaths from it.⁵

HPV IS NECESSARY BUT NOT SUFFICIENT FOR CERVICAL CANCER TO DEVELOP

For cervical cancer to develop, the essential first step is infection of the cervical epithelium with one of the oncogenic (high-risk) types of HPV (see below).^6–10 Walboomers et al⁹ tested cervical tissue samples taken from 932 women with cervical cancer and detected HPV DNA in 930 (99.8%) of them.

Fortunately, most HPV-infected women do not develop cervical cancer, as most young women clear the infection in an average of 8 to 24 months.^11,12 However, if the infection persists, and if it is one of the high-risk types of HPV, precursor lesions can develop that can progress to cervical cancer.¹³ The evidence conclusively supports the association between oncogenic HPV infection and the subsequent development of virtually all cases of cervical cancer.^6–10

Known risk factors for HPV persistence and the subsequent development of high-grade lesions are cigarette smoking and a compromised immune system.^14,15

Terminology: Results of Pap smears

• Normal
• Atypical squamous cells of undetermined significance (ASC-US)
• Low-grade squamous intraepithelial lesions (LSIL)
• High-grade squamous intraepithelial lesions (HSIL)
• Cancer.

Terminology: Results of cervical biopsy

• Normal
• Cervical intraepithelial neoplasia grade 1 (CIN1)
• CIN2 (previously called moderate dysplasia)
• CIN3 (previously called severe dysplasia)
• Carcinoma in situ
• Invasive cervical cancer.

Lesions that are CIN2 or higher are considered high-grade.¹³

The 18 high-risk HPV types

More than 40 types of HPV infect the genital tract¹⁶; 18 of these (types 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, and 82) are classified as high-risk because of their causative association with cervical cancer (ie, their oncogenic potential).¹⁷

How HPV causes cervical cancer

Basic science research has provided insight into how high-risk HPV causes cervical cancer (Figure 1).

In laboratory cultures, normal human cells die out after a few generations. However, if human epithelial cells are infected by one of the high-risk types of HPV, they can go on dividing indefinitely.^18,19

Two HPV proteins, E6 and E7, induce this cell “immortalization.”^20,21 E6 from high-risk HPV binds to the human tumor-suppressor protein p53 and rapidly degrades it in a proteolytic process. The p53 protein normally suppresses cell proliferation by arresting growth in the G1 phase of the cell cycle. Therefore, with less p53, the cell cannot suppress uncontrolled cell growth.^22–24

Similarly, E7 from high-risk HPV forms a complex with another human tumor suppressor, the retinoblastoma protein (pRB), and disrupts its binding to a transcriptional factor, E2F-1. The freed E2F-1 then stimulates DNA synthesis and uncontrolled cell growth.²⁵

Furthermore, HPV-16 E6 and E7 proteins can collectively cause cellular genetic instability.²⁶

The carcinogenic mechanism of high-risk HPV is complex. The host immune system and natural tumor suppression play important roles. However, the natural history of cervical intraepithelial neoplasia is not well understood. For example, it remains unclear if low-grade lesions such as CIN1 are necessary precursors to high-grade lesions and invasive cancer.^6,7,10

 

THE PAP TEST: SPECIFIC BUT NOT VERY SENSITIVE, AND PRONE TO ERROR

The principal advantage of cervical cytologic testing (ie, the Pap test) in detecting cervical dysplasia is its overall high specificity. Many studies have found that the specificity of conventional Pap testing can reach approximately 98%.²⁷

However, the conventional Pap test has drawbacks. Contaminants such as blood, discharge, and lubricant can make it difficult to interpret, and artifact can occur with air-drying of the Pap smear as it is transferred to the cell slide (“air-drying artifact”).

Liquid-based cytologic study has replaced the older method

To overcome these disadvantages, a liquid-based method of cervical cytologic study, ThinPrep (Hologic, Bedford, MA), was introduced in the mid-1990s. In this method, cell samples are first transferred to a liquid solution for mechanical separation from contaminants, and a representative sample of cells is then placed on a slide for review.

The liquid-based method filters out most contaminating blood, inflammatory cells, and debris. It also eliminates the air-drying artifact in the conventional Pap collection technique and improves specimen adequacy. Cytotechnologists find liquid-based specimens easier to read because the cells are more evenly distributed on a clearer background. Another advantage is that we can routinely test for HPV in the available residual specimen if the cytologic interpretation is abnormal.

The main disadvantages of the liquid-based method are that its specificity is lower than that of conventional Pap smears (around 78%) and that it costs more.²⁸ Nevertheless, the liquid-based technique has become the main method of cervical cytology, used by nearly 90% of gynecologists in the United States since 2003.¹

Cytology is still prone to false-negative results

Despite the success of both conventional Pap testing and liquid-based Pap testing, cervical cytology is inherently prone to sample-quality variation, subjective interpretation error, and false-negative results. False-negative results can be due to failure to transfer dysplastic cells to the slide or failure of the cytologist to recognize abnormal cells. In 30% of new cases of cervical cancer, the patient had recently had a Pap test that was interpreted as negative.^1,29

Errors in interpretation are exacerbated by inconsistency among cytopathologists. In one study,^6,30 when a group of quality-control pathologists reviewed nearly 5,000 cytology specimens, they came to the same conclusion that the original reviewers did more than 50% of the time only for negative and LSIL readings. Of the specimens initially reported as ASC-US, almost 40% were reclassified as negative on further review. Of those originally interpreted as HSIL, more than 50% were reclassified as LSIL, as ASC-US, or as negative.

Furthermore, many studies found that the sensitivity of conventional Pap testing was only around 50%.²⁷ The new liquid-based Pap test uses computer imaging, which has improved the rate of detection of cervical dysplasia but may still miss 15% to 35% of cases of HSIL (severe dysplasia) or cancer.³¹ Failure to detect cervical dysplasia or cancer on Pap smear has led to a number of lawsuits.³²

Clearly, with its relatively low sensitivity, cervical cytology is no longer good enough to use as a sole screening test in all situations. However, its high specificity is an advantage when it is combined with HPV testing in screening.

HPV TESTING AND PAP TESTING COMPLEMENT EACH OTHER

From 17% to 36% of HPV-infected women develop a cytologic abnormality within 5 years, compared with 4% to 15% of women who are HPV-negative.^33,34

The usefulness of testing for HPV in women who have had an abnormal Pap test has been well demonstrated in multiple studies.^35–38

The landmark Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS)³⁹ found that 82.9% of women with LSIL were HPV-positive. The investigators concluded that HPV testing has little utility in women with LSIL, as the test would likely be positive and thus would not change the decision to perform colposcopy.

However, in women with ASC-US, the sensitivity of HPV testing for predicting CIN3 or cancer was 96.3% and the negative predictive value was 99.5%. In contrast, the sensitivity of a single repeat Pap test was only 44.1%. This large randomized trial conclusively validates the important role of HPV testing in triaging women with ASC-US.

More recently, a meta-analysis of 20 studies of HPV testing in women with ASC-US found that it had a sensitivity of 92.5% and a specificity of 62.5% for detecting CIN2 or worse lesions, and a sensitivity of 95.6% and a specificity of 59.2% for detecting CIN3 or worse lesions.⁴⁰

Furthermore, HPV testing in primary cervical cancer screening is strongly supported by large cross-sectional studies^41–45 and randomized clinical trials.^46,47 These studies have conclusively shown that HPV testing is significantly more sensitive than Pap testing for detecting cervical intraepithelial neoplasia, and that, when combined with Pap testing, it can achieve nearly 100% clinical sensitivity and nearly 93% specificity in women age 30 or older. Women who have negative results on both the HPV test and the Pap test can be reassured that their risk of undetected CIN2, CIN3, or cervical cancer is extremely low, since HPV testing has a negative predictive value close to 100%.⁴⁶

In large multinational European studies involving more than 24,000 women, the risk of CIN3 or cancer after 6 years of follow-up was only 0.28% in women who had negative results on both HPV and Pap testing at baseline. This rate was basically the same as in women who tested negative for HPV alone (0.27%). However, it was significantly lower than that of all women who had negative Pap test results (0.97%). The combination of HPV testing and Pap testing at 6-year intervals offered better protection than Pap testing alone at 3-year intervals.⁴⁸

 

NEW STANDARD OF CARE: THE LATEST SCREENING GUIDELINES

Until the mid-1990s, the strategy for cervical cancer screening had remained largely unchanged for many years. Since then, several advances have prompted changes in the standard of care.

1996—The US Food and Drug Administration (FDA) approved liquid-based Thin-Prep for cervical cancer screening, which improved specimen adequacy and reduced ambiguous interpretations compared with the original slide-based method of collection.⁴⁹

2001—The Bethesda terminology for reporting cervical cytology results was updated. First proposed in 1988 to replace the original Papanicolaou system and revised in 1991, this standardized terminology enabled better clinical decision-making.⁵⁰

2001—The FDA approved HPV testing for women with ASC-US. This provided a better triage strategy for deciding which women need colposcopy to exclude true intraepithelial lesions. Following the FDA approval, the clinical effectiveness of HPV testing in women with ASC-US was validated by a large randomized clinical trial—the ALTS.⁵¹

2003—The FDA approved HPV testing in conjunction with Pap testing for women age 30 or older in routine primary screening.⁵²

Guidelines available

Based on these new developments in technology and reporting terminology, and the incorporation of HPV testing, several organizations issued guidelines.

The American Society for Colposcopy and Cervical Pathology published a consensus guideline on management of abnormal cervical cytology in 2001 and revised it in 2006.⁵³

The American Cancer Society issued its guideline for cervical cancer screening in 2002.⁵⁴

The US Preventive Services Task Force published its screening guidelines in 2003.⁵⁵

The American College of Obstetricians and Gynecologists (ACOG) also made new recommendations in 2003 and updated them in December 2009.¹

The following discussion highlights the consensus guidelines and the differences in the recommendations from these organizations (Table 1).⁵⁶

Start screening at age 21

Cervical cancer screening should begin at age 21 regardless of the age of onset of vaginal intercourse, according to the 2009 ACOG guidelines.¹ This represents a change from previous recommendations from ACOG, the American Cancer Society, and the US Preventive Services Task Force, which were to start screening within 3 years of the onset of vaginal intercourse.

Rationale. This latest recommendation is based on the high rates of clearance of HPV infection and of spontaneous dysplasia regression and the low incidence of cervical cancer in younger women.^57,58 HPV infections are common in young women who have had vaginal intercourse. However, most such HPV infections are cleared by the immune system within 1 to 2 years without causing cervical dysplasia.^11,12 Invasive cervical cancer in women younger than 21 years is very rare. The annual incidence is only one to two cases per 1 million women ages 15 to 19.^2,55

Another reason for not screening before age 21 is that a positive test result may lead to unnecessary anxiety and potentially harmful evaluations and procedures.

Screening intervals extended

The 2009 ACOG guidelines lengthen the cervical cancer screening interval to every 2 years in women under age 30.¹ (The 2003 ACOG guidelines said to screen every year.)

For women age 30 and older, the 2009 ACOG guidelines recommend extending the interval to every 3 years when combined Pap and HPV testing are negative (changed from every 2 to 3 years).¹

Rationale. Studies have shown little advantage in screening every year in women under the age of 30, with no higher risk of cervical cancer in women screened at a 2- to 3-year interval.^59–62 The absolute risk of cervical cancer in a well-screened population is very low.⁶³ Moreover, the absolute number of cervical cancer cases in women age 30 to 64 years screened at 3-year intervals is only four per 100,000 women.⁶⁴

HPV-plus-Pap testing for women over 30

Based on convincing evidence of the high sensitivity and the high negative predictive value of HPV testing, since 2003 ACOG had recommended HPV-plus-Pap testing in women over age 30. Its 2009 guidelines upgraded this recommendation to level A, ie, the highest grade, based on good and consistent scientific evidence.¹ (Previously the recommendation was level B.)

The American Cancer Society also recommends combined HPV and Pap testing as the optimal screening approach in women age 30 or older, with the subsequent screening interval 3 years if both tests are negative. It also endorses Pap testing alone every 2 to 3 years as an alternative screening strategy in this age group.

The US Preventive Services Task Force recommends Pap testing every 3 years in women age 30 or older, and it does not recommend for or against HPV testing. However, neither the US Preventive Services Task Force nor the American Cancer Society has updated its guidelines in 8 years.

Rationale. Women who undergo HPV-plus-Pap testing and who test negative on both are at very low risk of developing CIN2 or CIN3 during the next 4 to 6 years. The risk is much lower than that for women who have a sole negative Pap test result.^39,40 Because of this extremely high negative predictive value, women age 30 and older who had negative results on both Pap and HPV testing should be screened no more often than every 3 years.

We believe that the HPV-plus-Pap testing strategy recommended by the 2009 ACOG guidelines for women age 30 and older is the most effective screening approach. This strategy takes advantage of the high sensitivity and high negative predictive value of HPV testing, as well as the high specificity of Pap testing. It achieves almost 100% clinical sensitivity in detecting cervical dysplasia.⁴⁶

 

 

When to stop screening

The 2009 ACOG guidelines for the first time call for stopping cervical cancer screening in women 65 to 70 years of age who have had three negative Pap tests in a row and no abnormal tests in the previous 10 years.¹ The American Cancer Society recommends stopping screening at age 70,⁶⁵ while the US Preventive Services Task Force recommends stopping at age 65.⁵⁵

Rationale. Cervical cancer develops slowly, and risk factors tend to decline with age, Also, postmenopausal mucosal atrophy may predispose to false-positive Pap results, which can lead to additional procedures and unnecessary patient anxiety.⁶⁶

However, it is probably reasonable to continue screening in women age 70 and older who are sexually active with multiple partners and who have a history of abnormal Pap test results.¹

Women who have had a hysterectomy

According to the latest American Cancer Society, ACOG, and US Preventive Services Task Force guidelines, cervical cancer screening should be discontinued after total hysterectomy for benign indications in women who have no history of high-grade cervical intraepithelial neoplasia, ie, CIN2 or worse.¹

Rationale. If the patient has no cervix, continued vaginal cytology screening is not indicated, since the incidence of primary vaginal cancer is one to two cases per 100,000 women per year, much lower than that of cervical cancer.⁶⁵

However, before discontinuing screening, clinicians should verify that any Pap tests the patient had before the hysterectomy were all read as normal, that the hysterectomy specimen was normal, and that the cervix was completely removed during hysterectomy.

Be ready to explain the recommendations

It is very important for providers to understand the evidence supporting the latest guidelines, as many patients may not realize the significant technological improvements and improved understanding of the role of HPV in cervical cancer genesis that have resulted in the deferred onset of screening and the longer intervals between screenings. This knowledge gap for patients can result in anxiety when told they no longer need an annual Pap test or can start later, if the issue is not properly and thoroughly explained by a confident provider.

A FUTURE STRATEGY: HPV AS THE SOLE PRIMARY SCREENING TEST?

Since HPV testing is much more sensitive than Pap testing for detecting cervical lesions of grade CIN2 or higher, why not use HPV testing as the primary test and then do Pap testing (which is more specific) only if the HPV test is positive?

Several major randomized clinical trials evaluated whether HPV testing could be used as the primary test. Table 2 summarizes the key conclusions from several of these trials.^42,67–72

Mayrand et al⁴⁶ conducted the first large randomized trial in which HPV testing was compared directly as a stand-alone test with the Pap test in a North American population with access to quality care. Results were published in 2007. In Canada, a total of 10,154 women ages 30 to 69 years in Montreal and St. John’s were randomly assigned to undergo either conventional Pap testing or HPV testing. The sensitivity of HPV testing for CIN2 or CIN3 was 94.6%, whereas the sensitivity of Pap testing was only 55.4%. The specificity was 94.1% for HPV testing and 96.8% for Pap testing. In addition, HPV screening followed by Pap triage resulted in fewer referrals for colposcopy than did either test alone (1.1% vs 2.9% with Pap testing alone or 6.1% with HPV testing alone). In other words, HPV testing was almost 40% more sensitive and only 2.7% less specific than Pap testing in detecting cervical cancer precursors.

However, more controlled trials are needed to validate such a strategy. Furthermore, it remains unclear if a change from Pap testing to a primary HPV testing screening strategy will further reduce the mortality rate of cervical cancer, since the burden of cervical cancer worldwide lies in less-screened populations in low-resource settings.

Dillner et al,⁴⁸ in a 2008 European study, further demonstrated that HPV testing offers better long-term (6-year) predictive value for CIN3 or worse lesions than cytology does. These findings suggest that HPV testing, with its higher sensitivity and negative predictive value and its molecular focus on cervical carcinogenesis, may safely permit longer screening intervals in a low-risk population.

Sankaranarayanan et al⁷² performed a randomized trial in rural India in which 131,746 women age 30 to 59 years were randomly assigned to four groups: screening by HPV testing, screening by Pap testing, screening by visual inspection with acetic acid, and counseling only (the control group). At 8 years of follow-up, the numbers of cases of cervical cancer and of cervical cancer deaths were as follows:

• With HPV testing: 127 cases, 34 deaths
• With Pap testing: 152 cases, 54 deaths
• With visual inspection: 157 cases, 56 deaths
• With counseling only: 118 cases, 64 deaths.

The authors concluded that in a low-resource setting, a single round of HPV testing was associated with a significant reduction in the number of deaths from cervical cancer. Not only did the HPV testing group have a lower incidence of cancer-related deaths, there were no cancer deaths among the women in this group who tested negative for HPV. This is the first randomized trial to suggest that using HPV testing as the sole primary cervical cancer screening test may have a benefit in terms of the mortality rate.

At present, to the best of our knowledge, there are no US data validating the role of HPV testing as a stand-alone screening test for cervical cancer.

 

HPV VACCINATION DOES NOT MEAN THE END OF SCREENING

The development of an effective HPV vaccine and FDA approval of the first quadrivalent (active against HPV 6, 11, 16, and 18) recombinant vaccine (Gardasil) in 2006 has opened a new era of cervical cancer prevention.^73,74 At present, the Advisory Committee on Immunization Practices⁷⁵ recommends vaccination for females 9 to 26 years old.

However, HPV vaccination will not make screening obsolete, since not all women will be vaccinated, and those who have already contracted one of these high-risk HPV types will not benefit.^76,77 In addition, the current HPV vaccine does not protect against infection with other oncogenic HPV types. The experts estimate that the initial impact of the HPV vaccine on cervical cancer will not likely be apparent until at least 20 to 30 years after a nationwide vaccination program is implemented.^78,79 Therefore, the HPV vaccine certainly does not portend the end of screening. Vaccination combined with continued screening will provide added benefit for cervical cancer prevention.⁸⁰

The last decade has been an exciting period in the field of cervical cancer screening and prevention, with advances in technology, newly acquired knowledge, and the development of the HPV vaccine. As a result, our clinical practice has become a work in progress, continuing to evolve as we continue to discover more information. The possibility of eradicating cervical cancer has never been greater. The implementation of the most sensitive and effective screening strategy and of a worldwide HPV vaccination program will help us to eventually eradicate cervical cancer and make it a disease of the past.⁸¹

Cervical cancer screening and prevention have evolved rapidly in the last decade, especially in the 5 years since the introduction of the first cancer prevention vaccine, human papillomavirus (HPV) recombinant vaccine.¹

Providers need to understand the rationale for the recommendations so that they can explain them to patients. In particular, patients may wonder why we now begin screening for cervical cancer later than we used to, and why some women do not need to be screened as often. Both of these changes result from our enhanced understanding of the role of HPV in cervical cancer genesis.

In this article we will briefly review:

• The current understanding of the natural history of cervical cancer
• Advantages and disadvantages of cervical cytology, ie, the Papanicolaou (Pap) test
• The role of HPV testing in cervical cancer screening
• The latest screening guidelines (the new standard of care)
• A possible future screening strategy
• The impact of HPV vaccination on screening.

500,000 NEW CASES EVERY YEAR

The incidence of cervical cancer and its mortality rate have decreased more than 50% in the United States over the past 3 decades, largely as a result of screening with the Pap test.² In 2010, there were an estimated 12,200 new cases of invasive cervical cancer in the United States and 4,210 deaths from it,³ which are lower than the historical rates.

However, because most developing countries lack effective screening programs, cervical cancer remains the second-leading cause of death from cancer in women worldwide. According to a recent estimate, there are almost 500,000 new cases and 240,000 deaths from this disease worldwide every year.⁴ If effective global screening programs could be set up, they would markedly reduce the incidence of cervical cancer and deaths from it.⁵

HPV IS NECESSARY BUT NOT SUFFICIENT FOR CERVICAL CANCER TO DEVELOP

For cervical cancer to develop, the essential first step is infection of the cervical epithelium with one of the oncogenic (high-risk) types of HPV (see below).^6–10 Walboomers et al⁹ tested cervical tissue samples taken from 932 women with cervical cancer and detected HPV DNA in 930 (99.8%) of them.

Fortunately, most HPV-infected women do not develop cervical cancer, as most young women clear the infection in an average of 8 to 24 months.^11,12 However, if the infection persists, and if it is one of the high-risk types of HPV, precursor lesions can develop that can progress to cervical cancer.¹³ The evidence conclusively supports the association between oncogenic HPV infection and the subsequent development of virtually all cases of cervical cancer.^6–10

Known risk factors for HPV persistence and the subsequent development of high-grade lesions are cigarette smoking and a compromised immune system.^14,15

Terminology: Results of Pap smears

• Normal
• Atypical squamous cells of undetermined significance (ASC-US)
• Low-grade squamous intraepithelial lesions (LSIL)
• High-grade squamous intraepithelial lesions (HSIL)
• Cancer.

Terminology: Results of cervical biopsy

• Normal
• Cervical intraepithelial neoplasia grade 1 (CIN1)
• CIN2 (previously called moderate dysplasia)
• CIN3 (previously called severe dysplasia)
• Carcinoma in situ
• Invasive cervical cancer.

Lesions that are CIN2 or higher are considered high-grade.¹³

The 18 high-risk HPV types

More than 40 types of HPV infect the genital tract¹⁶; 18 of these (types 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, and 82) are classified as high-risk because of their causative association with cervical cancer (ie, their oncogenic potential).¹⁷

How HPV causes cervical cancer

Basic science research has provided insight into how high-risk HPV causes cervical cancer (Figure 1).

