Self-Monitoring Not Helpful for Type 2 Diabetes

Self-monitoring of blood glucose (SMBG) has very little effect on glycemic control in patients with type 2 diabetes who are not using insulin. In a review of data from 9 trials of SMBG involving 2324 participants, any effect on HbA1c levels was found to occur only in the first 6 months, during which time the HbA1c level decreased by 0.26% (95% confidence interval [CI], -0.39 to -0.13). Data from 2 trials involving 493 participants showed that the effect of SMBG was no longer significant at 12 months follow-up, with a decrease in HbA1c levels of 0.1% (95% CI, -0.3 to 0.04).

Uriell L. Malanda, MD, and colleagues from the VU University Medical Center in Amsterdam reviewed 12 studies involving 3259 patients with diabetes who are not insulin-dependent. The results are published in the latest issue of the Cochrane Library. "Regular self-monitoring of blood glucose in non-insulin-treated patients has minimal impact on glycemic control, has no impact on general well-being or quality of life, and is rather expensive," Dr. Malanda explained in a press release. "Consequently, it does not add to a clinically relevant long-term benefit."

Hypoglycemic episodes were reported more often in the SMBG group than in the control group in 4 of the studies that were reviewed. The authors explained this to be a result of patients using the SMBG device to confirm perceived hypoglycemic episodes.

In 9 of the trials that were reviewed, SMBG was compared with typical care without monitoring. One study compared SMBG with self-monitoring of urine glucose (SMUG). One study was a 3-armed trial comparing SMBG and SMUG with usual care. One study was a 3-armed trial comparing less intensive SMBG and more intensive SMBG with control participants. The reviewers found that 7 of the 12 studies demonstrated a low risk of bias for most of the indicators.

Two of the trials reported costs of self-monitoring. One trial compared the cost of SMBG with SMUG on the basis of 9 measurements per week, using 1990 prices in US dollars for self-monitoring. The authors concluded that the cost of SMBG (including the cost of a reflectance meter) were 12 times the cost of SBUG ($481 vs $40).

The second trial reported on the full economical evaluation of the costs and effects of self-monitoring. The costs were €104 for the control group, €212 for the less-intensive self-monitoring group, and €203 for the more intensive self-monitoring group. The authors documented higher losses to follow-up in the more intensive self-monitoring group. They felt that this contributed to the difference in costs between the more intense and less intense self-monitoring groups.

SMBG has been shown to be an effective tool for people with type 1 diabetes as well as for those with type 2 diabetes who use insulin therapy. Patients use the glucose levels to adjust insulin doses. This systemic review suggests that patients with type 2 diabetes are not using SMBG to adjust their diet and lifestyle. The authors note that more research is needed to determine the effect of SMBG on hypoglycemia and complications from type 2 diabetes.

The study was supported by the EMGO Institute for Health and Care Research, the Netherlands. Dr. Malanda and several other authors report taking part "in an ongoing study on the topic of interest in this review."

Cochrane Database of Systematic Reviews. 2012, Issue 1. Article

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Zinc Decreases Mortality in Children With Pneumonia

In a study conducted in Africa, children aged 6 to 59 months who had severe pneumonia had reduced mortality when receiving zinc in addition to standard antibiotics, a new study has found. In addition, the reduction in mortality was greater among HIV-infected than non-HIV-infected children.

Maheswari G. Srinivasan, from the Department of Pediatrics and Child Health at the School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda, and colleagues reported the findings in an article published online February 8 in BMC Medicine.

"Given these results, zinc could be considered for use as adjunct therapy for severe pneumonia, especially among Highly Active Antiretroviral Therapy naïve HIV infected children in our environment," the authors conclude.

According to the researchers, acute respiratory tract infections is the most common cause of morbidity and mortality in children younger than 5 years of age, and the "burden of acute lower respiratory tract infections is 2 to 10 times more common in developing than in developed countries."

The results with zinc supplementation in this setting have been mixed. "One randomized controlled study from Bangladesh showed that zinc adjunct therapy accelerated recovery of children with severe pneumonia," the authors note, "but other studies have shown no effect," and "no studies have assessed the impact of zinc adjunct therapy on case fatality of children with pneumonia."