In laboratory cultures, normal human cells die out after a few generations. However, if human epithelial cells are infected by one of the high-risk types of HPV, they can go on dividing indefinitely.^18,19

Two HPV proteins, E6 and E7, induce this cell “immortalization.”^20,21 E6 from high-risk HPV binds to the human tumor-suppressor protein p53 and rapidly degrades it in a proteolytic process. The p53 protein normally suppresses cell proliferation by arresting growth in the G1 phase of the cell cycle. Therefore, with less p53, the cell cannot suppress uncontrolled cell growth.^22–24

Similarly, E7 from high-risk HPV forms a complex with another human tumor suppressor, the retinoblastoma protein (pRB), and disrupts its binding to a transcriptional factor, E2F-1. The freed E2F-1 then stimulates DNA synthesis and uncontrolled cell growth.²⁵

Furthermore, HPV-16 E6 and E7 proteins can collectively cause cellular genetic instability.²⁶

The carcinogenic mechanism of high-risk HPV is complex. The host immune system and natural tumor suppression play important roles. However, the natural history of cervical intraepithelial neoplasia is not well understood. For example, it remains unclear if low-grade lesions such as CIN1 are necessary precursors to high-grade lesions and invasive cancer.^6,7,10

 

THE PAP TEST: SPECIFIC BUT NOT VERY SENSITIVE, AND PRONE TO ERROR

The principal advantage of cervical cytologic testing (ie, the Pap test) in detecting cervical dysplasia is its overall high specificity. Many studies have found that the specificity of conventional Pap testing can reach approximately 98%.²⁷

However, the conventional Pap test has drawbacks. Contaminants such as blood, discharge, and lubricant can make it difficult to interpret, and artifact can occur with air-drying of the Pap smear as it is transferred to the cell slide (“air-drying artifact”).

Liquid-based cytologic study has replaced the older method

To overcome these disadvantages, a liquid-based method of cervical cytologic study, ThinPrep (Hologic, Bedford, MA), was introduced in the mid-1990s. In this method, cell samples are first transferred to a liquid solution for mechanical separation from contaminants, and a representative sample of cells is then placed on a slide for review.

The liquid-based method filters out most contaminating blood, inflammatory cells, and debris. It also eliminates the air-drying artifact in the conventional Pap collection technique and improves specimen adequacy. Cytotechnologists find liquid-based specimens easier to read because the cells are more evenly distributed on a clearer background. Another advantage is that we can routinely test for HPV in the available residual specimen if the cytologic interpretation is abnormal.

The main disadvantages of the liquid-based method are that its specificity is lower than that of conventional Pap smears (around 78%) and that it costs more.²⁸ Nevertheless, the liquid-based technique has become the main method of cervical cytology, used by nearly 90% of gynecologists in the United States since 2003.¹

Cytology is still prone to false-negative results

Despite the success of both conventional Pap testing and liquid-based Pap testing, cervical cytology is inherently prone to sample-quality variation, subjective interpretation error, and false-negative results. False-negative results can be due to failure to transfer dysplastic cells to the slide or failure of the cytologist to recognize abnormal cells. In 30% of new cases of cervical cancer, the patient had recently had a Pap test that was interpreted as negative.^1,29

Errors in interpretation are exacerbated by inconsistency among cytopathologists. In one study,^6,30 when a group of quality-control pathologists reviewed nearly 5,000 cytology specimens, they came to the same conclusion that the original reviewers did more than 50% of the time only for negative and LSIL readings. Of the specimens initially reported as ASC-US, almost 40% were reclassified as negative on further review. Of those originally interpreted as HSIL, more than 50% were reclassified as LSIL, as ASC-US, or as negative.

Furthermore, many studies found that the sensitivity of conventional Pap testing was only around 50%.²⁷ The new liquid-based Pap test uses computer imaging, which has improved the rate of detection of cervical dysplasia but may still miss 15% to 35% of cases of HSIL (severe dysplasia) or cancer.³¹ Failure to detect cervical dysplasia or cancer on Pap smear has led to a number of lawsuits.³²

Clearly, with its relatively low sensitivity, cervical cytology is no longer good enough to use as a sole screening test in all situations. However, its high specificity is an advantage when it is combined with HPV testing in screening.

HPV TESTING AND PAP TESTING COMPLEMENT EACH OTHER

From 17% to 36% of HPV-infected women develop a cytologic abnormality within 5 years, compared with 4% to 15% of women who are HPV-negative.^33,34

The usefulness of testing for HPV in women who have had an abnormal Pap test has been well demonstrated in multiple studies.^35–38

The landmark Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS)³⁹ found that 82.9% of women with LSIL were HPV-positive. The investigators concluded that HPV testing has little utility in women with LSIL, as the test would likely be positive and thus would not change the decision to perform colposcopy.

However, in women with ASC-US, the sensitivity of HPV testing for predicting CIN3 or cancer was 96.3% and the negative predictive value was 99.5%. In contrast, the sensitivity of a single repeat Pap test was only 44.1%. This large randomized trial conclusively validates the important role of HPV testing in triaging women with ASC-US.

More recently, a meta-analysis of 20 studies of HPV testing in women with ASC-US found that it had a sensitivity of 92.5% and a specificity of 62.5% for detecting CIN2 or worse lesions, and a sensitivity of 95.6% and a specificity of 59.2% for detecting CIN3 or worse lesions.⁴⁰

Furthermore, HPV testing in primary cervical cancer screening is strongly supported by large cross-sectional studies^41–45 and randomized clinical trials.^46,47 These studies have conclusively shown that HPV testing is significantly more sensitive than Pap testing for detecting cervical intraepithelial neoplasia, and that, when combined with Pap testing, it can achieve nearly 100% clinical sensitivity and nearly 93% specificity in women age 30 or older. Women who have negative results on both the HPV test and the Pap test can be reassured that their risk of undetected CIN2, CIN3, or cervical cancer is extremely low, since HPV testing has a negative predictive value close to 100%.⁴⁶

In large multinational European studies involving more than 24,000 women, the risk of CIN3 or cancer after 6 years of follow-up was only 0.28% in women who had negative results on both HPV and Pap testing at baseline. This rate was basically the same as in women who tested negative for HPV alone (0.27%). However, it was significantly lower than that of all women who had negative Pap test results (0.97%). The combination of HPV testing and Pap testing at 6-year intervals offered better protection than Pap testing alone at 3-year intervals.⁴⁸

 

NEW STANDARD OF CARE: THE LATEST SCREENING GUIDELINES

Until the mid-1990s, the strategy for cervical cancer screening had remained largely unchanged for many years. Since then, several advances have prompted changes in the standard of care.

1996—The US Food and Drug Administration (FDA) approved liquid-based Thin-Prep for cervical cancer screening, which improved specimen adequacy and reduced ambiguous interpretations compared with the original slide-based method of collection.⁴⁹

2001—The Bethesda terminology for reporting cervical cytology results was updated. First proposed in 1988 to replace the original Papanicolaou system and revised in 1991, this standardized terminology enabled better clinical decision-making.⁵⁰

2001—The FDA approved HPV testing for women with ASC-US. This provided a better triage strategy for deciding which women need colposcopy to exclude true intraepithelial lesions. Following the FDA approval, the clinical effectiveness of HPV testing in women with ASC-US was validated by a large randomized clinical trial—the ALTS.⁵¹

2003—The FDA approved HPV testing in conjunction with Pap testing for women age 30 or older in routine primary screening.⁵²

Guidelines available

Based on these new developments in technology and reporting terminology, and the incorporation of HPV testing, several organizations issued guidelines.

The American Society for Colposcopy and Cervical Pathology published a consensus guideline on management of abnormal cervical cytology in 2001 and revised it in 2006.⁵³

The American Cancer Society issued its guideline for cervical cancer screening in 2002.⁵⁴

The US Preventive Services Task Force published its screening guidelines in 2003.⁵⁵

The American College of Obstetricians and Gynecologists (ACOG) also made new recommendations in 2003 and updated them in December 2009.¹

The following discussion highlights the consensus guidelines and the differences in the recommendations from these organizations (Table 1).⁵⁶

Start screening at age 21

Cervical cancer screening should begin at age 21 regardless of the age of onset of vaginal intercourse, according to the 2009 ACOG guidelines.¹ This represents a change from previous recommendations from ACOG, the American Cancer Society, and the US Preventive Services Task Force, which were to start screening within 3 years of the onset of vaginal intercourse.

Rationale. This latest recommendation is based on the high rates of clearance of HPV infection and of spontaneous dysplasia regression and the low incidence of cervical cancer in younger women.^57,58 HPV infections are common in young women who have had vaginal intercourse. However, most such HPV infections are cleared by the immune system within 1 to 2 years without causing cervical dysplasia.^11,12 Invasive cervical cancer in women younger than 21 years is very rare. The annual incidence is only one to two cases per 1 million women ages 15 to 19.^2,55

Another reason for not screening before age 21 is that a positive test result may lead to unnecessary anxiety and potentially harmful evaluations and procedures.

Screening intervals extended

The 2009 ACOG guidelines lengthen the cervical cancer screening interval to every 2 years in women under age 30.¹ (The 2003 ACOG guidelines said to screen every year.)

For women age 30 and older, the 2009 ACOG guidelines recommend extending the interval to every 3 years when combined Pap and HPV testing are negative (changed from every 2 to 3 years).¹

Rationale. Studies have shown little advantage in screening every year in women under the age of 30, with no higher risk of cervical cancer in women screened at a 2- to 3-year interval.^59–62 The absolute risk of cervical cancer in a well-screened population is very low.⁶³ Moreover, the absolute number of cervical cancer cases in women age 30 to 64 years screened at 3-year intervals is only four per 100,000 women.⁶⁴

HPV-plus-Pap testing for women over 30

Based on convincing evidence of the high sensitivity and the high negative predictive value of HPV testing, since 2003 ACOG had recommended HPV-plus-Pap testing in women over age 30. Its 2009 guidelines upgraded this recommendation to level A, ie, the highest grade, based on good and consistent scientific evidence.¹ (Previously the recommendation was level B.)

The American Cancer Society also recommends combined HPV and Pap testing as the optimal screening approach in women age 30 or older, with the subsequent screening interval 3 years if both tests are negative. It also endorses Pap testing alone every 2 to 3 years as an alternative screening strategy in this age group.

The US Preventive Services Task Force recommends Pap testing every 3 years in women age 30 or older, and it does not recommend for or against HPV testing. However, neither the US Preventive Services Task Force nor the American Cancer Society has updated its guidelines in 8 years.

Rationale. Women who undergo HPV-plus-Pap testing and who test negative on both are at very low risk of developing CIN2 or CIN3 during the next 4 to 6 years. The risk is much lower than that for women who have a sole negative Pap test result.^39,40 Because of this extremely high negative predictive value, women age 30 and older who had negative results on both Pap and HPV testing should be screened no more often than every 3 years.

We believe that the HPV-plus-Pap testing strategy recommended by the 2009 ACOG guidelines for women age 30 and older is the most effective screening approach. This strategy takes advantage of the high sensitivity and high negative predictive value of HPV testing, as well as the high specificity of Pap testing. It achieves almost 100% clinical sensitivity in detecting cervical dysplasia.⁴⁶

 

 

When to stop screening

The 2009 ACOG guidelines for the first time call for stopping cervical cancer screening in women 65 to 70 years of age who have had three negative Pap tests in a row and no abnormal tests in the previous 10 years.¹ The American Cancer Society recommends stopping screening at age 70,⁶⁵ while the US Preventive Services Task Force recommends stopping at age 65.⁵⁵

Rationale. Cervical cancer develops slowly, and risk factors tend to decline with age, Also, postmenopausal mucosal atrophy may predispose to false-positive Pap results, which can lead to additional procedures and unnecessary patient anxiety.⁶⁶

However, it is probably reasonable to continue screening in women age 70 and older who are sexually active with multiple partners and who have a history of abnormal Pap test results.¹

Women who have had a hysterectomy

According to the latest American Cancer Society, ACOG, and US Preventive Services Task Force guidelines, cervical cancer screening should be discontinued after total hysterectomy for benign indications in women who have no history of high-grade cervical intraepithelial neoplasia, ie, CIN2 or worse.¹

Rationale. If the patient has no cervix, continued vaginal cytology screening is not indicated, since the incidence of primary vaginal cancer is one to two cases per 100,000 women per year, much lower than that of cervical cancer.⁶⁵

However, before discontinuing screening, clinicians should verify that any Pap tests the patient had before the hysterectomy were all read as normal, that the hysterectomy specimen was normal, and that the cervix was completely removed during hysterectomy.

Be ready to explain the recommendations

It is very important for providers to understand the evidence supporting the latest guidelines, as many patients may not realize the significant technological improvements and improved understanding of the role of HPV in cervical cancer genesis that have resulted in the deferred onset of screening and the longer intervals between screenings. This knowledge gap for patients can result in anxiety when told they no longer need an annual Pap test or can start later, if the issue is not properly and thoroughly explained by a confident provider.

A FUTURE STRATEGY: HPV AS THE SOLE PRIMARY SCREENING TEST?

Since HPV testing is much more sensitive than Pap testing for detecting cervical lesions of grade CIN2 or higher, why not use HPV testing as the primary test and then do Pap testing (which is more specific) only if the HPV test is positive?

Several major randomized clinical trials evaluated whether HPV testing could be used as the primary test. Table 2 summarizes the key conclusions from several of these trials.^42,67–72

Mayrand et al⁴⁶ conducted the first large randomized trial in which HPV testing was compared directly as a stand-alone test with the Pap test in a North American population with access to quality care. Results were published in 2007. In Canada, a total of 10,154 women ages 30 to 69 years in Montreal and St. John’s were randomly assigned to undergo either conventional Pap testing or HPV testing. The sensitivity of HPV testing for CIN2 or CIN3 was 94.6%, whereas the sensitivity of Pap testing was only 55.4%. The specificity was 94.1% for HPV testing and 96.8% for Pap testing. In addition, HPV screening followed by Pap triage resulted in fewer referrals for colposcopy than did either test alone (1.1% vs 2.9% with Pap testing alone or 6.1% with HPV testing alone). In other words, HPV testing was almost 40% more sensitive and only 2.7% less specific than Pap testing in detecting cervical cancer precursors.

However, more controlled trials are needed to validate such a strategy. Furthermore, it remains unclear if a change from Pap testing to a primary HPV testing screening strategy will further reduce the mortality rate of cervical cancer, since the burden of cervical cancer worldwide lies in less-screened populations in low-resource settings.

Dillner et al,⁴⁸ in a 2008 European study, further demonstrated that HPV testing offers better long-term (6-year) predictive value for CIN3 or worse lesions than cytology does. These findings suggest that HPV testing, with its higher sensitivity and negative predictive value and its molecular focus on cervical carcinogenesis, may safely permit longer screening intervals in a low-risk population.

Sankaranarayanan et al⁷² performed a randomized trial in rural India in which 131,746 women age 30 to 59 years were randomly assigned to four groups: screening by HPV testing, screening by Pap testing, screening by visual inspection with acetic acid, and counseling only (the control group). At 8 years of follow-up, the numbers of cases of cervical cancer and of cervical cancer deaths were as follows:

• With HPV testing: 127 cases, 34 deaths
• With Pap testing: 152 cases, 54 deaths
• With visual inspection: 157 cases, 56 deaths
• With counseling only: 118 cases, 64 deaths.

The authors concluded that in a low-resource setting, a single round of HPV testing was associated with a significant reduction in the number of deaths from cervical cancer. Not only did the HPV testing group have a lower incidence of cancer-related deaths, there were no cancer deaths among the women in this group who tested negative for HPV. This is the first randomized trial to suggest that using HPV testing as the sole primary cervical cancer screening test may have a benefit in terms of the mortality rate.

At present, to the best of our knowledge, there are no US data validating the role of HPV testing as a stand-alone screening test for cervical cancer.

 

HPV VACCINATION DOES NOT MEAN THE END OF SCREENING

The development of an effective HPV vaccine and FDA approval of the first quadrivalent (active against HPV 6, 11, 16, and 18) recombinant vaccine (Gardasil) in 2006 has opened a new era of cervical cancer prevention.^73,74 At present, the Advisory Committee on Immunization Practices⁷⁵ recommends vaccination for females 9 to 26 years old.

However, HPV vaccination will not make screening obsolete, since not all women will be vaccinated, and those who have already contracted one of these high-risk HPV types will not benefit.^76,77 In addition, the current HPV vaccine does not protect against infection with other oncogenic HPV types. The experts estimate that the initial impact of the HPV vaccine on cervical cancer will not likely be apparent until at least 20 to 30 years after a nationwide vaccination program is implemented.^78,79 Therefore, the HPV vaccine certainly does not portend the end of screening. Vaccination combined with continued screening will provide added benefit for cervical cancer prevention.⁸⁰

The last decade has been an exciting period in the field of cervical cancer screening and prevention, with advances in technology, newly acquired knowledge, and the development of the HPV vaccine. As a result, our clinical practice has become a work in progress, continuing to evolve as we continue to discover more information. The possibility of eradicating cervical cancer has never been greater. The implementation of the most sensitive and effective screening strategy and of a worldwide HPV vaccination program will help us to eventually eradicate cervical cancer and make it a disease of the past.⁸¹

Cervical cancer screening and prevention have evolved rapidly in the last decade, especially in the 5 years since the introduction of the first cancer prevention vaccine, human papillomavirus (HPV) recombinant vaccine.¹

Providers need to understand the rationale for the recommendations so that they can explain them to patients. In particular, patients may wonder why we now begin screening for cervical cancer later than we used to, and why some women do not need to be screened as often. Both of these changes result from our enhanced understanding of the role of HPV in cervical cancer genesis.

In this article we will briefly review:

• The current understanding of the natural history of cervical cancer
• Advantages and disadvantages of cervical cytology, ie, the Papanicolaou (Pap) test
• The role of HPV testing in cervical cancer screening
• The latest screening guidelines (the new standard of care)
• A possible future screening strategy
• The impact of HPV vaccination on screening.

500,000 NEW CASES EVERY YEAR

The incidence of cervical cancer and its mortality rate have decreased more than 50% in the United States over the past 3 decades, largely as a result of screening with the Pap test.² In 2010, there were an estimated 12,200 new cases of invasive cervical cancer in the United States and 4,210 deaths from it,³ which are lower than the historical rates.

However, because most developing countries lack effective screening programs, cervical cancer remains the second-leading cause of death from cancer in women worldwide. According to a recent estimate, there are almost 500,000 new cases and 240,000 deaths from this disease worldwide every year.⁴ If effective global screening programs could be set up, they would markedly reduce the incidence of cervical cancer and deaths from it.⁵

HPV IS NECESSARY BUT NOT SUFFICIENT FOR CERVICAL CANCER TO DEVELOP

For cervical cancer to develop, the essential first step is infection of the cervical epithelium with one of the oncogenic (high-risk) types of HPV (see below).^6–10 Walboomers et al⁹ tested cervical tissue samples taken from 932 women with cervical cancer and detected HPV DNA in 930 (99.8%) of them.

Fortunately, most HPV-infected women do not develop cervical cancer, as most young women clear the infection in an average of 8 to 24 months.^11,12 However, if the infection persists, and if it is one of the high-risk types of HPV, precursor lesions can develop that can progress to cervical cancer.¹³ The evidence conclusively supports the association between oncogenic HPV infection and the subsequent development of virtually all cases of cervical cancer.^6–10

Known risk factors for HPV persistence and the subsequent development of high-grade lesions are cigarette smoking and a compromised immune system.^14,15

Terminology: Results of Pap smears

• Normal
• Atypical squamous cells of undetermined significance (ASC-US)
• Low-grade squamous intraepithelial lesions (LSIL)
• High-grade squamous intraepithelial lesions (HSIL)
• Cancer.

Terminology: Results of cervical biopsy

• Normal
• Cervical intraepithelial neoplasia grade 1 (CIN1)
• CIN2 (previously called moderate dysplasia)
• CIN3 (previously called severe dysplasia)
• Carcinoma in situ
• Invasive cervical cancer.

Lesions that are CIN2 or higher are considered high-grade.¹³

The 18 high-risk HPV types

More than 40 types of HPV infect the genital tract¹⁶; 18 of these (types 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, and 82) are classified as high-risk because of their causative association with cervical cancer (ie, their oncogenic potential).¹⁷

How HPV causes cervical cancer

Basic science research has provided insight into how high-risk HPV causes cervical cancer (Figure 1).

In laboratory cultures, normal human cells die out after a few generations. However, if human epithelial cells are infected by one of the high-risk types of HPV, they can go on dividing indefinitely.^18,19

Two HPV proteins, E6 and E7, induce this cell “immortalization.”^20,21 E6 from high-risk HPV binds to the human tumor-suppressor protein p53 and rapidly degrades it in a proteolytic process. The p53 protein normally suppresses cell proliferation by arresting growth in the G1 phase of the cell cycle. Therefore, with less p53, the cell cannot suppress uncontrolled cell growth.^22–24

Similarly, E7 from high-risk HPV forms a complex with another human tumor suppressor, the retinoblastoma protein (pRB), and disrupts its binding to a transcriptional factor, E2F-1. The freed E2F-1 then stimulates DNA synthesis and uncontrolled cell growth.²⁵

Furthermore, HPV-16 E6 and E7 proteins can collectively cause cellular genetic instability.²⁶

The carcinogenic mechanism of high-risk HPV is complex. The host immune system and natural tumor suppression play important roles. However, the natural history of cervical intraepithelial neoplasia is not well understood. For example, it remains unclear if low-grade lesions such as CIN1 are necessary precursors to high-grade lesions and invasive cancer.^6,7,10

 

THE PAP TEST: SPECIFIC BUT NOT VERY SENSITIVE, AND PRONE TO ERROR

The principal advantage of cervical cytologic testing (ie, the Pap test) in detecting cervical dysplasia is its overall high specificity. Many studies have found that the specificity of conventional Pap testing can reach approximately 98%.²⁷

However, the conventional Pap test has drawbacks. Contaminants such as blood, discharge, and lubricant can make it difficult to interpret, and artifact can occur with air-drying of the Pap smear as it is transferred to the cell slide (“air-drying artifact”).

Liquid-based cytologic study has replaced the older method

To overcome these disadvantages, a liquid-based method of cervical cytologic study, ThinPrep (Hologic, Bedford, MA), was introduced in the mid-1990s. In this method, cell samples are first transferred to a liquid solution for mechanical separation from contaminants, and a representative sample of cells is then placed on a slide for review.

The liquid-based method filters out most contaminating blood, inflammatory cells, and debris. It also eliminates the air-drying artifact in the conventional Pap collection technique and improves specimen adequacy. Cytotechnologists find liquid-based specimens easier to read because the cells are more evenly distributed on a clearer background. Another advantage is that we can routinely test for HPV in the available residual specimen if the cytologic interpretation is abnormal.

The main disadvantages of the liquid-based method are that its specificity is lower than that of conventional Pap smears (around 78%) and that it costs more.²⁸ Nevertheless, the liquid-based technique has become the main method of cervical cytology, used by nearly 90% of gynecologists in the United States since 2003.¹

Cytology is still prone to false-negative results

Despite the success of both conventional Pap testing and liquid-based Pap testing, cervical cytology is inherently prone to sample-quality variation, subjective interpretation error, and false-negative results. False-negative results can be due to failure to transfer dysplastic cells to the slide or failure of the cytologist to recognize abnormal cells. In 30% of new cases of cervical cancer, the patient had recently had a Pap test that was interpreted as negative.^1,29

Errors in interpretation are exacerbated by inconsistency among cytopathologists. In one study,^6,30 when a group of quality-control pathologists reviewed nearly 5,000 cytology specimens, they came to the same conclusion that the original reviewers did more than 50% of the time only for negative and LSIL readings. Of the specimens initially reported as ASC-US, almost 40% were reclassified as negative on further review. Of those originally interpreted as HSIL, more than 50% were reclassified as LSIL, as ASC-US, or as negative.

Furthermore, many studies found that the sensitivity of conventional Pap testing was only around 50%.²⁷ The new liquid-based Pap test uses computer imaging, which has improved the rate of detection of cervical dysplasia but may still miss 15% to 35% of cases of HSIL (severe dysplasia) or cancer.³¹ Failure to detect cervical dysplasia or cancer on Pap smear has led to a number of lawsuits.³²

Clearly, with its relatively low sensitivity, cervical cytology is no longer good enough to use as a sole screening test in all situations. However, its high specificity is an advantage when it is combined with HPV testing in screening.

HPV TESTING AND PAP TESTING COMPLEMENT EACH OTHER

From 17% to 36% of HPV-infected women develop a cytologic abnormality within 5 years, compared with 4% to 15% of women who are HPV-negative.^33,34

The usefulness of testing for HPV in women who have had an abnormal Pap test has been well demonstrated in multiple studies.^35–38

The landmark Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS)³⁹ found that 82.9% of women with LSIL were HPV-positive. The investigators concluded that HPV testing has little utility in women with LSIL, as the test would likely be positive and thus would not change the decision to perform colposcopy.

However, in women with ASC-US, the sensitivity of HPV testing for predicting CIN3 or cancer was 96.3% and the negative predictive value was 99.5%. In contrast, the sensitivity of a single repeat Pap test was only 44.1%. This large randomized trial conclusively validates the important role of HPV testing in triaging women with ASC-US.

More recently, a meta-analysis of 20 studies of HPV testing in women with ASC-US found that it had a sensitivity of 92.5% and a specificity of 62.5% for detecting CIN2 or worse lesions, and a sensitivity of 95.6% and a specificity of 59.2% for detecting CIN3 or worse lesions.⁴⁰

Furthermore, HPV testing in primary cervical cancer screening is strongly supported by large cross-sectional studies^41–45 and randomized clinical trials.^46,47 These studies have conclusively shown that HPV testing is significantly more sensitive than Pap testing for detecting cervical intraepithelial neoplasia, and that, when combined with Pap testing, it can achieve nearly 100% clinical sensitivity and nearly 93% specificity in women age 30 or older. Women who have negative results on both the HPV test and the Pap test can be reassured that their risk of undetected CIN2, CIN3, or cervical cancer is extremely low, since HPV testing has a negative predictive value close to 100%.⁴⁶

In large multinational European studies involving more than 24,000 women, the risk of CIN3 or cancer after 6 years of follow-up was only 0.28% in women who had negative results on both HPV and Pap testing at baseline. This rate was basically the same as in women who tested negative for HPV alone (0.27%). However, it was significantly lower than that of all women who had negative Pap test results (0.97%). The combination of HPV testing and Pap testing at 6-year intervals offered better protection than Pap testing alone at 3-year intervals.⁴⁸

 

NEW STANDARD OF CARE: THE LATEST SCREENING GUIDELINES

Until the mid-1990s, the strategy for cervical cancer screening had remained largely unchanged for many years. Since then, several advances have prompted changes in the standard of care.

1996—The US Food and Drug Administration (FDA) approved liquid-based Thin-Prep for cervical cancer screening, which improved specimen adequacy and reduced ambiguous interpretations compared with the original slide-based method of collection.⁴⁹

2001—The Bethesda terminology for reporting cervical cytology results was updated. First proposed in 1988 to replace the original Papanicolaou system and revised in 1991, this standardized terminology enabled better clinical decision-making.⁵⁰

2001—The FDA approved HPV testing for women with ASC-US. This provided a better triage strategy for deciding which women need colposcopy to exclude true intraepithelial lesions. Following the FDA approval, the clinical effectiveness of HPV testing in women with ASC-US was validated by a large randomized clinical trial—the ALTS.⁵¹

2003—The FDA approved HPV testing in conjunction with Pap testing for women age 30 or older in routine primary screening.⁵²

Guidelines available

Based on these new developments in technology and reporting terminology, and the incorporation of HPV testing, several organizations issued guidelines.

The American Society for Colposcopy and Cervical Pathology published a consensus guideline on management of abnormal cervical cytology in 2001 and revised it in 2006.⁵³

The American Cancer Society issued its guideline for cervical cancer screening in 2002.⁵⁴

The US Preventive Services Task Force published its screening guidelines in 2003.⁵⁵

The American College of Obstetricians and Gynecologists (ACOG) also made new recommendations in 2003 and updated them in December 2009.¹

The following discussion highlights the consensus guidelines and the differences in the recommendations from these organizations (Table 1).⁵⁶

Start screening at age 21

Cervical cancer screening should begin at age 21 regardless of the age of onset of vaginal intercourse, according to the 2009 ACOG guidelines.¹ This represents a change from previous recommendations from ACOG, the American Cancer Society, and the US Preventive Services Task Force, which were to start screening within 3 years of the onset of vaginal intercourse.

Rationale. This latest recommendation is based on the high rates of clearance of HPV infection and of spontaneous dysplasia regression and the low incidence of cervical cancer in younger women.^57,58 HPV infections are common in young women who have had vaginal intercourse. However, most such HPV infections are cleared by the immune system within 1 to 2 years without causing cervical dysplasia.^11,12 Invasive cervical cancer in women younger than 21 years is very rare. The annual incidence is only one to two cases per 1 million women ages 15 to 19.^2,55

Another reason for not screening before age 21 is that a positive test result may lead to unnecessary anxiety and potentially harmful evaluations and procedures.

Screening intervals extended

The 2009 ACOG guidelines lengthen the cervical cancer screening interval to every 2 years in women under age 30.¹ (The 2003 ACOG guidelines said to screen every year.)

For women age 30 and older, the 2009 ACOG guidelines recommend extending the interval to every 3 years when combined Pap and HPV testing are negative (changed from every 2 to 3 years).¹

Rationale. Studies have shown little advantage in screening every year in women under the age of 30, with no higher risk of cervical cancer in women screened at a 2- to 3-year interval.^59–62 The absolute risk of cervical cancer in a well-screened population is very low.⁶³ Moreover, the absolute number of cervical cancer cases in women age 30 to 64 years screened at 3-year intervals is only four per 100,000 women.⁶⁴

HPV-plus-Pap testing for women over 30

Based on convincing evidence of the high sensitivity and the high negative predictive value of HPV testing, since 2003 ACOG had recommended HPV-plus-Pap testing in women over age 30. Its 2009 guidelines upgraded this recommendation to level A, ie, the highest grade, based on good and consistent scientific evidence.¹ (Previously the recommendation was level B.)

The American Cancer Society also recommends combined HPV and Pap testing as the optimal screening approach in women age 30 or older, with the subsequent screening interval 3 years if both tests are negative. It also endorses Pap testing alone every 2 to 3 years as an alternative screening strategy in this age group.

The US Preventive Services Task Force recommends Pap testing every 3 years in women age 30 or older, and it does not recommend for or against HPV testing. However, neither the US Preventive Services Task Force nor the American Cancer Society has updated its guidelines in 8 years.

Rationale. Women who undergo HPV-plus-Pap testing and who test negative on both are at very low risk of developing CIN2 or CIN3 during the next 4 to 6 years. The risk is much lower than that for women who have a sole negative Pap test result.^39,40 Because of this extremely high negative predictive value, women age 30 and older who had negative results on both Pap and HPV testing should be screened no more often than every 3 years.

We believe that the HPV-plus-Pap testing strategy recommended by the 2009 ACOG guidelines for women age 30 and older is the most effective screening approach. This strategy takes advantage of the high sensitivity and high negative predictive value of HPV testing, as well as the high specificity of Pap testing. It achieves almost 100% clinical sensitivity in detecting cervical dysplasia.⁴⁶

 

 

When to stop screening

The 2009 ACOG guidelines for the first time call for stopping cervical cancer screening in women 65 to 70 years of age who have had three negative Pap tests in a row and no abnormal tests in the previous 10 years.¹ The American Cancer Society recommends stopping screening at age 70,⁶⁵ while the US Preventive Services Task Force recommends stopping at age 65.⁵⁵

Rationale. Cervical cancer develops slowly, and risk factors tend to decline with age, Also, postmenopausal mucosal atrophy may predispose to false-positive Pap results, which can lead to additional procedures and unnecessary patient anxiety.⁶⁶

However, it is probably reasonable to continue screening in women age 70 and older who are sexually active with multiple partners and who have a history of abnormal Pap test results.¹

Women who have had a hysterectomy

According to the latest American Cancer Society, ACOG, and US Preventive Services Task Force guidelines, cervical cancer screening should be discontinued after total hysterectomy for benign indications in women who have no history of high-grade cervical intraepithelial neoplasia, ie, CIN2 or worse.¹

Rationale. If the patient has no cervix, continued vaginal cytology screening is not indicated, since the incidence of primary vaginal cancer is one to two cases per 100,000 women per year, much lower than that of cervical cancer.⁶⁵

However, before discontinuing screening, clinicians should verify that any Pap tests the patient had before the hysterectomy were all read as normal, that the hysterectomy specimen was normal, and that the cervix was completely removed during hysterectomy.

Be ready to explain the recommendations

It is very important for providers to understand the evidence supporting the latest guidelines, as many patients may not realize the significant technological improvements and improved understanding of the role of HPV in cervical cancer genesis that have resulted in the deferred onset of screening and the longer intervals between screenings. This knowledge gap for patients can result in anxiety when told they no longer need an annual Pap test or can start later, if the issue is not properly and thoroughly explained by a confident provider.

A FUTURE STRATEGY: HPV AS THE SOLE PRIMARY SCREENING TEST?

Since HPV testing is much more sensitive than Pap testing for detecting cervical lesions of grade CIN2 or higher, why not use HPV testing as the primary test and then do Pap testing (which is more specific) only if the HPV test is positive?

Several major randomized clinical trials evaluated whether HPV testing could be used as the primary test. Table 2 summarizes the key conclusions from several of these trials.^42,67–72

Mayrand et al⁴⁶ conducted the first large randomized trial in which HPV testing was compared directly as a stand-alone test with the Pap test in a North American population with access to quality care. Results were published in 2007. In Canada, a total of 10,154 women ages 30 to 69 years in Montreal and St. John’s were randomly assigned to undergo either conventional Pap testing or HPV testing. The sensitivity of HPV testing for CIN2 or CIN3 was 94.6%, whereas the sensitivity of Pap testing was only 55.4%. The specificity was 94.1% for HPV testing and 96.8% for Pap testing. In addition, HPV screening followed by Pap triage resulted in fewer referrals for colposcopy than did either test alone (1.1% vs 2.9% with Pap testing alone or 6.1% with HPV testing alone). In other words, HPV testing was almost 40% more sensitive and only 2.7% less specific than Pap testing in detecting cervical cancer precursors.

However, more controlled trials are needed to validate such a strategy. Furthermore, it remains unclear if a change from Pap testing to a primary HPV testing screening strategy will further reduce the mortality rate of cervical cancer, since the burden of cervical cancer worldwide lies in less-screened populations in low-resource settings.

Dillner et al,⁴⁸ in a 2008 European study, further demonstrated that HPV testing offers better long-term (6-year) predictive value for CIN3 or worse lesions than cytology does. These findings suggest that HPV testing, with its higher sensitivity and negative predictive value and its molecular focus on cervical carcinogenesis, may safely permit longer screening intervals in a low-risk population.

Sankaranarayanan et al⁷² performed a randomized trial in rural India in which 131,746 women age 30 to 59 years were randomly assigned to four groups: screening by HPV testing, screening by Pap testing, screening by visual inspection with acetic acid, and counseling only (the control group). At 8 years of follow-up, the numbers of cases of cervical cancer and of cervical cancer deaths were as follows:

• With HPV testing: 127 cases, 34 deaths
• With Pap testing: 152 cases, 54 deaths
• With visual inspection: 157 cases, 56 deaths
• With counseling only: 118 cases, 64 deaths.

The authors concluded that in a low-resource setting, a single round of HPV testing was associated with a significant reduction in the number of deaths from cervical cancer. Not only did the HPV testing group have a lower incidence of cancer-related deaths, there were no cancer deaths among the women in this group who tested negative for HPV. This is the first randomized trial to suggest that using HPV testing as the sole primary cervical cancer screening test may have a benefit in terms of the mortality rate.

At present, to the best of our knowledge, there are no US data validating the role of HPV testing as a stand-alone screening test for cervical cancer.

 

HPV VACCINATION DOES NOT MEAN THE END OF SCREENING

The development of an effective HPV vaccine and FDA approval of the first quadrivalent (active against HPV 6, 11, 16, and 18) recombinant vaccine (Gardasil) in 2006 has opened a new era of cervical cancer prevention.^73,74 At present, the Advisory Committee on Immunization Practices⁷⁵ recommends vaccination for females 9 to 26 years old.

However, HPV vaccination will not make screening obsolete, since not all women will be vaccinated, and those who have already contracted one of these high-risk HPV types will not benefit.^76,77 In addition, the current HPV vaccine does not protect against infection with other oncogenic HPV types. The experts estimate that the initial impact of the HPV vaccine on cervical cancer will not likely be apparent until at least 20 to 30 years after a nationwide vaccination program is implemented.^78,79 Therefore, the HPV vaccine certainly does not portend the end of screening. Vaccination combined with continued screening will provide added benefit for cervical cancer prevention.⁸⁰

The last decade has been an exciting period in the field of cervical cancer screening and prevention, with advances in technology, newly acquired knowledge, and the development of the HPV vaccine. As a result, our clinical practice has become a work in progress, continuing to evolve as we continue to discover more information. The possibility of eradicating cervical cancer has never been greater. The implementation of the most sensitive and effective screening strategy and of a worldwide HPV vaccination program will help us to eventually eradicate cervical cancer and make it a disease of the past.⁸¹

A 22-year-old man was brought to the emergency room after a motor vehicle accident. He was in a deep coma, with a Glasgow coma score of 4 out of 15 (3 being the worst score) and a core body temperature of 36°C (96.8°F). The next day, clinical evidence of brain death was noted, and his core body temperature dropped as low as 29.6°C (85.3°F). At that time, his electrocardiogram revealed sinus bradycardia, with a rate of 48 beats per minute, PR interval 0.24 second, QRS interval 0.16 second, corrected QT duration 0.5 second, and classic high-amplitude Osborn waves (J waves) that were evident in all leads. Figures 1, 2, and 3 show the effect of various degrees of hypothermia on the electrocardiogram.

The Osborn wave¹ (J wave) is the result of a transient, outward, potassium-mediated current in the ventricular epicardium but not the endocardium, corresponding to a notch in the action potential. This gives rise to a transmural voltage gradient during early repolarization, which appears as the J wave on electrocardiography. It is more pronounced in hypothermia, disappears after normalization of the body temperature, and is usually evident in the inferolateral leads.

Although Osborn waves are a marker of hypothermia, they also occur in nonhypothermic conditions. Brainstem death is a precursor of the J wave, and this is explained by impaired thermoregulatory ability resulting from hypothalamic dysfunction and subsequent hypothermia.

The three electrocardiograms presented here illustrate several points:

• Classic findings in hypothermia include J waves, sinus bradycardia, prolongation of the PR interval, widening of the QRS complex, and prolongation of the QT interval.
• The lower the core body temperature, the higher the amplitude of the J wave.
• The J wave in brain death (unlike hypothermic causes of the J wave) is not associated with the characteristic signs of shivering in the surface electrocardiogram.
• As hypothermia becomes more profound, the J wave becomes evident in all leads, not only the inferolateral leads.

A 22-year-old man was brought to the emergency room after a motor vehicle accident. He was in a deep coma, with a Glasgow coma score of 4 out of 15 (3 being the worst score) and a core body temperature of 36°C (96.8°F). The next day, clinical evidence of brain death was noted, and his core body temperature dropped as low as 29.6°C (85.3°F). At that time, his electrocardiogram revealed sinus bradycardia, with a rate of 48 beats per minute, PR interval 0.24 second, QRS interval 0.16 second, corrected QT duration 0.5 second, and classic high-amplitude Osborn waves (J waves) that were evident in all leads. Figures 1, 2, and 3 show the effect of various degrees of hypothermia on the electrocardiogram.

The Osborn wave¹ (J wave) is the result of a transient, outward, potassium-mediated current in the ventricular epicardium but not the endocardium, corresponding to a notch in the action potential. This gives rise to a transmural voltage gradient during early repolarization, which appears as the J wave on electrocardiography. It is more pronounced in hypothermia, disappears after normalization of the body temperature, and is usually evident in the inferolateral leads.

Although Osborn waves are a marker of hypothermia, they also occur in nonhypothermic conditions. Brainstem death is a precursor of the J wave, and this is explained by impaired thermoregulatory ability resulting from hypothalamic dysfunction and subsequent hypothermia.

The three electrocardiograms presented here illustrate several points:

• Classic findings in hypothermia include J waves, sinus bradycardia, prolongation of the PR interval, widening of the QRS complex, and prolongation of the QT interval.
• The lower the core body temperature, the higher the amplitude of the J wave.
• The J wave in brain death (unlike hypothermic causes of the J wave) is not associated with the characteristic signs of shivering in the surface electrocardiogram.
• As hypothermia becomes more profound, the J wave becomes evident in all leads, not only the inferolateral leads.

A 22-year-old man was brought to the emergency room after a motor vehicle accident. He was in a deep coma, with a Glasgow coma score of 4 out of 15 (3 being the worst score) and a core body temperature of 36°C (96.8°F). The next day, clinical evidence of brain death was noted, and his core body temperature dropped as low as 29.6°C (85.3°F). At that time, his electrocardiogram revealed sinus bradycardia, with a rate of 48 beats per minute, PR interval 0.24 second, QRS interval 0.16 second, corrected QT duration 0.5 second, and classic high-amplitude Osborn waves (J waves) that were evident in all leads. Figures 1, 2, and 3 show the effect of various degrees of hypothermia on the electrocardiogram.

The Osborn wave¹ (J wave) is the result of a transient, outward, potassium-mediated current in the ventricular epicardium but not the endocardium, corresponding to a notch in the action potential. This gives rise to a transmural voltage gradient during early repolarization, which appears as the J wave on electrocardiography. It is more pronounced in hypothermia, disappears after normalization of the body temperature, and is usually evident in the inferolateral leads.

Although Osborn waves are a marker of hypothermia, they also occur in nonhypothermic conditions. Brainstem death is a precursor of the J wave, and this is explained by impaired thermoregulatory ability resulting from hypothalamic dysfunction and subsequent hypothermia.

The three electrocardiograms presented here illustrate several points:

• Classic findings in hypothermia include J waves, sinus bradycardia, prolongation of the PR interval, widening of the QRS complex, and prolongation of the QT interval.
• The lower the core body temperature, the higher the amplitude of the J wave.
• The J wave in brain death (unlike hypothermic causes of the J wave) is not associated with the characteristic signs of shivering in the surface electrocardiogram.
• As hypothermia becomes more profound, the J wave becomes evident in all leads, not only the inferolateral leads.

A 38-year-old woman presented with a pruriginous and erythematous lesion on her nose that appeared during periods of cold weather. She said she is completely asymptomatic during the summer months.

A physical examination revealed acrocyanotic lesions on the nose that were covered with scales (Figure 1). Laboratory testing showed increased cholesterol levels, a positive antinuclear antibody titer (1:160 or higher is positive), and a positive anti-Ro/SS-A antibody titer (1:80 or higher is positive). Tests for cryoglobulin, cold agglutinins, anti-double-stranded DNA antibody, anti-extractable nuclear antigens, C3 and C4 complement proteins, and anticardiolipin antibody were normal or negative.

Histologic examination revealed degeneration of the basal layer of the dermis, with periadnexal and perivascular inflammatory infiltrates (Figure 2). On immunofluorescence testing, linear deposits of immunoglobulin M were noted at the dermoepidermal junction.

Q: What is the most likely diagnosis?

• Lupus pernio
• Rosacea
• Seborrheic dermatitis
• Chilblain lupus erythematosus
• Lupus vulgaris

A: The diagnosis is chilblain lupus erythematosus.

The differential diagnosis of an erythematous lesion on the nose of a middle-aged woman also includes rosacea, lupus pernio, lupus vulgaris, and seborrheic dermatitis. Some of these lesions are exacerbated by cold. Usually, the diagnosis is based on clinical findings, but in some cases histologic features on biopsy study confirm the diagnosis.

Lesions of lupus pernio (sarcoidosis) remain unaltered with changes in temperature, and biopsy study usually shows granulomas without caseous necrosis with little inflammatory infiltrate at the periphery.

Rosacea usually gets worse with heat and with alcohol consumption, although it can be exacerbated by cold. Biopsy study shows a nonspecific perivascular and perifollicular lymphohistiocytic infiltrate accompanied occasionally by multinucleated cells.

Seborrheic dermatitis is a papulosquamous disorder characterized by greasy scaling over inflamed skin on the scalp, face, and trunk. Disease activity is increased in winter and spring, with remissions commonly occurring in summer. The histologic features of seborrheic dermatitis are nonspecific; in this case, the histologic features were compatible with chilblain lupus without changes of seborrheic dermatitis.

Lupus vulgaris is a chronic form of cutaneous tuberculosis characterized by redbrown papules with central atrophy. The nose and ears are usually affected. Histologically, granulomatous tubercles with epithelioid cells and caseation necrosis are usually found.

CHILBLAIN LUPUS ERYTHEMATOSUS

Pernio, or chilblain, is a localized inflammatory lesion of the skin resulting from an abnormal response to cold.¹ The cutaneous lesions of chilblain may be classified as idiopathic, autoimmune-related (as in systemic lupus erythematosus, subacute cutaneous lupus), and induced by drugs such as terbinafine (Lamisil)² or infliximab (Remicade).^,3

Chilblain lupus is a rare form of cutaneous lupus erythematosus and should not be confused with lupus pernio, which is a misleading name used for a type of cutaneous sarcoidosis.⁴

Chilblain lupus is characterized by reddish-purple plaques in acral areas (more often the hands and feet, but also the nose and ears) that are induced by exposure to cold—unlike other lesions of lupus erythematosus, which worsen with exposure to sunlight. The main difference from the cutaneous variety of sarcoidosis (lupus pernio) is the histopathologic appearance. In patients with chilblain lupus, epidermal atrophy, perivascular and periadnexal inflammatory infiltrates, and degeneration of the basal layer are found, whereas in lupus pernio (sarcoidosis), we observe granulomas without caseous necrosis, but with few inflammatory infiltrates on the periphery.

PROPOSED DIAGNOSTIC CRITERIA

Su et al⁵ have proposed diagnostic criteria for chilblain lupus. Their two major criteria are skin lesions in acral locations induced by exposure to cold or a drop in temperature, and evidence of lupus erythematosus in the skin lesions by histopathologic examination or immunofluorescence study. Both of these criteria must be met, plus one of three minor criteria: the coexistence of systemic lupus erythematosus or of skin lesions of discoid lupus erythematosus; response to lupus therapy; and negative results of testing for cryoglobulin and cold agglutinins.

CHILBLAIN LUPUS VS SYSTEMIC LUPUS

Chilblain lupus is an uncommon manifestation of systemic lupus erythematosus, and it is reported to occur in about 20% of patients with that condition.⁶ Often, the onset of chilblain lupus precedes the systemic disease. Patients with systemic lupus erythematosus and chilblain lupus do not usually present with renal disease, mucosal lesions, or central nervous system involvement. However, Raynaud phenomenon and photosensitivity have been reported to be more frequently associated with chilblain lupus.⁷

A disorder of peripheral circulation could be involved in the pathogenesis of chilblain lupus, and the association with Raynaud phenomenon, livedo reticularis, antiphospholipid syndrome, and changes in nailfold capillaries supports this hypothesis. Antinuclear antibody and anti-Ro/SS-A antibody are commonly detected in the serum of patients with chilblain lupus, and anti-Ro/SS-A antibody seems to be a major serologic marker of chilblain lupus in patients with systemic lupus erythematosus.⁷

TREATMENT

Protection from cold by physical measures is very important, as well as the use of topical or oral antibiotics if the lesions are infected. In severe cases unresponsive to topical corticosteroids, a calcium channel blocker is a good therapeutic option; antimalarials, commonly used in the treatment of lupus erythematosus, can also have a positive effect in patients with chilblain lupus.

CASE CONCLUDED

Our patient was advised to protect herself from the cold. Topical corticosteroids and oral hydroxychloroquine (200 mg/day) were prescribed, and they produced a good response. In severe cases, oral corticosteroids, etretinate (Tegison), mycophenolate (CellCept), or thalidomide (Thalomid) may be used.⁸

A 38-year-old woman presented with a pruriginous and erythematous lesion on her nose that appeared during periods of cold weather. She said she is completely asymptomatic during the summer months.

A physical examination revealed acrocyanotic lesions on the nose that were covered with scales (Figure 1). Laboratory testing showed increased cholesterol levels, a positive antinuclear antibody titer (1:160 or higher is positive), and a positive anti-Ro/SS-A antibody titer (1:80 or higher is positive). Tests for cryoglobulin, cold agglutinins, anti-double-stranded DNA antibody, anti-extractable nuclear antigens, C3 and C4 complement proteins, and anticardiolipin antibody were normal or negative.

Histologic examination revealed degeneration of the basal layer of the dermis, with periadnexal and perivascular inflammatory infiltrates (Figure 2). On immunofluorescence testing, linear deposits of immunoglobulin M were noted at the dermoepidermal junction.

Q: What is the most likely diagnosis?

• Lupus pernio
• Rosacea
• Seborrheic dermatitis
• Chilblain lupus erythematosus
• Lupus vulgaris

A: The diagnosis is chilblain lupus erythematosus.

The differential diagnosis of an erythematous lesion on the nose of a middle-aged woman also includes rosacea, lupus pernio, lupus vulgaris, and seborrheic dermatitis. Some of these lesions are exacerbated by cold. Usually, the diagnosis is based on clinical findings, but in some cases histologic features on biopsy study confirm the diagnosis.

Lesions of lupus pernio (sarcoidosis) remain unaltered with changes in temperature, and biopsy study usually shows granulomas without caseous necrosis with little inflammatory infiltrate at the periphery.

Rosacea usually gets worse with heat and with alcohol consumption, although it can be exacerbated by cold. Biopsy study shows a nonspecific perivascular and perifollicular lymphohistiocytic infiltrate accompanied occasionally by multinucleated cells.

Seborrheic dermatitis is a papulosquamous disorder characterized by greasy scaling over inflamed skin on the scalp, face, and trunk. Disease activity is increased in winter and spring, with remissions commonly occurring in summer. The histologic features of seborrheic dermatitis are nonspecific; in this case, the histologic features were compatible with chilblain lupus without changes of seborrheic dermatitis.

Lupus vulgaris is a chronic form of cutaneous tuberculosis characterized by redbrown papules with central atrophy. The nose and ears are usually affected. Histologically, granulomatous tubercles with epithelioid cells and caseation necrosis are usually found.

CHILBLAIN LUPUS ERYTHEMATOSUS

Pernio, or chilblain, is a localized inflammatory lesion of the skin resulting from an abnormal response to cold.¹ The cutaneous lesions of chilblain may be classified as idiopathic, autoimmune-related (as in systemic lupus erythematosus, subacute cutaneous lupus), and induced by drugs such as terbinafine (Lamisil)² or infliximab (Remicade).^,3

Chilblain lupus is a rare form of cutaneous lupus erythematosus and should not be confused with lupus pernio, which is a misleading name used for a type of cutaneous sarcoidosis.⁴

Chilblain lupus is characterized by reddish-purple plaques in acral areas (more often the hands and feet, but also the nose and ears) that are induced by exposure to cold—unlike other lesions of lupus erythematosus, which worsen with exposure to sunlight. The main difference from the cutaneous variety of sarcoidosis (lupus pernio) is the histopathologic appearance. In patients with chilblain lupus, epidermal atrophy, perivascular and periadnexal inflammatory infiltrates, and degeneration of the basal layer are found, whereas in lupus pernio (sarcoidosis), we observe granulomas without caseous necrosis, but with few inflammatory infiltrates on the periphery.

PROPOSED DIAGNOSTIC CRITERIA

Su et al⁵ have proposed diagnostic criteria for chilblain lupus. Their two major criteria are skin lesions in acral locations induced by exposure to cold or a drop in temperature, and evidence of lupus erythematosus in the skin lesions by histopathologic examination or immunofluorescence study. Both of these criteria must be met, plus one of three minor criteria: the coexistence of systemic lupus erythematosus or of skin lesions of discoid lupus erythematosus; response to lupus therapy; and negative results of testing for cryoglobulin and cold agglutinins.

CHILBLAIN LUPUS VS SYSTEMIC LUPUS

Chilblain lupus is an uncommon manifestation of systemic lupus erythematosus, and it is reported to occur in about 20% of patients with that condition.⁶ Often, the onset of chilblain lupus precedes the systemic disease. Patients with systemic lupus erythematosus and chilblain lupus do not usually present with renal disease, mucosal lesions, or central nervous system involvement. However, Raynaud phenomenon and photosensitivity have been reported to be more frequently associated with chilblain lupus.⁷

A disorder of peripheral circulation could be involved in the pathogenesis of chilblain lupus, and the association with Raynaud phenomenon, livedo reticularis, antiphospholipid syndrome, and changes in nailfold capillaries supports this hypothesis. Antinuclear antibody and anti-Ro/SS-A antibody are commonly detected in the serum of patients with chilblain lupus, and anti-Ro/SS-A antibody seems to be a major serologic marker of chilblain lupus in patients with systemic lupus erythematosus.⁷

TREATMENT

Protection from cold by physical measures is very important, as well as the use of topical or oral antibiotics if the lesions are infected. In severe cases unresponsive to topical corticosteroids, a calcium channel blocker is a good therapeutic option; antimalarials, commonly used in the treatment of lupus erythematosus, can also have a positive effect in patients with chilblain lupus.

CASE CONCLUDED

Our patient was advised to protect herself from the cold. Topical corticosteroids and oral hydroxychloroquine (200 mg/day) were prescribed, and they produced a good response. In severe cases, oral corticosteroids, etretinate (Tegison), mycophenolate (CellCept), or thalidomide (Thalomid) may be used.⁸

A 38-year-old woman presented with a pruriginous and erythematous lesion on her nose that appeared during periods of cold weather. She said she is completely asymptomatic during the summer months.

A physical examination revealed acrocyanotic lesions on the nose that were covered with scales (Figure 1). Laboratory testing showed increased cholesterol levels, a positive antinuclear antibody titer (1:160 or higher is positive), and a positive anti-Ro/SS-A antibody titer (1:80 or higher is positive). Tests for cryoglobulin, cold agglutinins, anti-double-stranded DNA antibody, anti-extractable nuclear antigens, C3 and C4 complement proteins, and anticardiolipin antibody were normal or negative.

Histologic examination revealed degeneration of the basal layer of the dermis, with periadnexal and perivascular inflammatory infiltrates (Figure 2). On immunofluorescence testing, linear deposits of immunoglobulin M were noted at the dermoepidermal junction.

Q: What is the most likely diagnosis?

• Lupus pernio
• Rosacea
• Seborrheic dermatitis
• Chilblain lupus erythematosus
• Lupus vulgaris

A: The diagnosis is chilblain lupus erythematosus.

The differential diagnosis of an erythematous lesion on the nose of a middle-aged woman also includes rosacea, lupus pernio, lupus vulgaris, and seborrheic dermatitis. Some of these lesions are exacerbated by cold. Usually, the diagnosis is based on clinical findings, but in some cases histologic features on biopsy study confirm the diagnosis.

Lesions of lupus pernio (sarcoidosis) remain unaltered with changes in temperature, and biopsy study usually shows granulomas without caseous necrosis with little inflammatory infiltrate at the periphery.

Rosacea usually gets worse with heat and with alcohol consumption, although it can be exacerbated by cold. Biopsy study shows a nonspecific perivascular and perifollicular lymphohistiocytic infiltrate accompanied occasionally by multinucleated cells.

Seborrheic dermatitis is a papulosquamous disorder characterized by greasy scaling over inflamed skin on the scalp, face, and trunk. Disease activity is increased in winter and spring, with remissions commonly occurring in summer. The histologic features of seborrheic dermatitis are nonspecific; in this case, the histologic features were compatible with chilblain lupus without changes of seborrheic dermatitis.

Lupus vulgaris is a chronic form of cutaneous tuberculosis characterized by redbrown papules with central atrophy. The nose and ears are usually affected. Histologically, granulomatous tubercles with epithelioid cells and caseation necrosis are usually found.

CHILBLAIN LUPUS ERYTHEMATOSUS

Pernio, or chilblain, is a localized inflammatory lesion of the skin resulting from an abnormal response to cold.¹ The cutaneous lesions of chilblain may be classified as idiopathic, autoimmune-related (as in systemic lupus erythematosus, subacute cutaneous lupus), and induced by drugs such as terbinafine (Lamisil)² or infliximab (Remicade).^,3

Chilblain lupus is a rare form of cutaneous lupus erythematosus and should not be confused with lupus pernio, which is a misleading name used for a type of cutaneous sarcoidosis.⁴

Chilblain lupus is characterized by reddish-purple plaques in acral areas (more often the hands and feet, but also the nose and ears) that are induced by exposure to cold—unlike other lesions of lupus erythematosus, which worsen with exposure to sunlight. The main difference from the cutaneous variety of sarcoidosis (lupus pernio) is the histopathologic appearance. In patients with chilblain lupus, epidermal atrophy, perivascular and periadnexal inflammatory infiltrates, and degeneration of the basal layer are found, whereas in lupus pernio (sarcoidosis), we observe granulomas without caseous necrosis, but with few inflammatory infiltrates on the periphery.

PROPOSED DIAGNOSTIC CRITERIA

Su et al⁵ have proposed diagnostic criteria for chilblain lupus. Their two major criteria are skin lesions in acral locations induced by exposure to cold or a drop in temperature, and evidence of lupus erythematosus in the skin lesions by histopathologic examination or immunofluorescence study. Both of these criteria must be met, plus one of three minor criteria: the coexistence of systemic lupus erythematosus or of skin lesions of discoid lupus erythematosus; response to lupus therapy; and negative results of testing for cryoglobulin and cold agglutinins.

CHILBLAIN LUPUS VS SYSTEMIC LUPUS

Chilblain lupus is an uncommon manifestation of systemic lupus erythematosus, and it is reported to occur in about 20% of patients with that condition.⁶ Often, the onset of chilblain lupus precedes the systemic disease. Patients with systemic lupus erythematosus and chilblain lupus do not usually present with renal disease, mucosal lesions, or central nervous system involvement. However, Raynaud phenomenon and photosensitivity have been reported to be more frequently associated with chilblain lupus.⁷

A disorder of peripheral circulation could be involved in the pathogenesis of chilblain lupus, and the association with Raynaud phenomenon, livedo reticularis, antiphospholipid syndrome, and changes in nailfold capillaries supports this hypothesis. Antinuclear antibody and anti-Ro/SS-A antibody are commonly detected in the serum of patients with chilblain lupus, and anti-Ro/SS-A antibody seems to be a major serologic marker of chilblain lupus in patients with systemic lupus erythematosus.⁷

TREATMENT

Protection from cold by physical measures is very important, as well as the use of topical or oral antibiotics if the lesions are infected. In severe cases unresponsive to topical corticosteroids, a calcium channel blocker is a good therapeutic option; antimalarials, commonly used in the treatment of lupus erythematosus, can also have a positive effect in patients with chilblain lupus.

CASE CONCLUDED

Our patient was advised to protect herself from the cold. Topical corticosteroids and oral hydroxychloroquine (200 mg/day) were prescribed, and they produced a good response. In severe cases, oral corticosteroids, etretinate (Tegison), mycophenolate (CellCept), or thalidomide (Thalomid) may be used.⁸

Every physician—general internist, subspecialist, or surgeon—has had to deal with complications of glucocorticoid therapy. Infections may be the most worrisome in terms of risk of death, as these drugs can both open the door to opportunistic organisms and delay the diagnosis by blunting the signs and symptoms of infection-associated inflammation. But the metabolic ravages of long-term steroid therapy can also plague patients and their physicians.

For many of those long-term effects, such as osteoporosis, cushingoid features, skin fragility, and cataracts, all we can do is hope that they don’t occur, since there is little we can do to screen for or prevent them. We have previously discussed steroid-associated osteoporosis in the Journal,¹ and strategies for preventing it have been proposed by specialty societies.² For other complications such as hypertension, weight gain, and glucose intolerance, we can offer common-sense protective suggestions, monitor for them, and intervene if they occur.

In this issue, Dr. M. Cecilia Lansang and Ms. Leighanne Kramer Hustak³ discuss the management of steroid-induced adrenal suppression and diabetes. They offer practical management suggestions but also point out that the evidence base for our treatment decisions is surprisingly limited.

Nearly all patients chronically receiving high-dose glucocorticoid therapy develop glucose intolerance, but knowing when that is happening is not always easy. In patients destined to develop type 2 diabetes, the laboratory or clinical signs of hyperglycemia appear only when the pancreas can no longer maintain the insulin production necessary to overcome peripheral insulin resistance. Steroid-induced diabetes is characterized by increased gluconeogenesis, insulin resistance, and excessive postprandial surges, so fasting glucose levels are not sensitive for this clinical syndrome.

The degree and duration of the chronic hyperinsulinemia and hyperglycemia dictates the risk of microvascular complications and thus will be linked to duration of steroid therapy (unless the steroid is unmasking preexisting mild diabetes). Although issues surrounding tight control of blood glucose levels in the acute setting remain unresolved, I believe that even short-term significant steroid-induced hyperglycemia should be prevented when reasonably possible, at the least keeping in mind the additive ill effects of hyperglycemia and steroid therapy on the risk of nuisance infections such as oral and vaginal candidiasis and urinary tract infections that, in the setting of high-dose steroid therapy, can rapidly turn nasty.

Every physician—general internist, subspecialist, or surgeon—has had to deal with complications of glucocorticoid therapy. Infections may be the most worrisome in terms of risk of death, as these drugs can both open the door to opportunistic organisms and delay the diagnosis by blunting the signs and symptoms of infection-associated inflammation. But the metabolic ravages of long-term steroid therapy can also plague patients and their physicians.

For many of those long-term effects, such as osteoporosis, cushingoid features, skin fragility, and cataracts, all we can do is hope that they don’t occur, since there is little we can do to screen for or prevent them. We have previously discussed steroid-associated osteoporosis in the Journal,¹ and strategies for preventing it have been proposed by specialty societies.² For other complications such as hypertension, weight gain, and glucose intolerance, we can offer common-sense protective suggestions, monitor for them, and intervene if they occur.

In this issue, Dr. M. Cecilia Lansang and Ms. Leighanne Kramer Hustak³ discuss the management of steroid-induced adrenal suppression and diabetes. They offer practical management suggestions but also point out that the evidence base for our treatment decisions is surprisingly limited.

Nearly all patients chronically receiving high-dose glucocorticoid therapy develop glucose intolerance, but knowing when that is happening is not always easy. In patients destined to develop type 2 diabetes, the laboratory or clinical signs of hyperglycemia appear only when the pancreas can no longer maintain the insulin production necessary to overcome peripheral insulin resistance. Steroid-induced diabetes is characterized by increased gluconeogenesis, insulin resistance, and excessive postprandial surges, so fasting glucose levels are not sensitive for this clinical syndrome.

The degree and duration of the chronic hyperinsulinemia and hyperglycemia dictates the risk of microvascular complications and thus will be linked to duration of steroid therapy (unless the steroid is unmasking preexisting mild diabetes). Although issues surrounding tight control of blood glucose levels in the acute setting remain unresolved, I believe that even short-term significant steroid-induced hyperglycemia should be prevented when reasonably possible, at the least keeping in mind the additive ill effects of hyperglycemia and steroid therapy on the risk of nuisance infections such as oral and vaginal candidiasis and urinary tract infections that, in the setting of high-dose steroid therapy, can rapidly turn nasty.

Every physician—general internist, subspecialist, or surgeon—has had to deal with complications of glucocorticoid therapy. Infections may be the most worrisome in terms of risk of death, as these drugs can both open the door to opportunistic organisms and delay the diagnosis by blunting the signs and symptoms of infection-associated inflammation. But the metabolic ravages of long-term steroid therapy can also plague patients and their physicians.

For many of those long-term effects, such as osteoporosis, cushingoid features, skin fragility, and cataracts, all we can do is hope that they don’t occur, since there is little we can do to screen for or prevent them. We have previously discussed steroid-associated osteoporosis in the Journal,¹ and strategies for preventing it have been proposed by specialty societies.² For other complications such as hypertension, weight gain, and glucose intolerance, we can offer common-sense protective suggestions, monitor for them, and intervene if they occur.

In this issue, Dr. M. Cecilia Lansang and Ms. Leighanne Kramer Hustak³ discuss the management of steroid-induced adrenal suppression and diabetes. They offer practical management suggestions but also point out that the evidence base for our treatment decisions is surprisingly limited.

Nearly all patients chronically receiving high-dose glucocorticoid therapy develop glucose intolerance, but knowing when that is happening is not always easy. In patients destined to develop type 2 diabetes, the laboratory or clinical signs of hyperglycemia appear only when the pancreas can no longer maintain the insulin production necessary to overcome peripheral insulin resistance. Steroid-induced diabetes is characterized by increased gluconeogenesis, insulin resistance, and excessive postprandial surges, so fasting glucose levels are not sensitive for this clinical syndrome.

The degree and duration of the chronic hyperinsulinemia and hyperglycemia dictates the risk of microvascular complications and thus will be linked to duration of steroid therapy (unless the steroid is unmasking preexisting mild diabetes). Although issues surrounding tight control of blood glucose levels in the acute setting remain unresolved, I believe that even short-term significant steroid-induced hyperglycemia should be prevented when reasonably possible, at the least keeping in mind the additive ill effects of hyperglycemia and steroid therapy on the risk of nuisance infections such as oral and vaginal candidiasis and urinary tract infections that, in the setting of high-dose steroid therapy, can rapidly turn nasty.

Glucocorticoids are commonly prescribed by primary care physicians and specialists alike for multiple medical problems, acute as well as chronic.

However, these useful drugs have adverse effects on multiple endocrine systems, effects that include diabetes (or worsening of hyperglycemia in those with known diabetes), Cushing syndrome, adrenal suppression, osteoporosis (reviewed in the Cleveland Clinic Journal of Medicine in August 2010),¹ and dyslipidemia. In addition, suppression of gonadotropins, growth hormone, and, acutely, thyrotropin can ensue.

The focus of this review is on the diabetogenic and adrenal suppressive effects of glucocorticoids and their management. We describe the rationale for choosing specific drugs to counter hyperglycemia, tests for determining adrenal suppression and systemic glucocorticoid absorption, and how and why to taper these drugs.

WIDELY USED DRUGS

Although glucocorticoids (often simply called steroids or corticosteroids, although not all steroids are corticosteroids, and not all corticosteroids are glucocorticoids) are the core treatment for adrenal insufficiency, in most cases they are prescribed for their anti-inflammatory effects. They act through multiple pathways at the cellular and molecular levels, suppressing the cascades that would otherwise result in inflammation and promoting pathways that produce anti-inflammatory proteins.²

In addition to formulations that are intended to have systemic effects, other, “local” formulations are made for specific conditions, such as intra-articular injections for arthritis, epidural injections for lumbar disk pain, eye drops for uveitis, nasal sprays for allergic rhinitis, inhalers for asthma, and topical ointments and creams for eczema. However, as we will discuss, even these preparations can have systemic effects.

GLUCOCORTICOID-INDUCED DIABETES IS COMMON

Glucocorticoids are the most common cause of drug-induced diabetes. Though the exact prevalence is not known, a few observations suggest that glucocorticoid-induced diabetes or hyperglycemia is common:

• In patients with rheumatoid arthritis, mean age 62 years, nearly 9% developed diabetes in the 2 years after starting glucocorticoid treatment, which was a higher rate than expected.³
• In nondiabetic patients with primary renal disease treated with prednisolone 0.75 mg/kg/day, 42% were found to have 2-hour post-lunch plasma glucose concentrations higher than 200 mg/dL but normal fasting glucose levels.⁴
• In a case-control study, the odds ratio of starting an oral hypoglycemic agent or insulin was 1.77 for patients receiving a hydrocortisone-equivalent dose of 1 to 39 mg/day, 3.02 for 40 to 79 mg/day, 5.82 for 80 to 119 mg/day, and 10.34 for 120 mg/day or more.⁵ (For a full discussion of glucocorticoid equivalents, see the section below on Cushing syndrome and adrenal suppression.)
• In patients with type 1 diabetes, prednisone 60 mg/day raised the blood glucose levels starting 6 hours after the prednisone dose.⁶
• Diabetic ketoacidosis and hyperosmolar nonketotic syndrome have been reported as a result of glucocorticoid treatment.^7–9

GLUCOCORTICOIDS CAUSE DIABETES MAINLY VIA INSULIN RESISTANCE

The mechanism by which glucocorticoids cause diabetes predominantly involves insulin resistance rather than decreased insulin production. In fact, in a study in healthy volunteers, ¹⁰ hydrocortisone infusion resulted in higher insulin production than saline infusion did. (In high doses, however, glucocorticoids have been shown to decrease insulin secretion.¹¹)

Normally, in response to insulin, the liver decreases its output of glucose. Glucocorticoids decrease the liver’s sensitivity to insulin, thereby increasing hepatic glucose output.¹² They also inhibit glucose uptake in muscle and fat, reducing insulin sensitivity as much as 60% in healthy volunteers. This seems primarily due to a postreceptor effect, ie, inhibition of glucose transport.^13–15

THE PEAK EFFECT OCCURS 4 TO 6 HOURS AFTER DOSING

To understand the optimal time for checking plasma glucose and to apply appropriate treatment, we should consider the pharmacokinetic profile of glucocorticoids.

Studied using the whole-blood lymphocyte proliferation technique, prednisone shows a peak effect at about 4 to 6 hours and a duration of action of 13 to 16 hours.¹⁶ This closely resembles what we see in terms of glucose excursion with this drug.¹⁷ Two studies of intravenous dexamethasone 10 mg showed that glucose levels rose within 4 hours of injection, but did not pursue this beyond that time frame.^18,19

 

PATIENTS WITHOUT A PREVIOUS DIAGNOSIS OF DIABETES

Be alert for new-onset diabetes

For most diseases treated with glucocorticoids, clinicians can estimate in advance how long the patient will need to take the drug. We can arbitrarily classify the projected exposure as either short-term (3 to 4 weeks or less, such as a 6-day course of methylprednisolone for allergic conditions) or long-term (such as in transplant recipients to prevent rejection or to treat graft-vs-host disease). Hyperglycemia is a potential concern with both short-term and long-term treatment. However, guidelines on checking blood sugar levels, as opposed to relying on symptoms alone, are available only for long-term glucocorticoid treatment.

Patients beginning treatment should be warned of typical diabetes symptoms such as thirst and increased urination and, should these occur, to seek medical attention to have their blood glucose level checked. It is also reasonable to have them return in a week for a random postprandial plasma glucose test in the mid-afternoon.

Why this timing? In most once-daily regimens, glucocorticoids are given in the morning to prevent adrenal suppression (discussed below). In our experience, glucose levels start to rise mid-morning and continue to increase until bedtime. Measuring glucose levels 1 to 2 hours after lunch allows for both the glucocorticoid action and the carbohydrate absorption from lunch to reach their peaks. If hyperglycemia is going to happen, it should be detectable by then. A glucose level of 200 mg/dL or higher should prompt the practitioner to pursue this further.

If glucocorticoid treatment is to continue beyond 3 to 4 weeks, the only population for which there are published guidelines on managing glucocorticoid-related diabetes is transplant recipients. International consensus guidelines, published in 2003, suggest checking the fasting plasma glucose level once a week for the first 4 weeks after transplantation, then at 3 months, at 6 months, and then once a year.²⁰

Though practical, this suggestion does not reflect the fact that glucocorticoids often do not affect fasting plasma glucose, especially if given once daily in the morning at doses of 30 mg or less of prednisone or its equivalent. These guidelines thus may not be applicable to other populations with glucocorticoid-induced diabetes.

The transplant guidelines do mention that an oral glucose tolerance test may be more sensitive, but this is often cumbersome to perform. We believe that checking random postprandial plasma glucose levels is helpful in this regard.

The American Diabetes Association cutoff for diagnosing diabetes when using a random (ie, nonfasting) plasma glucose level is 200 mg/dL or higher in a patient with classic symptoms of hyperglycemia such as polyuria and polydipsia (Table 1).²¹ In the absence of such symptoms, a hemoglobin A_1c, fasting plasma glucose, or oral glucose tolerance test may be used and the results confirmed with repeat testing.

If the patient was at risk of developing diabetes even before receiving a glucocorticoid (for example, if he or she is overweight, has a family history of diabetes, or had a previous hemoglobin A_1c of 5.7% or higher), then a fasting plasma glucose level of 126 mg/dL or higher or a hemoglobin A_1c of 6.5% or higher might suffice to diagnose diabetes. Results should be confirmed on a separate day in the absence of unequivocal hyperglycemia. Fasting hyperglycemia can also be seen in patients receiving higher once-daily glucocorticoid doses—in our experience, an equivalent of prednisone 40 mg once a day in the morning— or twice-daily dosing.

A hemoglobin A_1c checked less than 2 to 3 months after starting glucocorticoid treatment will not be sensitive in picking up glucocorticoid-induced diabetes if the patient did not have underlying diabetes.

Diet and exercise may not be practical

Though diet and exercise are important in managing diabetes, the condition for which the patient is receiving a glucocorticoid may prevent him or her from exercising, at least in the acute phase of the illness.

In addition, though the exact mechanism is not known, glucocorticoids increase hunger, and so decreasing food intake is not easy either. Nonetheless, patients should be familiarized with what carbohydrates are and should be advised to reduce their intake of them.

For suspected type 1 diabetes, start insulin

If type 1 diabetes is suspected, for example, in patients who are lean, younger than 30 years, or who had presented with diabetic ketoacidosis, then insulin should be started. In equivocal cases, insulin therapy can commence while testing is done for C-peptide, glutamic acid decarboxylase antibodies, islet cell antibodies, and insulinoma-associated protein antibodies.

For all other patients, keep in mind the characteristics of glucocorticoids (Table 2) that may affect the drug treatment of diabetes.

Starting oral antidiabetic drugs

Some patients may have contraindications to specific drugs. For example, metformin (Glucophage) is contraindicated if the serum creatinine level is elevated, an abnormality that renal transplant patients may continue to have.

If the patient has no such contraindications, we have found the following medications suitable in view of their efficacy, low risk of hypoglycemia, or lack of distressing side effects. They will often lower glucose levels enough to achieve capillary blood glucose or fingerstick goals (discussed below). None of them has been specifically approved by the US Food and Drug Administration for glucocorticoid-induced diabetes, but they are approved for type 2 diabetes.

Guidelines from the American Association of Clinical Endocrinologists for type 2 diabetes call for starting monotherapy if the hemoglobin A_1c is 6.5% to 7.5%, dual therapy if it is 7.6% to 9%, triple therapy if it is higher than 9% and the patient has no symptoms, and insulin if it is higher than 9% and the patient does have symptoms.²²

In terms of estimated average glucose levels, these categories correspond to 140 to 169 mg/dL for monotherapy, 171 to 212 mg/dL for dual therapy, and higher than 212 mg/dL for triple therapy or insulin. Since estimated average levels also include fasting glucose levels (which are lower in glucocorticoid-induced diabetes compared with nonfasting levels), and because we use the American Diabetes Association general hemoglobin A_1c goal of less than 7%, we believe that our suggestions below are reasonable.

We divide our recommendations according to initial random (ideally, 1- to 2-hour postprandial) plasma glucose levels.

 

 

If the random or 1- to 2-hour post-meal plasma glucose is lower than 220 mg/dL

In this situation the choices are:

• Metformin
• Dipeptidyl peptidase-4 (DPP-4) inhibitors (“gliptins”)
• Meglitinides (“glinides”). The guidelines on new-onset diabetes after transplantation point out that meglitinides may be the safest agents apart from insulin in the renal transplant population, but does acknowledge that efficacies of different oral agents have not been compared in this group.²⁰
• Glucagon-like protein-1 (GLP-1) agonists
• Sulfonylureas. However, the longer-acting forms such as glimepiride (Amaryl) are not suitable if the fasting plasma glucose is not affected.

We have not used thiazolidinediones (“glitazones”) routinely because they can cause weight gain and edema—problems that are already seen with the use of steroids—and have a slower onset of action.

If the random or 1- to 2-hour post-meal plasma glucose is 220 to 300 mg/dL

Often, a combination of drugs or insulin (see below) is needed. However, you can start with one agent and add a second agent within 2 or 3 months (as is recommended for type 2 diabetes).^22,23 The following combinations of the agents listed above are supported by published guidelines for type 2 diabetes:

• Metformin plus a sulfonylurea^22,23
• Metformin plus a glinide²²
• Metformin plus a GLP-1 agonist²³
• Metformin plus a DPP-4 inhibitor.²²

If the random or 1- to 2-hour post-meal plasma glucose is higher than 300 mg/dL

In our experience, if their plasma glucose levels are this high, patients are experiencing frank symptoms of hyperglycemia.

Insulin addresses those symptoms and avoids the prolonged wait that often results from unsuccessfully starting one agent and then adding another. Of all the available drugs, insulin is the only one that can be used despite multiple underlying illnesses; it does not cause a lot of drug interactions, and the dose can be adjusted upward and downward in increments to fit the patient’s needs, especially when a larger glucocorticoid load is given up front and then is tapered either slowly or rapidly. However, it can cause hypoglycemia and weight gain.

The initial total daily dose of insulin can be based on the patient’s weight. A starting total daily dose of 0.15 to 0.3 U/kg is reasonable— on the lower end if only the postprandial glucose levels are elevated, and on the higher end if both fasting and postprandial glucose levels are affected.

If fasting glucose levels are not elevated, then Neutral Protamine Hagedorn insulin (which is intermediate-acting) or a premixed combination of an intermediate-acting plus a fast- or short-acting insulin can be given once a day before breakfast, or even before lunch if the glucose levels start to rise only after lunch.

If both the fasting and the postprandial glucose levels are elevated, regimens similar to those for type 1 or insulin-requiring type 2 diabetes can be used, except that the ratios of the doses are tilted more toward covering postprandial than fasting hyperglycemia:

• Long-acting insulin plus prandial insulin, in a ratio of 30:70 to 50:50. As glucocorticoids are tapered, the long-acting insulin may have to be discontinued while the prandial doses are continued, since the fasting glucose level decreases first.
• Premixed insulins, with one-half to two-thirds of the dose given before breakfast and the rest before the evening meal, with the possibility of a third injection before lunch. As glucocorticoids are tapered, the evening dose is tapered first.
• Intermediate-acting insulin plus short- or fast-acting insulin in the morning (these two will make up one-half to two-thirds of the total daily dose), short- or fast-acting insulin before the evening meal, and intermediate-acting insulin at bedtime. As glucocorticoids are tapered, the bedtime insulin is tapered first.

Capillary blood glucose (fingerstick) checks

The timing and frequency of fingerstick checks depend on the treatment.

Though postprandial testing is ideal, it is often not practical or convenient. Before lunch, before dinner, and at bedtime are good alternatives since they reflect the pattern of glucose rise throughout the day. For patients on diet and exercise with or without agents other than insulin, testing once or twice a day is reasonable, rotating times before meals (including fasting if this time is affected) and at bedtime.

For patients on insulin, checking two to four times a day initially would help match insulin doses with glucose excursions. For continued care, the American Diabetes Association recommends fingerstick checks three times daily in patients on multiple insulin injections, but it has no specific recommendations for those on once-a-day insulin.²¹ We have been recommending that our patients on once-daily insulin check at least twice a day.

Goal fingerstick glucose levels that we use are in accordance with the American Diabetes Association guidelines for diabetes in general²¹:

• Before meals 70 to 130 mg/dL or
• 1 to 2 hours after meals < 180 mg/dL.

During steroid taper, if the glucocorticoid dose is in the lower range (eg, a prednisone-equivalent dose of approximately 7.5 mg per day or less), the fingerstick glucose levels are at the lower end of the target range, and the patient is on a single antidiabetic agent that does not often cause hypoglycemia (eg, metformin), then it is reasonable to ask the patient to not take the antidiabetic medication for 3 to 7 days while continuing to check fingersticks to see if it needs to be resumed. Patients on agents that can cause hypoglycemia need to check more often during the 1 to 3 days after the glucocorticoid dose reduction, as it may take this much time for the glycemic effect to diminish and to adjust the diabetes medication to the appropriate dose.

STARTING GLUCOCORTICOIDS IN PATIENTS WITH KNOWN DIABETES

Fingerstick checks more often

Most patients will already have a glucose meter. They should be instructed to check as discussed above if they do not have a previous diagnosis of diabetes, or to continue as they are doing if they are already checking more often. Patients who have been checking only fasting levels should be instructed to check later in the day, either before or 1 to 2 hours after meals, as discussed above. Patients on oral medications may need additional oral agents or insulin.

 

 

Adjust medications if glucose is not at goal

Patients with type 2 diabetes treated with diet and exercise alone can be started on the medications discussed above if their fingerstick readings are not at goal.

If they are already on insulin, we advise them to increase the short- or fast-acting insulins and the morning intermediate-acting insulin by at least 10% to 20% as soon as an elevation in glucose is detected. Long-acting insulin or nighttime intermediate-acting insulin should be increased if fasting glucose levels are affected.

Insulin requirements can double depending on the glucocorticoid dose. In patients with type 1 diabetes who were given prednisone 60 mg orally for 3 days, mean blood glucose levels increased from a baseline of 110 mg/dL at baseline to 149 mg/dL on the days on prednisone.⁶ The average blood glucose level remained elevated at 141 mg/dL on the day after the last dose of prednisone. The insulin dose increased by 31% to 102% (mean 69%).

CUSHING SYNDROME AND ADRENAL SUPPRESSION

Unlike glucocorticoid-induced diabetes, in which the dilemma is often when to initiate antidiabetic treatment, the question for patients in whom Cushing syndrome or adrenal suppression has developed is when to discontinue glucocorticoids.

Adrenal suppression for the most part goes hand in hand with exogenous Cushing syndrome. If cushingoid features develop, we can infer that the dose of exogenous glucocorticoid exceeds the physiologic needs. This supraphysiologic dosing also leads to suppression of endogenous cortisol production. The suppression occurs at the level of the hypothalamus and pituitary gland, with subsequent atrophy of the part of the adrenal cortex that produces endogenous glucocorticoids.

To understand further the concept of supraphysiologic dosing, the following interconversion of systemic glucocorticoid effects is helpful^24,25:

However, there is not much information on interconversion for the local preparations (intra-articular, epidural, inhaled, topical).

Moreover, the definition of supraphysiologic dosing seems to be evolving. Though a total hydrocortisone-equivalent dose of 30 mg/day is still often touted as physiologic replacement, many patients require less. Several studies in the early 1990s, mostly in children and adolescents, showed the mean daily cortisol production rate to be 4.8 to 6.8 mg/m²/day, or closer to 10 to 15 mg/day.^26–28 For purposes of this discussion, a physiologic dose will be defined as up to 30 mg hydrocortisone per day or its equivalent.

Adrenal suppression vs insufficiency

Adrenal suppression is often confused with adrenal insufficiency.

Adrenal suppression occurs when cortisol production is decreased because of the presence of exogenous glucocorticoids or other drugs, such as megestrol acetate (Megace), that act on the glucocorticoid receptor. Another situation beyond the scope of this review is excess endogenous cortisol production by an adrenal adenoma or adrenal carcinoma that causes suppression of the contralateral adrenal gland.²⁹

In contrast, adrenal insufficiency is caused by failure of the adrenal gland to produce cortisol as a result of an innate disorder of the adrenal gland (eg, Addison disease) or pituitary gland (eg, pituitary surgery).

Hence, endogenous cortisol production in a patient taking supraphysiologic doses of exogenous glucocorticoids may be suppressed. Recovery of endogenous cortisol production is expected after stopping the exogenous glucocorticoid, though the time to recovery can vary and the patient can be adrenally insufficient if the glucocorticoid is stopped abruptly.

In addition, during times of intercurrent illness, a patient with adrenal suppression may be relatively adrenally insufficient and may need larger doses (“stress doses”) of glucocorticoids, since the adrenal glands may be unable to mount a stress response.²⁹

Local steroids can suppress the adrenal glands

Glucocorticoids are the most common cause of Cushing syndrome. Oral formulations such as dexamethasone, prednisone, and hydrocortisone taken in supraphysiologic doses and for prolonged durations are easily recognized as obvious causes of Cushing syndrome. However, intra-articular, epidural, inhaled, nasal, ocular, and topical steroids—so-called local preparations—have also been linked to Cushing syndrome, and physicians are less likely to recognize them as causes.^30–38

In a study in 16 pediatric patients with asthma and 48 controls, inhaled beclomethasone dipropionate (Qvar) 300 to 500 μg daily resulted in adrenal suppression in 100% of patients after 6 to 42 months, as determined by an insulin tolerance test.³⁰

The topical steroid betamethasone (Diprosone) carries a warning that systemic absorption of topical steroids can cause adrenal suppression.³⁹ Intra-articular, intranasal, epidural, and ocular routes are also reported to cause adrenal suppression.^32–38

When is adrenal suppression more likely?

Adrenal suppression is more likely in the following situations:

• Longer duration of treatment. Studies have shown that exposure to supraphysiologic steroid doses for 2 weeks or less might already suppress the adrenal glands, but the clinical significance of this is unclear since some recovery already occurs a few days after the glucocorticoids are discontinued.^31,40
• Supraphysiologic doses, stronger formulations, longer-acting formulations.⁴¹

When is adrenal suppression less likely?

Adrenal suppression is less likely in the following situations:

• Regimens that mimic the diurnal rhythm of cortisol (higher dose in the morning, lower dose in the afternoon)⁴²
• Alternate-day dosing of steroids.⁴³

 

 

Steroid withdrawal vs adrenal insufficiency

Another phenomenon that can be confused with adrenal insufficiency or glucocorticoid insufficiency is steroid withdrawal, in which patients experience lethargy, muscle aches, nausea, vomiting, and postural hypotension as glucocorticoids are tapered and their effects wane.⁴² Increasing the glucocorticoid dose for presumed adrenal insufficiency may delay recovery of the adrenal function and would have to be weighed against the patient’s symptoms.

The following may help distinguish the two: if the patient is on supraphysiologic glucocorticoid doses, then he or she is not glucocorticoid-deficient and is likely suffering from steroid withdrawal. At this point, patients may just need reassurance, symptomatic treatment, or if necessary, a brief (1-week) increase of the previous lowest dose, followed by reevaluation.

With local glucocorticoid preparations that may be systemically absorbed, however, there is no good way of estimating dose equivalence. In these situations, the decision to simply reassure the patient or give symptomatic treatment—as opposed to giving low-dose oral glucocorticoids such as hydrocortisone 5 to 10 mg daily for a week followed by reevaluation— depends on the severity of symptoms and whether the patient has quick access to medical attention should he or she develop an intercurrent illness.

Identifying patients at risk of adrenal suppression

Patients presenting with weight gain or symptoms suggesting Cushing syndrome should be asked about steroid intake and should be prompted to recall possible nonoral routes. In addition, patients presenting with muscle aches and fatigue—symptoms of steroid withdrawal— may have received unrecognized local glucocorticoids that were systemically absorbed, now with diminishing effects.

The ACTH stimulation test for adrenal recovery

Testing can be done to see if the adrenal glands have recovered and glucocorticoid therapy can be discontinued (see Tapering from glucocorticoids, below).

The test most often used is the corticotropin (ACTH) stimulation test. Since the suppression is at the level of the hypothalamus and the pituitary gland, the ACTH stimulation test is an indirect method of assessing hypothalamic and pituitary function in the context of glucocorticoid-induced adrenal suppression. It has good correlation with the insulin tolerance test, the gold-standard test for an intact hypothalamic-pituitary-adrenal axis.

The synthetic ACTH cosyntropin (Cortrosyn) 250 μg is injected intravenously or intramuscularly, and a cortisol level is drawn at baseline and 30 and 60 minutes later. Other doses such as 1 μg or 10 μg have been reported but are not yet widely accepted. A cortisol level of greater than 18 to 20 μg/dL at any time point shows that the adrenals have regained function and the steroids may be discontinued.⁴² If adrenal suppression persists, weaning from steroids should continue.

In reality, it may not be possible or practical to do an ACTH stimulation test, as not all physicians’ offices have a supply of cosyntropin or the manpower to perform the test correctly. In these cases, weaning can progress with monitoring of symptoms.

Testing for synthetic glucocorticoids in the urine and serum can demonstrate systemic absorption and may be helpful in patients who do not recall receiving steroids.³³

Tapering from glucocorticoids

Several tapering schedules have been suggested (although not necessarily validated). Whether and how to taper depend on how long the glucocorticoid has been taken.

If taken for less than 1 week, glucocorticoids can be stopped without tapering, regardless of the dose.

If taken for 1 to 3 weeks, the decision to taper depends on the clinician’s assessment of the patient’s general health or constitution and the illness for which the glucocorticoid was prescribed. For example, if the underlying disease is less likely to flare with a gradual dose reduction, then tapering would be suitable.⁴⁴

If taken for more than 3 weeks, the practice has been a more rapid taper at the beginning until a physiologic dose is reached. How quickly to reduce the dose depends on whether the underlying illness is expected to flare up, or if the patient might experience steroid withdrawal symptoms.

One schedule is to lower the glucocorticoid dose by an amount equivalent to prednisolone 2.5 mg every 3 to 4 days when above the physiologic dose, then to taper more slowly by 1 mg every 2 to 4 weeks.⁴⁴ Once the physiologic dose is reached, one can switch to the equivalent dose of hydrocortisone and decrease the dose by 2.5 mg a week until a daily dose of 10 mg a day is reached and maintained for 2 to 3 months, and then perform a test of adrenal function (see above).⁴⁴ Passing the test implies that the adrenal glands have recovered and the glucocorticoid can be stopped.

Another option is to switch to alternate-day therapy once a physiologic dose is reached and to test 8:00 am cortisol levels, continuing the glucocorticoid and retesting in 4 to 6 weeks if the value is less than 3 μg/dL; stopping the glucocorticoid if the value is higher than 20 μg/dL; and performing an ACTH stimulation test for values in between.⁴⁵

A review of other tapering regimens for chronic diseases, mostly pulmonary, did not find enough evidence to recommend one particular schedule over another.⁴⁶ The tapering schedule may have to be adjusted to prevent disease flare and symptoms of steroid withdrawal.

Locally administered steroids. Since the equivalence of systemically absorbed local glucocorticoids is not known, these patients are likely to present when they have symptoms of steroid withdrawal. In this situation, testing adrenal function will help.

Glucocorticoids are commonly prescribed by primary care physicians and specialists alike for multiple medical problems, acute as well as chronic.

However, these useful drugs have adverse effects on multiple endocrine systems, effects that include diabetes (or worsening of hyperglycemia in those with known diabetes), Cushing syndrome, adrenal suppression, osteoporosis (reviewed in the Cleveland Clinic Journal of Medicine in August 2010),¹ and dyslipidemia. In addition, suppression of gonadotropins, growth hormone, and, acutely, thyrotropin can ensue.

The focus of this review is on the diabetogenic and adrenal suppressive effects of glucocorticoids and their management. We describe the rationale for choosing specific drugs to counter hyperglycemia, tests for determining adrenal suppression and systemic glucocorticoid absorption, and how and why to taper these drugs.

WIDELY USED DRUGS

Although glucocorticoids (often simply called steroids or corticosteroids, although not all steroids are corticosteroids, and not all corticosteroids are glucocorticoids) are the core treatment for adrenal insufficiency, in most cases they are prescribed for their anti-inflammatory effects. They act through multiple pathways at the cellular and molecular levels, suppressing the cascades that would otherwise result in inflammation and promoting pathways that produce anti-inflammatory proteins.²

In addition to formulations that are intended to have systemic effects, other, “local” formulations are made for specific conditions, such as intra-articular injections for arthritis, epidural injections for lumbar disk pain, eye drops for uveitis, nasal sprays for allergic rhinitis, inhalers for asthma, and topical ointments and creams for eczema. However, as we will discuss, even these preparations can have systemic effects.

GLUCOCORTICOID-INDUCED DIABETES IS COMMON

Glucocorticoids are the most common cause of drug-induced diabetes. Though the exact prevalence is not known, a few observations suggest that glucocorticoid-induced diabetes or hyperglycemia is common:

• In patients with rheumatoid arthritis, mean age 62 years, nearly 9% developed diabetes in the 2 years after starting glucocorticoid treatment, which was a higher rate than expected.³
• In nondiabetic patients with primary renal disease treated with prednisolone 0.75 mg/kg/day, 42% were found to have 2-hour post-lunch plasma glucose concentrations higher than 200 mg/dL but normal fasting glucose levels.⁴
• In a case-control study, the odds ratio of starting an oral hypoglycemic agent or insulin was 1.77 for patients receiving a hydrocortisone-equivalent dose of 1 to 39 mg/day, 3.02 for 40 to 79 mg/day, 5.82 for 80 to 119 mg/day, and 10.34 for 120 mg/day or more.⁵ (For a full discussion of glucocorticoid equivalents, see the section below on Cushing syndrome and adrenal suppression.)
• In patients with type 1 diabetes, prednisone 60 mg/day raised the blood glucose levels starting 6 hours after the prednisone dose.⁶
• Diabetic ketoacidosis and hyperosmolar nonketotic syndrome have been reported as a result of glucocorticoid treatment.^7–9

GLUCOCORTICOIDS CAUSE DIABETES MAINLY VIA INSULIN RESISTANCE

The mechanism by which glucocorticoids cause diabetes predominantly involves insulin resistance rather than decreased insulin production. In fact, in a study in healthy volunteers, ¹⁰ hydrocortisone infusion resulted in higher insulin production than saline infusion did. (In high doses, however, glucocorticoids have been shown to decrease insulin secretion.¹¹)

Normally, in response to insulin, the liver decreases its output of glucose. Glucocorticoids decrease the liver’s sensitivity to insulin, thereby increasing hepatic glucose output.¹² They also inhibit glucose uptake in muscle and fat, reducing insulin sensitivity as much as 60% in healthy volunteers. This seems primarily due to a postreceptor effect, ie, inhibition of glucose transport.^13–15

THE PEAK EFFECT OCCURS 4 TO 6 HOURS AFTER DOSING

To understand the optimal time for checking plasma glucose and to apply appropriate treatment, we should consider the pharmacokinetic profile of glucocorticoids.

Studied using the whole-blood lymphocyte proliferation technique, prednisone shows a peak effect at about 4 to 6 hours and a duration of action of 13 to 16 hours.¹⁶ This closely resembles what we see in terms of glucose excursion with this drug.¹⁷ Two studies of intravenous dexamethasone 10 mg showed that glucose levels rose within 4 hours of injection, but did not pursue this beyond that time frame.^18,19

 

PATIENTS WITHOUT A PREVIOUS DIAGNOSIS OF DIABETES

Be alert for new-onset diabetes

For most diseases treated with glucocorticoids, clinicians can estimate in advance how long the patient will need to take the drug. We can arbitrarily classify the projected exposure as either short-term (3 to 4 weeks or less, such as a 6-day course of methylprednisolone for allergic conditions) or long-term (such as in transplant recipients to prevent rejection or to treat graft-vs-host disease). Hyperglycemia is a potential concern with both short-term and long-term treatment. However, guidelines on checking blood sugar levels, as opposed to relying on symptoms alone, are available only for long-term glucocorticoid treatment.

Patients beginning treatment should be warned of typical diabetes symptoms such as thirst and increased urination and, should these occur, to seek medical attention to have their blood glucose level checked. It is also reasonable to have them return in a week for a random postprandial plasma glucose test in the mid-afternoon.

Why this timing? In most once-daily regimens, glucocorticoids are given in the morning to prevent adrenal suppression (discussed below). In our experience, glucose levels start to rise mid-morning and continue to increase until bedtime. Measuring glucose levels 1 to 2 hours after lunch allows for both the glucocorticoid action and the carbohydrate absorption from lunch to reach their peaks. If hyperglycemia is going to happen, it should be detectable by then. A glucose level of 200 mg/dL or higher should prompt the practitioner to pursue this further.

If glucocorticoid treatment is to continue beyond 3 to 4 weeks, the only population for which there are published guidelines on managing glucocorticoid-related diabetes is transplant recipients. International consensus guidelines, published in 2003, suggest checking the fasting plasma glucose level once a week for the first 4 weeks after transplantation, then at 3 months, at 6 months, and then once a year.²⁰

Though practical, this suggestion does not reflect the fact that glucocorticoids often do not affect fasting plasma glucose, especially if given once daily in the morning at doses of 30 mg or less of prednisone or its equivalent. These guidelines thus may not be applicable to other populations with glucocorticoid-induced diabetes.

The transplant guidelines do mention that an oral glucose tolerance test may be more sensitive, but this is often cumbersome to perform. We believe that checking random postprandial plasma glucose levels is helpful in this regard.

The American Diabetes Association cutoff for diagnosing diabetes when using a random (ie, nonfasting) plasma glucose level is 200 mg/dL or higher in a patient with classic symptoms of hyperglycemia such as polyuria and polydipsia (Table 1).²¹ In the absence of such symptoms, a hemoglobin A_1c, fasting plasma glucose, or oral glucose tolerance test may be used and the results confirmed with repeat testing.

If the patient was at risk of developing diabetes even before receiving a glucocorticoid (for example, if he or she is overweight, has a family history of diabetes, or had a previous hemoglobin A_1c of 5.7% or higher), then a fasting plasma glucose level of 126 mg/dL or higher or a hemoglobin A_1c of 6.5% or higher might suffice to diagnose diabetes. Results should be confirmed on a separate day in the absence of unequivocal hyperglycemia. Fasting hyperglycemia can also be seen in patients receiving higher once-daily glucocorticoid doses—in our experience, an equivalent of prednisone 40 mg once a day in the morning— or twice-daily dosing.

A hemoglobin A_1c checked less than 2 to 3 months after starting glucocorticoid treatment will not be sensitive in picking up glucocorticoid-induced diabetes if the patient did not have underlying diabetes.

Diet and exercise may not be practical

Though diet and exercise are important in managing diabetes, the condition for which the patient is receiving a glucocorticoid may prevent him or her from exercising, at least in the acute phase of the illness.

In addition, though the exact mechanism is not known, glucocorticoids increase hunger, and so decreasing food intake is not easy either. Nonetheless, patients should be familiarized with what carbohydrates are and should be advised to reduce their intake of them.

For suspected type 1 diabetes, start insulin

If type 1 diabetes is suspected, for example, in patients who are lean, younger than 30 years, or who had presented with diabetic ketoacidosis, then insulin should be started. In equivocal cases, insulin therapy can commence while testing is done for C-peptide, glutamic acid decarboxylase antibodies, islet cell antibodies, and insulinoma-associated protein antibodies.

For all other patients, keep in mind the characteristics of glucocorticoids (Table 2) that may affect the drug treatment of diabetes.

Starting oral antidiabetic drugs

Some patients may have contraindications to specific drugs. For example, metformin (Glucophage) is contraindicated if the serum creatinine level is elevated, an abnormality that renal transplant patients may continue to have.

If the patient has no such contraindications, we have found the following medications suitable in view of their efficacy, low risk of hypoglycemia, or lack of distressing side effects. They will often lower glucose levels enough to achieve capillary blood glucose or fingerstick goals (discussed below). None of them has been specifically approved by the US Food and Drug Administration for glucocorticoid-induced diabetes, but they are approved for type 2 diabetes.

Guidelines from the American Association of Clinical Endocrinologists for type 2 diabetes call for starting monotherapy if the hemoglobin A_1c is 6.5% to 7.5%, dual therapy if it is 7.6% to 9%, triple therapy if it is higher than 9% and the patient has no symptoms, and insulin if it is higher than 9% and the patient does have symptoms.²²

In terms of estimated average glucose levels, these categories correspond to 140 to 169 mg/dL for monotherapy, 171 to 212 mg/dL for dual therapy, and higher than 212 mg/dL for triple therapy or insulin. Since estimated average levels also include fasting glucose levels (which are lower in glucocorticoid-induced diabetes compared with nonfasting levels), and because we use the American Diabetes Association general hemoglobin A_1c goal of less than 7%, we believe that our suggestions below are reasonable.

We divide our recommendations according to initial random (ideally, 1- to 2-hour postprandial) plasma glucose levels.

 

 

If the random or 1- to 2-hour post-meal plasma glucose is lower than 220 mg/dL

In this situation the choices are:

• Metformin
• Dipeptidyl peptidase-4 (DPP-4) inhibitors (“gliptins”)
• Meglitinides (“glinides”). The guidelines on new-onset diabetes after transplantation point out that meglitinides may be the safest agents apart from insulin in the renal transplant population, but does acknowledge that efficacies of different oral agents have not been compared in this group.²⁰
• Glucagon-like protein-1 (GLP-1) agonists
• Sulfonylureas. However, the longer-acting forms such as glimepiride (Amaryl) are not suitable if the fasting plasma glucose is not affected.

We have not used thiazolidinediones (“glitazones”) routinely because they can cause weight gain and edema—problems that are already seen with the use of steroids—and have a slower onset of action.

If the random or 1- to 2-hour post-meal plasma glucose is 220 to 300 mg/dL

Often, a combination of drugs or insulin (see below) is needed. However, you can start with one agent and add a second agent within 2 or 3 months (as is recommended for type 2 diabetes).^22,23 The following combinations of the agents listed above are supported by published guidelines for type 2 diabetes:

• Metformin plus a sulfonylurea^22,23
• Metformin plus a glinide²²
• Metformin plus a GLP-1 agonist²³
• Metformin plus a DPP-4 inhibitor.²²

If the random or 1- to 2-hour post-meal plasma glucose is higher than 300 mg/dL

In our experience, if their plasma glucose levels are this high, patients are experiencing frank symptoms of hyperglycemia.

Insulin addresses those symptoms and avoids the prolonged wait that often results from unsuccessfully starting one agent and then adding another. Of all the available drugs, insulin is the only one that can be used despite multiple underlying illnesses; it does not cause a lot of drug interactions, and the dose can be adjusted upward and downward in increments to fit the patient’s needs, especially when a larger glucocorticoid load is given up front and then is tapered either slowly or rapidly. However, it can cause hypoglycemia and weight gain.

The initial total daily dose of insulin can be based on the patient’s weight. A starting total daily dose of 0.15 to 0.3 U/kg is reasonable— on the lower end if only the postprandial glucose levels are elevated, and on the higher end if both fasting and postprandial glucose levels are affected.

If fasting glucose levels are not elevated, then Neutral Protamine Hagedorn insulin (which is intermediate-acting) or a premixed combination of an intermediate-acting plus a fast- or short-acting insulin can be given once a day before breakfast, or even before lunch if the glucose levels start to rise only after lunch.

If both the fasting and the postprandial glucose levels are elevated, regimens similar to those for type 1 or insulin-requiring type 2 diabetes can be used, except that the ratios of the doses are tilted more toward covering postprandial than fasting hyperglycemia:

• Long-acting insulin plus prandial insulin, in a ratio of 30:70 to 50:50. As glucocorticoids are tapered, the long-acting insulin may have to be discontinued while the prandial doses are continued, since the fasting glucose level decreases first.
• Premixed insulins, with one-half to two-thirds of the dose given before breakfast and the rest before the evening meal, with the possibility of a third injection before lunch. As glucocorticoids are tapered, the evening dose is tapered first.
• Intermediate-acting insulin plus short- or fast-acting insulin in the morning (these two will make up one-half to two-thirds of the total daily dose), short- or fast-acting insulin before the evening meal, and intermediate-acting insulin at bedtime. As glucocorticoids are tapered, the bedtime insulin is tapered first.

Capillary blood glucose (fingerstick) checks

The timing and frequency of fingerstick checks depend on the treatment.

Though postprandial testing is ideal, it is often not practical or convenient. Before lunch, before dinner, and at bedtime are good alternatives since they reflect the pattern of glucose rise throughout the day. For patients on diet and exercise with or without agents other than insulin, testing once or twice a day is reasonable, rotating times before meals (including fasting if this time is affected) and at bedtime.

For patients on insulin, checking two to four times a day initially would help match insulin doses with glucose excursions. For continued care, the American Diabetes Association recommends fingerstick checks three times daily in patients on multiple insulin injections, but it has no specific recommendations for those on once-a-day insulin.²¹ We have been recommending that our patients on once-daily insulin check at least twice a day.

Goal fingerstick glucose levels that we use are in accordance with the American Diabetes Association guidelines for diabetes in general²¹:

• Before meals 70 to 130 mg/dL or
• 1 to 2 hours after meals < 180 mg/dL.

During steroid taper, if the glucocorticoid dose is in the lower range (eg, a prednisone-equivalent dose of approximately 7.5 mg per day or less), the fingerstick glucose levels are at the lower end of the target range, and the patient is on a single antidiabetic agent that does not often cause hypoglycemia (eg, metformin), then it is reasonable to ask the patient to not take the antidiabetic medication for 3 to 7 days while continuing to check fingersticks to see if it needs to be resumed. Patients on agents that can cause hypoglycemia need to check more often during the 1 to 3 days after the glucocorticoid dose reduction, as it may take this much time for the glycemic effect to diminish and to adjust the diabetes medication to the appropriate dose.

STARTING GLUCOCORTICOIDS IN PATIENTS WITH KNOWN DIABETES

Fingerstick checks more often

Most patients will already have a glucose meter. They should be instructed to check as discussed above if they do not have a previous diagnosis of diabetes, or to continue as they are doing if they are already checking more often. Patients who have been checking only fasting levels should be instructed to check later in the day, either before or 1 to 2 hours after meals, as discussed above. Patients on oral medications may need additional oral agents or insulin.

 

 

Adjust medications if glucose is not at goal

Patients with type 2 diabetes treated with diet and exercise alone can be started on the medications discussed above if their fingerstick readings are not at goal.

If they are already on insulin, we advise them to increase the short- or fast-acting insulins and the morning intermediate-acting insulin by at least 10% to 20% as soon as an elevation in glucose is detected. Long-acting insulin or nighttime intermediate-acting insulin should be increased if fasting glucose levels are affected.

Insulin requirements can double depending on the glucocorticoid dose. In patients with type 1 diabetes who were given prednisone 60 mg orally for 3 days, mean blood glucose levels increased from a baseline of 110 mg/dL at baseline to 149 mg/dL on the days on prednisone.⁶ The average blood glucose level remained elevated at 141 mg/dL on the day after the last dose of prednisone. The insulin dose increased by 31% to 102% (mean 69%).

CUSHING SYNDROME AND ADRENAL SUPPRESSION

Unlike glucocorticoid-induced diabetes, in which the dilemma is often when to initiate antidiabetic treatment, the question for patients in whom Cushing syndrome or adrenal suppression has developed is when to discontinue glucocorticoids.

Adrenal suppression for the most part goes hand in hand with exogenous Cushing syndrome. If cushingoid features develop, we can infer that the dose of exogenous glucocorticoid exceeds the physiologic needs. This supraphysiologic dosing also leads to suppression of endogenous cortisol production. The suppression occurs at the level of the hypothalamus and pituitary gland, with subsequent atrophy of the part of the adrenal cortex that produces endogenous glucocorticoids.

To understand further the concept of supraphysiologic dosing, the following interconversion of systemic glucocorticoid effects is helpful^24,25:

However, there is not much information on interconversion for the local preparations (intra-articular, epidural, inhaled, topical).

Moreover, the definition of supraphysiologic dosing seems to be evolving. Though a total hydrocortisone-equivalent dose of 30 mg/day is still often touted as physiologic replacement, many patients require less. Several studies in the early 1990s, mostly in children and adolescents, showed the mean daily cortisol production rate to be 4.8 to 6.8 mg/m²/day, or closer to 10 to 15 mg/day.^26–28 For purposes of this discussion, a physiologic dose will be defined as up to 30 mg hydrocortisone per day or its equivalent.

Adrenal suppression vs insufficiency

Adrenal suppression is often confused with adrenal insufficiency.

Adrenal suppression occurs when cortisol production is decreased because of the presence of exogenous glucocorticoids or other drugs, such as megestrol acetate (Megace), that act on the glucocorticoid receptor. Another situation beyond the scope of this review is excess endogenous cortisol production by an adrenal adenoma or adrenal carcinoma that causes suppression of the contralateral adrenal gland.²⁹

In contrast, adrenal insufficiency is caused by failure of the adrenal gland to produce cortisol as a result of an innate disorder of the adrenal gland (eg, Addison disease) or pituitary gland (eg, pituitary surgery).

Hence, endogenous cortisol production in a patient taking supraphysiologic doses of exogenous glucocorticoids may be suppressed. Recovery of endogenous cortisol production is expected after stopping the exogenous glucocorticoid, though the time to recovery can vary and the patient can be adrenally insufficient if the glucocorticoid is stopped abruptly.

In addition, during times of intercurrent illness, a patient with adrenal suppression may be relatively adrenally insufficient and may need larger doses (“stress doses”) of glucocorticoids, since the adrenal glands may be unable to mount a stress response.²⁹

Local steroids can suppress the adrenal glands

Glucocorticoids are the most common cause of Cushing syndrome. Oral formulations such as dexamethasone, prednisone, and hydrocortisone taken in supraphysiologic doses and for prolonged durations are easily recognized as obvious causes of Cushing syndrome. However, intra-articular, epidural, inhaled, nasal, ocular, and topical steroids—so-called local preparations—have also been linked to Cushing syndrome, and physicians are less likely to recognize them as causes.^30–38

In a study in 16 pediatric patients with asthma and 48 controls, inhaled beclomethasone dipropionate (Qvar) 300 to 500 μg daily resulted in adrenal suppression in 100% of patients after 6 to 42 months, as determined by an insulin tolerance test.³⁰

The topical steroid betamethasone (Diprosone) carries a warning that systemic absorption of topical steroids can cause adrenal suppression.³⁹ Intra-articular, intranasal, epidural, and ocular routes are also reported to cause adrenal suppression.^32–38

When is adrenal suppression more likely?

Adrenal suppression is more likely in the following situations:

• Longer duration of treatment. Studies have shown that exposure to supraphysiologic steroid doses for 2 weeks or less might already suppress the adrenal glands, but the clinical significance of this is unclear since some recovery already occurs a few days after the glucocorticoids are discontinued.^31,40
• Supraphysiologic doses, stronger formulations, longer-acting formulations.⁴¹

When is adrenal suppression less likely?

Adrenal suppression is less likely in the following situations:

• Regimens that mimic the diurnal rhythm of cortisol (higher dose in the morning, lower dose in the afternoon)⁴²
• Alternate-day dosing of steroids.⁴³

 

 

Steroid withdrawal vs adrenal insufficiency

Another phenomenon that can be confused with adrenal insufficiency or glucocorticoid insufficiency is steroid withdrawal, in which patients experience lethargy, muscle aches, nausea, vomiting, and postural hypotension as glucocorticoids are tapered and their effects wane.⁴² Increasing the glucocorticoid dose for presumed adrenal insufficiency may delay recovery of the adrenal function and would have to be weighed against the patient’s symptoms.

The following may help distinguish the two: if the patient is on supraphysiologic glucocorticoid doses, then he or she is not glucocorticoid-deficient and is likely suffering from steroid withdrawal. At this point, patients may just need reassurance, symptomatic treatment, or if necessary, a brief (1-week) increase of the previous lowest dose, followed by reevaluation.

With local glucocorticoid preparations that may be systemically absorbed, however, there is no good way of estimating dose equivalence. In these situations, the decision to simply reassure the patient or give symptomatic treatment—as opposed to giving low-dose oral glucocorticoids such as hydrocortisone 5 to 10 mg daily for a week followed by reevaluation— depends on the severity of symptoms and whether the patient has quick access to medical attention should he or she develop an intercurrent illness.

Identifying patients at risk of adrenal suppression

Patients presenting with weight gain or symptoms suggesting Cushing syndrome should be asked about steroid intake and should be prompted to recall possible nonoral routes. In addition, patients presenting with muscle aches and fatigue—symptoms of steroid withdrawal— may have received unrecognized local glucocorticoids that were systemically absorbed, now with diminishing effects.

The ACTH stimulation test for adrenal recovery

Testing can be done to see if the adrenal glands have recovered and glucocorticoid therapy can be discontinued (see Tapering from glucocorticoids, below).

The test most often used is the corticotropin (ACTH) stimulation test. Since the suppression is at the level of the hypothalamus and the pituitary gland, the ACTH stimulation test is an indirect method of assessing hypothalamic and pituitary function in the context of glucocorticoid-induced adrenal suppression. It has good correlation with the insulin tolerance test, the gold-standard test for an intact hypothalamic-pituitary-adrenal axis.

The synthetic ACTH cosyntropin (Cortrosyn) 250 μg is injected intravenously or intramuscularly, and a cortisol level is drawn at baseline and 30 and 60 minutes later. Other doses such as 1 μg or 10 μg have been reported but are not yet widely accepted. A cortisol level of greater than 18 to 20 μg/dL at any time point shows that the adrenals have regained function and the steroids may be discontinued.⁴² If adrenal suppression persists, weaning from steroids should continue.

In reality, it may not be possible or practical to do an ACTH stimulation test, as not all physicians’ offices have a supply of cosyntropin or the manpower to perform the test correctly. In these cases, weaning can progress with monitoring of symptoms.

Testing for synthetic glucocorticoids in the urine and serum can demonstrate systemic absorption and may be helpful in patients who do not recall receiving steroids.³³

Tapering from glucocorticoids

Several tapering schedules have been suggested (although not necessarily validated). Whether and how to taper depend on how long the glucocorticoid has been taken.

If taken for less than 1 week, glucocorticoids can be stopped without tapering, regardless of the dose.

If taken for 1 to 3 weeks, the decision to taper depends on the clinician’s assessment of the patient’s general health or constitution and the illness for which the glucocorticoid was prescribed. For example, if the underlying disease is less likely to flare with a gradual dose reduction, then tapering would be suitable.⁴⁴

If taken for more than 3 weeks, the practice has been a more rapid taper at the beginning until a physiologic dose is reached. How quickly to reduce the dose depends on whether the underlying illness is expected to flare up, or if the patient might experience steroid withdrawal symptoms.

One schedule is to lower the glucocorticoid dose by an amount equivalent to prednisolone 2.5 mg every 3 to 4 days when above the physiologic dose, then to taper more slowly by 1 mg every 2 to 4 weeks.⁴⁴ Once the physiologic dose is reached, one can switch to the equivalent dose of hydrocortisone and decrease the dose by 2.5 mg a week until a daily dose of 10 mg a day is reached and maintained for 2 to 3 months, and then perform a test of adrenal function (see above).⁴⁴ Passing the test implies that the adrenal glands have recovered and the glucocorticoid can be stopped.

Another option is to switch to alternate-day therapy once a physiologic dose is reached and to test 8:00 am cortisol levels, continuing the glucocorticoid and retesting in 4 to 6 weeks if the value is less than 3 μg/dL; stopping the glucocorticoid if the value is higher than 20 μg/dL; and performing an ACTH stimulation test for values in between.⁴⁵

A review of other tapering regimens for chronic diseases, mostly pulmonary, did not find enough evidence to recommend one particular schedule over another.⁴⁶ The tapering schedule may have to be adjusted to prevent disease flare and symptoms of steroid withdrawal.

Locally administered steroids. Since the equivalence of systemically absorbed local glucocorticoids is not known, these patients are likely to present when they have symptoms of steroid withdrawal. In this situation, testing adrenal function will help.

Glucocorticoids are commonly prescribed by primary care physicians and specialists alike for multiple medical problems, acute as well as chronic.

However, these useful drugs have adverse effects on multiple endocrine systems, effects that include diabetes (or worsening of hyperglycemia in those with known diabetes), Cushing syndrome, adrenal suppression, osteoporosis (reviewed in the Cleveland Clinic Journal of Medicine in August 2010),¹ and dyslipidemia. In addition, suppression of gonadotropins, growth hormone, and, acutely, thyrotropin can ensue.

The focus of this review is on the diabetogenic and adrenal suppressive effects of glucocorticoids and their management. We describe the rationale for choosing specific drugs to counter hyperglycemia, tests for determining adrenal suppression and systemic glucocorticoid absorption, and how and why to taper these drugs.

WIDELY USED DRUGS

Although glucocorticoids (often simply called steroids or corticosteroids, although not all steroids are corticosteroids, and not all corticosteroids are glucocorticoids) are the core treatment for adrenal insufficiency, in most cases they are prescribed for their anti-inflammatory effects. They act through multiple pathways at the cellular and molecular levels, suppressing the cascades that would otherwise result in inflammation and promoting pathways that produce anti-inflammatory proteins.²

In addition to formulations that are intended to have systemic effects, other, “local” formulations are made for specific conditions, such as intra-articular injections for arthritis, epidural injections for lumbar disk pain, eye drops for uveitis, nasal sprays for allergic rhinitis, inhalers for asthma, and topical ointments and creams for eczema. However, as we will discuss, even these preparations can have systemic effects.

GLUCOCORTICOID-INDUCED DIABETES IS COMMON

Glucocorticoids are the most common cause of drug-induced diabetes. Though the exact prevalence is not known, a few observations suggest that glucocorticoid-induced diabetes or hyperglycemia is common:

• In patients with rheumatoid arthritis, mean age 62 years, nearly 9% developed diabetes in the 2 years after starting glucocorticoid treatment, which was a higher rate than expected.³
• In nondiabetic patients with primary renal disease treated with prednisolone 0.75 mg/kg/day, 42% were found to have 2-hour post-lunch plasma glucose concentrations higher than 200 mg/dL but normal fasting glucose levels.⁴
• In a case-control study, the odds ratio of starting an oral hypoglycemic agent or insulin was 1.77 for patients receiving a hydrocortisone-equivalent dose of 1 to 39 mg/day, 3.02 for 40 to 79 mg/day, 5.82 for 80 to 119 mg/day, and 10.34 for 120 mg/day or more.⁵ (For a full discussion of glucocorticoid equivalents, see the section below on Cushing syndrome and adrenal suppression.)
• In patients with type 1 diabetes, prednisone 60 mg/day raised the blood glucose levels starting 6 hours after the prednisone dose.⁶
• Diabetic ketoacidosis and hyperosmolar nonketotic syndrome have been reported as a result of glucocorticoid treatment.^7–9

GLUCOCORTICOIDS CAUSE DIABETES MAINLY VIA INSULIN RESISTANCE

The mechanism by which glucocorticoids cause diabetes predominantly involves insulin resistance rather than decreased insulin production. In fact, in a study in healthy volunteers, ¹⁰ hydrocortisone infusion resulted in higher insulin production than saline infusion did. (In high doses, however, glucocorticoids have been shown to decrease insulin secretion.¹¹)

Normally, in response to insulin, the liver decreases its output of glucose. Glucocorticoids decrease the liver’s sensitivity to insulin, thereby increasing hepatic glucose output.¹² They also inhibit glucose uptake in muscle and fat, reducing insulin sensitivity as much as 60% in healthy volunteers. This seems primarily due to a postreceptor effect, ie, inhibition of glucose transport.^13–15

THE PEAK EFFECT OCCURS 4 TO 6 HOURS AFTER DOSING

To understand the optimal time for checking plasma glucose and to apply appropriate treatment, we should consider the pharmacokinetic profile of glucocorticoids.

Studied using the whole-blood lymphocyte proliferation technique, prednisone shows a peak effect at about 4 to 6 hours and a duration of action of 13 to 16 hours.¹⁶ This closely resembles what we see in terms of glucose excursion with this drug.¹⁷ Two studies of intravenous dexamethasone 10 mg showed that glucose levels rose within 4 hours of injection, but did not pursue this beyond that time frame.^18,19

 

PATIENTS WITHOUT A PREVIOUS DIAGNOSIS OF DIABETES

Be alert for new-onset diabetes

For most diseases treated with glucocorticoids, clinicians can estimate in advance how long the patient will need to take the drug. We can arbitrarily classify the projected exposure as either short-term (3 to 4 weeks or less, such as a 6-day course of methylprednisolone for allergic conditions) or long-term (such as in transplant recipients to prevent rejection or to treat graft-vs-host disease). Hyperglycemia is a potential concern with both short-term and long-term treatment. However, guidelines on checking blood sugar levels, as opposed to relying on symptoms alone, are available only for long-term glucocorticoid treatment.

Patients beginning treatment should be warned of typical diabetes symptoms such as thirst and increased urination and, should these occur, to seek medical attention to have their blood glucose level checked. It is also reasonable to have them return in a week for a random postprandial plasma glucose test in the mid-afternoon.

Why this timing? In most once-daily regimens, glucocorticoids are given in the morning to prevent adrenal suppression (discussed below). In our experience, glucose levels start to rise mid-morning and continue to increase until bedtime. Measuring glucose levels 1 to 2 hours after lunch allows for both the glucocorticoid action and the carbohydrate absorption from lunch to reach their peaks. If hyperglycemia is going to happen, it should be detectable by then. A glucose level of 200 mg/dL or higher should prompt the practitioner to pursue this further.

If glucocorticoid treatment is to continue beyond 3 to 4 weeks, the only population for which there are published guidelines on managing glucocorticoid-related diabetes is transplant recipients. International consensus guidelines, published in 2003, suggest checking the fasting plasma glucose level once a week for the first 4 weeks after transplantation, then at 3 months, at 6 months, and then once a year.²⁰

Though practical, this suggestion does not reflect the fact that glucocorticoids often do not affect fasting plasma glucose, especially if given once daily in the morning at doses of 30 mg or less of prednisone or its equivalent. These guidelines thus may not be applicable to other populations with glucocorticoid-induced diabetes.

The transplant guidelines do mention that an oral glucose tolerance test may be more sensitive, but this is often cumbersome to perform. We believe that checking random postprandial plasma glucose levels is helpful in this regard.

The American Diabetes Association cutoff for diagnosing diabetes when using a random (ie, nonfasting) plasma glucose level is 200 mg/dL or higher in a patient with classic symptoms of hyperglycemia such as polyuria and polydipsia (Table 1).²¹ In the absence of such symptoms, a hemoglobin A_1c, fasting plasma glucose, or oral glucose tolerance test may be used and the results confirmed with repeat testing.

If the patient was at risk of developing diabetes even before receiving a glucocorticoid (for example, if he or she is overweight, has a family history of diabetes, or had a previous hemoglobin A_1c of 5.7% or higher), then a fasting plasma glucose level of 126 mg/dL or higher or a hemoglobin A_1c of 6.5% or higher might suffice to diagnose diabetes. Results should be confirmed on a separate day in the absence of unequivocal hyperglycemia. Fasting hyperglycemia can also be seen in patients receiving higher once-daily glucocorticoid doses—in our experience, an equivalent of prednisone 40 mg once a day in the morning— or twice-daily dosing.

A hemoglobin A_1c checked less than 2 to 3 months after starting glucocorticoid treatment will not be sensitive in picking up glucocorticoid-induced diabetes if the patient did not have underlying diabetes.

Diet and exercise may not be practical

Though diet and exercise are important in managing diabetes, the condition for which the patient is receiving a glucocorticoid may prevent him or her from exercising, at least in the acute phase of the illness.

In addition, though the exact mechanism is not known, glucocorticoids increase hunger, and so decreasing food intake is not easy either. Nonetheless, patients should be familiarized with what carbohydrates are and should be advised to reduce their intake of them.

For suspected type 1 diabetes, start insulin

If type 1 diabetes is suspected, for example, in patients who are lean, younger than 30 years, or who had presented with diabetic ketoacidosis, then insulin should be started. In equivocal cases, insulin therapy can commence while testing is done for C-peptide, glutamic acid decarboxylase antibodies, islet cell antibodies, and insulinoma-associated protein antibodies.

For all other patients, keep in mind the characteristics of glucocorticoids (Table 2) that may affect the drug treatment of diabetes.

Starting oral antidiabetic drugs

Some patients may have contraindications to specific drugs. For example, metformin (Glucophage) is contraindicated if the serum creatinine level is elevated, an abnormality that renal transplant patients may continue to have.

If the patient has no such contraindications, we have found the following medications suitable in view of their efficacy, low risk of hypoglycemia, or lack of distressing side effects. They will often lower glucose levels enough to achieve capillary blood glucose or fingerstick goals (discussed below). None of them has been specifically approved by the US Food and Drug Administration for glucocorticoid-induced diabetes, but they are approved for type 2 diabetes.

Guidelines from the American Association of Clinical Endocrinologists for type 2 diabetes call for starting monotherapy if the hemoglobin A_1c is 6.5% to 7.5%, dual therapy if it is 7.6% to 9%, triple therapy if it is higher than 9% and the patient has no symptoms, and insulin if it is higher than 9% and the patient does have symptoms.²²

In terms of estimated average glucose levels, these categories correspond to 140 to 169 mg/dL for monotherapy, 171 to 212 mg/dL for dual therapy, and higher than 212 mg/dL for triple therapy or insulin. Since estimated average levels also include fasting glucose levels (which are lower in glucocorticoid-induced diabetes compared with nonfasting levels), and because we use the American Diabetes Association general hemoglobin A_1c goal of less than 7%, we believe that our suggestions below are reasonable.

We divide our recommendations according to initial random (ideally, 1- to 2-hour postprandial) plasma glucose levels.

 

 

If the random or 1- to 2-hour post-meal plasma glucose is lower than 220 mg/dL

In this situation the choices are:

• Metformin
• Dipeptidyl peptidase-4 (DPP-4) inhibitors (“gliptins”)
• Meglitinides (“glinides”). The guidelines on new-onset diabetes after transplantation point out that meglitinides may be the safest agents apart from insulin in the renal transplant population, but does acknowledge that efficacies of different oral agents have not been compared in this group.²⁰
• Glucagon-like protein-1 (GLP-1) agonists
• Sulfonylureas. However, the longer-acting forms such as glimepiride (Amaryl) are not suitable if the fasting plasma glucose is not affected.

We have not used thiazolidinediones (“glitazones”) routinely because they can cause weight gain and edema—problems that are already seen with the use of steroids—and have a slower onset of action.

If the random or 1- to 2-hour post-meal plasma glucose is 220 to 300 mg/dL

Often, a combination of drugs or insulin (see below) is needed. However, you can start with one agent and add a second agent within 2 or 3 months (as is recommended for type 2 diabetes).^22,23 The following combinations of the agents listed above are supported by published guidelines for type 2 diabetes:

• Metformin plus a sulfonylurea^22,23
• Metformin plus a glinide²²
• Metformin plus a GLP-1 agonist²³
• Metformin plus a DPP-4 inhibitor.²²

If the random or 1- to 2-hour post-meal plasma glucose is higher than 300 mg/dL

In our experience, if their plasma glucose levels are this high, patients are experiencing frank symptoms of hyperglycemia.

Insulin addresses those symptoms and avoids the prolonged wait that often results from unsuccessfully starting one agent and then adding another. Of all the available drugs, insulin is the only one that can be used despite multiple underlying illnesses; it does not cause a lot of drug interactions, and the dose can be adjusted upward and downward in increments to fit the patient’s needs, especially when a larger glucocorticoid load is given up front and then is tapered either slowly or rapidly. However, it can cause hypoglycemia and weight gain.

The initial total daily dose of insulin can be based on the patient’s weight. A starting total daily dose of 0.15 to 0.3 U/kg is reasonable— on the lower end if only the postprandial glucose levels are elevated, and on the higher end if both fasting and postprandial glucose levels are affected.

If fasting glucose levels are not elevated, then Neutral Protamine Hagedorn insulin (which is intermediate-acting) or a premixed combination of an intermediate-acting plus a fast- or short-acting insulin can be given once a day before breakfast, or even before lunch if the glucose levels start to rise only after lunch.

If both the fasting and the postprandial glucose levels are elevated, regimens similar to those for type 1 or insulin-requiring type 2 diabetes can be used, except that the ratios of the doses are tilted more toward covering postprandial than fasting hyperglycemia:

• Long-acting insulin plus prandial insulin, in a ratio of 30:70 to 50:50. As glucocorticoids are tapered, the long-acting insulin may have to be discontinued while the prandial doses are continued, since the fasting glucose level decreases first.
• Premixed insulins, with one-half to two-thirds of the dose given before breakfast and the rest before the evening meal, with the possibility of a third injection before lunch. As glucocorticoids are tapered, the evening dose is tapered first.
• Intermediate-acting insulin plus short- or fast-acting insulin in the morning (these two will make up one-half to two-thirds of the total daily dose), short- or fast-acting insulin before the evening meal, and intermediate-acting insulin at bedtime. As glucocorticoids are tapered, the bedtime insulin is tapered first.

Capillary blood glucose (fingerstick) checks

The timing and frequency of fingerstick checks depend on the treatment.

Though postprandial testing is ideal, it is often not practical or convenient. Before lunch, before dinner, and at bedtime are good alternatives since they reflect the pattern of glucose rise throughout the day. For patients on diet and exercise with or without agents other than insulin, testing once or twice a day is reasonable, rotating times before meals (including fasting if this time is affected) and at bedtime.

For patients on insulin, checking two to four times a day initially would help match insulin doses with glucose excursions. For continued care, the American Diabetes Association recommends fingerstick checks three times daily in patients on multiple insulin injections, but it has no specific recommendations for those on once-a-day insulin.²¹ We have been recommending that our patients on once-daily insulin check at least twice a day.

Goal fingerstick glucose levels that we use are in accordance with the American Diabetes Association guidelines for diabetes in general²¹:

• Before meals 70 to 130 mg/dL or
• 1 to 2 hours after meals < 180 mg/dL.

During steroid taper, if the glucocorticoid dose is in the lower range (eg, a prednisone-equivalent dose of approximately 7.5 mg per day or less), the fingerstick glucose levels are at the lower end of the target range, and the patient is on a single antidiabetic agent that does not often cause hypoglycemia (eg, metformin), then it is reasonable to ask the patient to not take the antidiabetic medication for 3 to 7 days while continuing to check fingersticks to see if it needs to be resumed. Patients on agents that can cause hypoglycemia need to check more often during the 1 to 3 days after the glucocorticoid dose reduction, as it may take this much time for the glycemic effect to diminish and to adjust the diabetes medication to the appropriate dose.

STARTING GLUCOCORTICOIDS IN PATIENTS WITH KNOWN DIABETES

Fingerstick checks more often

Most patients will already have a glucose meter. They should be instructed to check as discussed above if they do not have a previous diagnosis of diabetes, or to continue as they are doing if they are already checking more often. Patients who have been checking only fasting levels should be instructed to check later in the day, either before or 1 to 2 hours after meals, as discussed above. Patients on oral medications may need additional oral agents or insulin.

 

 

Adjust medications if glucose is not at goal

Patients with type 2 diabetes treated with diet and exercise alone can be started on the medications discussed above if their fingerstick readings are not at goal.

If they are already on insulin, we advise them to increase the short- or fast-acting insulins and the morning intermediate-acting insulin by at least 10% to 20% as soon as an elevation in glucose is detected. Long-acting insulin or nighttime intermediate-acting insulin should be increased if fasting glucose levels are affected.

Insulin requirements can double depending on the glucocorticoid dose. In patients with type 1 diabetes who were given prednisone 60 mg orally for 3 days, mean blood glucose levels increased from a baseline of 110 mg/dL at baseline to 149 mg/dL on the days on prednisone.⁶ The average blood glucose level remained elevated at 141 mg/dL on the day after the last dose of prednisone. The insulin dose increased by 31% to 102% (mean 69%).

CUSHING SYNDROME AND ADRENAL SUPPRESSION

Unlike glucocorticoid-induced diabetes, in which the dilemma is often when to initiate antidiabetic treatment, the question for patients in whom Cushing syndrome or adrenal suppression has developed is when to discontinue glucocorticoids.

Adrenal suppression for the most part goes hand in hand with exogenous Cushing syndrome. If cushingoid features develop, we can infer that the dose of exogenous glucocorticoid exceeds the physiologic needs. This supraphysiologic dosing also leads to suppression of endogenous cortisol production. The suppression occurs at the level of the hypothalamus and pituitary gland, with subsequent atrophy of the part of the adrenal cortex that produces endogenous glucocorticoids.

To understand further the concept of supraphysiologic dosing, the following interconversion of systemic glucocorticoid effects is helpful^24,25:

However, there is not much information on interconversion for the local preparations (intra-articular, epidural, inhaled, topical).

Moreover, the definition of supraphysiologic dosing seems to be evolving. Though a total hydrocortisone-equivalent dose of 30 mg/day is still often touted as physiologic replacement, many patients require less. Several studies in the early 1990s, mostly in children and adolescents, showed the mean daily cortisol production rate to be 4.8 to 6.8 mg/m²/day, or closer to 10 to 15 mg/day.^26–28 For purposes of this discussion, a physiologic dose will be defined as up to 30 mg hydrocortisone per day or its equivalent.

Adrenal suppression vs insufficiency

Adrenal suppression is often confused with adrenal insufficiency.

Adrenal suppression occurs when cortisol production is decreased because of the presence of exogenous glucocorticoids or other drugs, such as megestrol acetate (Megace), that act on the glucocorticoid receptor. Another situation beyond the scope of this review is excess endogenous cortisol production by an adrenal adenoma or adrenal carcinoma that causes suppression of the contralateral adrenal gland.²⁹

In contrast, adrenal insufficiency is caused by failure of the adrenal gland to produce cortisol as a result of an innate disorder of the adrenal gland (eg, Addison disease) or pituitary gland (eg, pituitary surgery).

Hence, endogenous cortisol production in a patient taking supraphysiologic doses of exogenous glucocorticoids may be suppressed. Recovery of endogenous cortisol production is expected after stopping the exogenous glucocorticoid, though the time to recovery can vary and the patient can be adrenally insufficient if the glucocorticoid is stopped abruptly.

In addition, during times of intercurrent illness, a patient with adrenal suppression may be relatively adrenally insufficient and may need larger doses (“stress doses”) of glucocorticoids, since the adrenal glands may be unable to mount a stress response.²⁹

Local steroids can suppress the adrenal glands

Glucocorticoids are the most common cause of Cushing syndrome. Oral formulations such as dexamethasone, prednisone, and hydrocortisone taken in supraphysiologic doses and for prolonged durations are easily recognized as obvious causes of Cushing syndrome. However, intra-articular, epidural, inhaled, nasal, ocular, and topical steroids—so-called local preparations—have also been linked to Cushing syndrome, and physicians are less likely to recognize them as causes.^30–38

In a study in 16 pediatric patients with asthma and 48 controls, inhaled beclomethasone dipropionate (Qvar) 300 to 500 μg daily resulted in adrenal suppression in 100% of patients after 6 to 42 months, as determined by an insulin tolerance test.³⁰

The topical steroid betamethasone (Diprosone) carries a warning that systemic absorption of topical steroids can cause adrenal suppression.³⁹ Intra-articular, intranasal, epidural, and ocular routes are also reported to cause adrenal suppression.^32–38

When is adrenal suppression more likely?

Adrenal suppression is more likely in the following situations:

• Longer duration of treatment. Studies have shown that exposure to supraphysiologic steroid doses for 2 weeks or less might already suppress the adrenal glands, but the clinical significance of this is unclear since some recovery already occurs a few days after the glucocorticoids are discontinued.^31,40
• Supraphysiologic doses, stronger formulations, longer-acting formulations.⁴¹

When is adrenal suppression less likely?

Adrenal suppression is less likely in the following situations:

• Regimens that mimic the diurnal rhythm of cortisol (higher dose in the morning, lower dose in the afternoon)⁴²
• Alternate-day dosing of steroids.⁴³

 

 

Steroid withdrawal vs adrenal insufficiency

Another phenomenon that can be confused with adrenal insufficiency or glucocorticoid insufficiency is steroid withdrawal, in which patients experience lethargy, muscle aches, nausea, vomiting, and postural hypotension as glucocorticoids are tapered and their effects wane.⁴² Increasing the glucocorticoid dose for presumed adrenal insufficiency may delay recovery of the adrenal function and would have to be weighed against the patient’s symptoms.

The following may help distinguish the two: if the patient is on supraphysiologic glucocorticoid doses, then he or she is not glucocorticoid-deficient and is likely suffering from steroid withdrawal. At this point, patients may just need reassurance, symptomatic treatment, or if necessary, a brief (1-week) increase of the previous lowest dose, followed by reevaluation.

With local glucocorticoid preparations that may be systemically absorbed, however, there is no good way of estimating dose equivalence. In these situations, the decision to simply reassure the patient or give symptomatic treatment—as opposed to giving low-dose oral glucocorticoids such as hydrocortisone 5 to 10 mg daily for a week followed by reevaluation— depends on the severity of symptoms and whether the patient has quick access to medical attention should he or she develop an intercurrent illness.

Identifying patients at risk of adrenal suppression

Patients presenting with weight gain or symptoms suggesting Cushing syndrome should be asked about steroid intake and should be prompted to recall possible nonoral routes. In addition, patients presenting with muscle aches and fatigue—symptoms of steroid withdrawal— may have received unrecognized local glucocorticoids that were systemically absorbed, now with diminishing effects.

The ACTH stimulation test for adrenal recovery

Testing can be done to see if the adrenal glands have recovered and glucocorticoid therapy can be discontinued (see Tapering from glucocorticoids, below).

The test most often used is the corticotropin (ACTH) stimulation test. Since the suppression is at the level of the hypothalamus and the pituitary gland, the ACTH stimulation test is an indirect method of assessing hypothalamic and pituitary function in the context of glucocorticoid-induced adrenal suppression. It has good correlation with the insulin tolerance test, the gold-standard test for an intact hypothalamic-pituitary-adrenal axis.

The synthetic ACTH cosyntropin (Cortrosyn) 250 μg is injected intravenously or intramuscularly, and a cortisol level is drawn at baseline and 30 and 60 minutes later. Other doses such as 1 μg or 10 μg have been reported but are not yet widely accepted. A cortisol level of greater than 18 to 20 μg/dL at any time point shows that the adrenals have regained function and the steroids may be discontinued.⁴² If adrenal suppression persists, weaning from steroids should continue.

In reality, it may not be possible or practical to do an ACTH stimulation test, as not all physicians’ offices have a supply of cosyntropin or the manpower to perform the test correctly. In these cases, weaning can progress with monitoring of symptoms.

Testing for synthetic glucocorticoids in the urine and serum can demonstrate systemic absorption and may be helpful in patients who do not recall receiving steroids.³³

Tapering from glucocorticoids

Several tapering schedules have been suggested (although not necessarily validated). Whether and how to taper depend on how long the glucocorticoid has been taken.

If taken for less than 1 week, glucocorticoids can be stopped without tapering, regardless of the dose.

If taken for 1 to 3 weeks, the decision to taper depends on the clinician’s assessment of the patient’s general health or constitution and the illness for which the glucocorticoid was prescribed. For example, if the underlying disease is less likely to flare with a gradual dose reduction, then tapering would be suitable.⁴⁴

If taken for more than 3 weeks, the practice has been a more rapid taper at the beginning until a physiologic dose is reached. How quickly to reduce the dose depends on whether the underlying illness is expected to flare up, or if the patient might experience steroid withdrawal symptoms.

One schedule is to lower the glucocorticoid dose by an amount equivalent to prednisolone 2.5 mg every 3 to 4 days when above the physiologic dose, then to taper more slowly by 1 mg every 2 to 4 weeks.⁴⁴ Once the physiologic dose is reached, one can switch to the equivalent dose of hydrocortisone and decrease the dose by 2.5 mg a week until a daily dose of 10 mg a day is reached and maintained for 2 to 3 months, and then perform a test of adrenal function (see above).⁴⁴ Passing the test implies that the adrenal glands have recovered and the glucocorticoid can be stopped.

Another option is to switch to alternate-day therapy once a physiologic dose is reached and to test 8:00 am cortisol levels, continuing the glucocorticoid and retesting in 4 to 6 weeks if the value is less than 3 μg/dL; stopping the glucocorticoid if the value is higher than 20 μg/dL; and performing an ACTH stimulation test for values in between.⁴⁵

A review of other tapering regimens for chronic diseases, mostly pulmonary, did not find enough evidence to recommend one particular schedule over another.⁴⁶ The tapering schedule may have to be adjusted to prevent disease flare and symptoms of steroid withdrawal.

Locally administered steroids. Since the equivalence of systemically absorbed local glucocorticoids is not known, these patients are likely to present when they have symptoms of steroid withdrawal. In this situation, testing adrenal function will help.

Nocturia is common, but elderly patients infrequently volunteer this complaint, and even when they do, some clinicians may dismiss it as simply a part of aging. Nevertheless, nocturia causes significant distress and impairment of quality of life. It is associated with very serious consequences such as depression, social isolation, and a higher risk of death.

In this article, we review the concepts behind frequent nighttime voiding in older adults. We will start with two case scenarios to aid in understanding these concepts; near the end of the article, we will discuss the most appropriate management strategies for these two patients.

CASE SCENARIOS

Case 1: An 82-year-old man with fatigue

An 82-year-old obese white man with a history of hypertension, diabetes, and benign prostatic hyperplasia comes in to see his primary care provider, complaining of fatigue. He wakes up tired and has difficulty completing his daytime tasks. He gets up every 1 to 2 hours at night to urinate and has slow urinary flow and a feeling of incomplete bladder emptying.

See related patient education material

He says his wife has been increasingly bothered by his loud snoring. Recently, he had a car accident when he fell asleep while driving.

Case 2: An 85-year-old woman with incontinence

An 85-year-old white woman is in her family physician’s office with a primary complaint of waking up at least four times at night to urinate, and often ends up soaking her bed or adult diapers. She is bothered by urinary urgency and frequency during the day as well. She denies dysuria and hematuria.

She has a history of hypertension and urinary incontinence, and she has seven children. Her current medications are diltiazem (Cardizem), metoprolol (Toprol), and oxybutynin (Ditropan).

In these two cases, what would account for the nocturia? What would be the best way to help these patients?

THE NORM, NOT THE EXCEPTION

Although nocturia is defined as an awakening by the need to urinate even once in a night, many experts consider that it begins to be clinically significant only when the patient voids at least twice during the night.¹

In older adults, nocturia is the norm rather than the exception. Studies done between 1990 and 2009 found that 68.9% to 93% of men age 70 and older get up at least once a night to void. The prevalence in women is somewhat lower, at 74.1% to 77.1%.² Clinically significant nocturia is present in a majority of the elderly: more than 60% of both men and women.³

An Austrian study⁴ reported that elderly men got up to urinate a mean of 2.8 times per night, while women got up significantly more often—3.1 times. Women were also bothered more by this symptom, and their quality of life was significantly more decreased.

In another study,⁵ whites had a significantly higher nocturia ratio (ratio of nighttime urine volume to the 24-hour urine volume) than Asians. Asians, on the other hand, had a significantly higher nocturnal bladder capacity index than whites. (See below for definitions of the various indices of nocturia.) This information implies that nocturia may be a more prominent problem for elderly whites than for other racial groups.

In an epidemiologic study in Sweden,⁶ the death rate was as much as twice as high in both men and women who had three or more nocturnal voids, even after taking into account the influence of cardiac disease, diabetes mellitus, and stroke.

If nocturia is not addressed in the physician-patient encounter, patients may try to “self-manage” it by restricting their fluid intake or by limiting their social exposure,⁷ with limited success and with unwanted social isolation.

WHAT CAUSES NOCTURIA?

In almost all cases of nocturia in elderly people, the cause is multifactorial (Table 1).

Advancing age is primary among these factors. Age-related structural changes in the urinary system include decreased functional bladder capacity, a decreased maximum urinary flow rate,⁶ a decreased ability to postpone urination,⁸ and an age-related increase in postvoiding residual urine volume.⁹ The aging kidney is also less able to concentrate urine. Also implicated are histologic changes in the detrusor muscle¹⁰ that lead to diminished bladder compliance and, together with detrusor overactivity, result in increased urinary frequency.

Nocturnal polyuria or nocturnal urine overproduction is common in patients with nocturia.¹¹

Although the pathophysiology of nocturnal polyuria is still unclear, some investigators believe that low levels of antidiuretic hormone (ADH) at night are involved, reflecting an alteration in the circadian rhythm seen in diurnal plasma arginine vasopressin levels.¹² In patients with nocturnal polyuria, ADH levels drop to very low or undetectable levels at night, which increases nocturnal urine output. In some extreme cases, the low to absent levels of ADH increase nocturnal voiding to 85% of the total 24-hour urine volume.¹³

Other causes of nocturnal polyuria include mobilization of fluids in patients with edema,¹⁴ and autonomic dysfunction. Other biochemical changes that contribute to nocturia include a decrease in nighttime plasma melatonin levels, an increase in nighttime plasma catecholamine levels, an increase in nighttime plasma natriuretic peptide levels, an increase in blood pressure, and an increase in total urine volume.¹⁵

A decreased ability to store urine also leads to nocturia. This is caused by decreased nocturnal bladder capacity, more irritative symptoms, and comorbid conditions such as overactive bladder, pelvic floor laxity resulting in pelvic organ prolapse, and, in men, benign prostatic hyperplasia.

Neural inputs to the bladder can also be impaired, as in patients who have diabetes mellitus or spinal stenosis, leading to chronic urinary retention, detrusor dysfunction, nocturia, and incontinence.

 

WHICH PATIENTS ARE AT RISK?

Nocturia is associated with a number of risk factors (Table 2).

Obesity is associated with a higher incidence of moderate to severe nocturia.¹⁵ Studies have shown that the higher the body mass index, the greater the number of nighttime voids, especially in women.¹⁶

Habitually eating at night, with poor daytime appetite, is shown to be associated with increased nighttime diuresis.

Obstructive sleep apnea¹⁷ and untreated depressive symptoms such as frequent napping¹⁸ are also associated with moderate to severe nocturia.¹⁹

Higher systolic blood pressures are associated with more urine production at night. Plasma ADH regulation is also altered, which contributes to nocturnal polyuria.²¹

Other comorbid conditions associated with nocturia include recurrent cystitis, lung disease, congestive heart failure, neurodegenerative conditions (eg, Alzheimer disease and parkinsonism), and chronic kidney disease.²¹

Drugs associated with nocturia include cholinesterase inhibitors (for dementia),²² beta-blockers,²³ and calcium channel blockers.²⁴

Lifestyle factors. Alcohol and coffee have shown either no or only a mild diuretic effect. Smoking has not been shown to be associated with nocturia.¹⁵

Seasonal differences also exist, with increased frequency of nocturia in the winter.²⁵

WHAT ARE THE CLINICAL CONSEQUENCES OF NOCTURIA?

Nocturia’s effects are varied and are very important to address (Table 3).

Quality of life can be profoundly affected, and if nocturia is left untreated, it may lead to morbidity and even death. Elderly patients may feel simultaneously debilitated, frustrated, distressed, and puzzled. Nocturia may also increase their fear of falling and may negatively affect personal relationships.²⁶

Falls, injuries. Nocturia exposes elderly patients to injuries such as hip fractures due to falling, significantly increasing the incidence of this injury.²⁶ This occurs as elderly patients get up from bed and walk to the bathroom to void.²⁷ In addition, during the day, superficial and fragmented sleep leads to daytime sleepiness and impaired perception and balance, also increasing the risk of falls.²⁸ The complications of immobility and the need for surgery in many cases lead to debility, increased risk of infections, decubitus ulcers, and death. The risk of hip fractures can lead elderly patients with nocturia to associate this symptom with a fear of falling and can alter their concept of their own age (“Nocturia makes me feel old”),²⁹ further diminishing quality of life.

The estimated medical cost of nocturia-associated falls in the elderly is about $1.5 billion per year, part of the $61 billion in lost productivity due to nocturia in adults.³⁰

Long-term complications (eg, debilitation, poor sleep, obesity, decreased energy), increase the overall mortality rate, especially in patients who report voiding more than three times per night.²⁹ Elderly patients with nocturia also have a greater need for emergency care.³¹

Nocturia also complicates other comorbid conditions, such as dementia, which increases the risk of urinary incontinence.³² In patients who have had a stroke, nocturia is the most frequent lower urinary tract symptom, and represents a major impact on daily life.³³

Sleep disturbance is another important consequence. In one survey,³⁴ nocturia was cited as a cause of poor sleep four times more often than the cause cited next most often, ie, pain. Because the elderly patient is awakened from sleep numerous times throughout the night, nocturia leads to more fatigue,³⁵ lower energy levels, and poorer quality of sleep.³⁶ Depression may be linked to poor sleep, as men with two or more nocturnal episodes were shown to be six times more likely to experience depression.

The patient is not the only person who loses sleep: so do the patient’s family members or sleeping partner.⁷ It is therefore not surprising that sleep disruption caused by nocturia has been cited as a principal reason for admitting older relatives to care homes.³⁷

The risk of death is higher for elderly patients with coronary heart disease if they have nocturia. The causative link is the hemodynamic changes (increases in blood pressure and heart rate) that accompany awakening and arising, which may cause cardiovascular strain and lead to cardiovascular events. The 12-year survival rate has been shown to be significantly lower in patients with nighttime voiding, making nocturia a highly significant independent predictor of death in coronary heart disease patients.³⁸

HOW TO EVALUATE AN OLDER ADULT WHO PRESENTS WITH NOCTURIA

A thorough history and physical examination are crucial in diagnosing nocturia. The goal is to identify any treatable underlying condition, such as diabetes mellitus, obstructive sleep apnea, diabetes insipidus, overactive bladder, benign prostatic hyperplasia, urinary tract infection, and congestive heart failure. Laboratory tests and imaging studies can help rule out these underlying conditions.

Other important facets in the history that must be elicited are medication use, patterns of fluid intake, and a history of other urinary complaints.³⁹

A voiding diary and indices of nocturia

A voiding diary is extremely useful and should be used whenever possible. Episodes of incontinence, time of voids, volume voided, and frequency and volume of fluid intake are recorded. From the raw data, one can determine the following:

Total nocturnal urine volume, ie, the sum volume of the nighttime voids

Maximum voided volume, ie, the largest single recorded volume voided in a 24-hour period

Nocturia index, ie, the total nocturnal urine volume divided by the maximum voided volume. A nocturia index greater than 1 shows that nocturnal urine production is greater than the functional bladder capacity. Clinically significant nocturia is observed in patients with a nocturia index of 2.1 or greater.

Nocturnal polyuria index, ie, total nocturnal urine volume divided by the 24-hour urine output. A nocturnal polyuria index higher than 33% implies nocturnal polyuria.⁴⁰

Nocturnal bladder capacity index, ie, the actual number of nightly voids minus the predicted number of nightly voids, which in turn is calculated as the nocturia index minus 1.

It is especially important to encourage patients to make a voiding diary, as some patients may find this cumbersome, and compliance can be low unless its importance is emphasized. A diary over 7 days usually gives meaningful data. The results from the diary typically confirm the presence of nocturnal polyuria or a decrease in bladder capacity, influencing management.⁴¹

 

WHAT ARE THE TREATMENT OPTIONS?

Therapy must be directed at the primary cause, addressing any underlying conditions that can contribute to nocturia. Examples³⁹:

• Tight control of blood sugar for patients with diabetes mellitus
• Treatment of diabetes insipidus
• Referral for patients with primary polydipsia
• Management of hypercalcemia and hypokalemia
• A survey of medications
• Treatment of infections.

Nonpharmacologic measures

Tailored behavioral therapy can also be instituted, but the patient needs to have realistic expectations, as these measures are rarely effective alone.

Avoiding nighttime fluid intake, including alcohol and caffeine, has shown promise.

Wearing compression stockings and elevating the legs in the afternoon decrease the retention of fluid that otherwise would return to the circulation at night.

Identifying and eliminating nighttime influences that disturb sleep has variable efficacy. The use of continuous positive airway pressure helps to treat sleep apnea. Moderate exercise, reducing nonsleep time spent in bed,⁴² and sleeping in a warm bed⁴³ to decrease cold diuresis have also been shown to improve sleep quality.⁴⁴ Patients with nocturia may have a disrupted circadian rhythm, and phototherapy may help resynchronize the diurnal rhythm and melatonin secretion.

Pharmacotherapy

Pharmacotherapy of nocturia includes desmopressin (DDAVP) to manage nocturnal polyuria and antimuscarinic agents to manage the patient’s decreased ability to store urine. Alpha-blockers such as tamsulosin (Flomax) and 5-alpha-reductase inhibitors such as finasteride (Proscar) are used for men with benign prostatic hyperplasia. Novel and second-line therapies include diuretics such as furosemide (Lasix), cyclooxygenase-2 inhibitors, as well as botulinum toxin injected directly into the detrusor muscle for overactive bladder.⁴⁵

Desmopressin in a low oral dose (0.1–0.4 mg) at bedtime can be initiated and the response assessed. Patients with nocturnal polyuria and disorders of the vasopressin system have been found to be more sensitive to desmopressin therapy.⁴⁶ Fluid retention and hyponatremia can complicate therapy, and desmopressin must be avoided in patients with liver cirrhosis, renal failure, or congestive heart failure.⁴⁷

Antimuscarinic agents are effective for patients who have lower urinary tract symptoms and for those with a diminished ability to store urine. They act by decreasing both voluntary and involuntary bladder contractions by blocking muscarinic receptors on the detrusor muscle. This reduces the bladder’s ability to contract and the urge to urinate, thereby increasing bladder capacity.⁴⁸ These agents include oxybutynin (Ditropan), tolterodine (Detrol), solifenacin (Vesicare), and propiverine (not available in the United States).

Diuretics are being used as second-line agents or for patients who cannot tolerate desmopressin.⁴⁹ Hydrochlorothiazide is taken 8 hours before bedtime to prevent water accumulation before the early sleeping hours.⁵⁰ Furosemide has also led to a reduction in the mean number of nocturnal voids.⁵¹ The effect of these drugs on nocturia are especially beneficial to patients with concomitant hypertension or cardiovascular disease.

Cyclo-oxygenase-2 inhibitors such as celecoxib (Celebrex)⁵² and other nonsteroidal anti-inflammatory drugs such as diclofenac (Voltaren, others)⁵³ and loxoprofen (not available in the United States)⁵⁴ have been shown to decrease urine production, detrusor muscle tone, and inflammation, especially in men with benign prostatic hyperplasia.

Botulinum toxin has been used, usually in patients refractory to first-line treatment.⁴⁴

Referral to specialists is guided by underlying causes. Referral to a pulmonologist or sleep specialist may be helpful if the patient has obstructive sleep apnea. Referral to a urologist may be prudent if the patient has benign prostatic hyperplasia, and a gynecologist can address issues such as pelvic relaxation.

Table 4 summarizes the treatment strategies for nocturia.

CASES REVISITED

The first patient described above has nocturia caused by several concomitant diseases, ie, hypertension, diabetes, benign prostatic hyperplasia, and obstructive sleep apnea. In addition to controlling his blood pressure and blood sugar, his primary care provider referred him to a pulmonologist, who confirmed obstructive sleep apnea with polysomnography and prescribed nightly use of a continuous positive airway pressure apparatus. A few weeks later, the patient’s nocturia had improved significantly, and his level of fatigue had decreased.

Apart from hypertension, the second patient’s nocturia was mostly attributed to her existing urinary incontinence. Recognizing that her current antihypertensive regimen may worsen nocturia, her family physician changed it to enalapril (Vasotec) and doxazosin (Cardura) and counseled her to restrict her fluid intake 2 hours before bedtime. She was also referred to a gynecologist, who found a moderate degree of cystocele and treated her with a collagen injection. Her nocturia improved significantly.