To evaluate this issue, the researchers randomly assigned children aged 6 to 59 months who had severe pneumonia to receive either zinc once daily for 7 days (n = 176; 20 mg for children aged 12 months or older and 10 mg for younger children) or a placebo once daily for 7 days (n = 176).

Children also received standard antibiotics for severe pneumonia and were assessed every 6 hours for oxygen saturation, respiratory rate, and temperature.

Among the children receiving zinc, 7 (4.0%) died compared with 21 patients (11.9%) in the placebo group. This represented nearly a 70% reduction in mortality risk in favor of zinc supplementation (relative risk [RR] reduction, 0.67; 95% confidence interval [CI], 0.24 - 0.85).

The greatest risk reduction was seen in HIV-infected children. Among HIV-infected children, case fatality was 7 of 27 children in the placebo group vs 0 of 28 children in the zinc group (RR, 0.1; 95% CI, 0.0 - 1.0).

In contrast, in HIV-uninfected children, no difference in case fatality was observed with zinc vs placebo: case fatality was 7/127 (5.5%) with placebo vs 5/129 (3.9%) among HIV-uninfected children receiving zinc (RR, 0.7; 95% CI, 0.2 - 2.2).

According to the researchers, the excess risk with placebo was substantially greater among HIV-positive children than in HIV-negative children (absolute risk reduction, 26/100 children vs 2/100 children, respectively; P = .006).

They estimated that 13 patients needed to be treated to avert 1 death, and that children who received the placebo were 3 times more likely to die compared with those who received zinc.

"There are two key findings in this study: overall, zinc supplementation in these children significantly decreased case fatality, but did not reduce the time to normalization of the parameters for disease severity," the authors conclude.

According to the researchers, zinc supplementation might increase the immune response by boosting phagocytosis and averting apoptosis of T lymphocytes in HIV-infected patients.

They add that zinc deficiency (present in from 20% to 69% of children in this setting) "compromises immunity through a number of mechanisms, such as T cell dysfunction and dysregulation of intracellular killing."

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Obesity Is Associated With Urinary Tract Infections

Obesity as measured by body mass index (BMI) is associated with increased risk for urinary tract infection (UTI) and pyelonephritis in both sexes, according to a retrospective, cross-sectional study.

Overall, the incidences of UTI and pyelonephritis were 2.5- and 5-fold higher among obese individuals (BMI ≥ 30 kg/m²) than among nonobese individuals, report Michelle J. Semins, MD, and colleagues from the Johns Hopkins University School of Medicine in Baltimore, Maryland, in an article published in the February issue of Urology.

"Obesity has also been associated with urological conditions such as male and female sexual dysfunction, infertility, incontinence, genitourinary malignancy, and nephrolithiasis," the authors write. "A similar relationship between obesity and [UTI] may exist but it has not been as well defined."

To better characterize the potential association, the researchers examined UTI rates among 95,598 participants who were drawn from a national private insurance claims database. All participants were insured by Blue Cross and Blue Shield in 7 states during the period of 2002 to 2006 and had undergone a health risk assessment that included BMI screening.

In total, 13% of participants developed UTIs, and 0.84% developed pyelonephritis. The incidence of UTI was higher among both men and women with a BMI of from 30.0 to 34.9 kg/m² than among those with a BMI lower than 30 kg/m² (men: odds ratio, 1.59; 95% confidence interval [CI], 1.43 - 1.76; P < .0001; women: odds ratio, 1.22; 95% CI, 1.15 - 1.28; P < .0001). In addition, women were 4.2- and 3.6-fold more likely to develop UTIs and pyelonephritis than men, respectively.

The authors defined UTI and pyelonephritis according to International Classification of Diseases, Ninth Revision, codes. In this study, "UTI" included both UTI and cystitis, whereas "pyelonephritis" was restricted to acute and chronic pyelonephritis.

The authors mention that the association between obesity and infection could have medical and financial implications. "[T]he high incidence of infection observed in the obese population places a meaningful financial burden on health care resource use and may also lead to other medical complications," the authors write. "Further study to determine whether weight loss among the obese population translates to a reduced risk of infection should be undertaken."

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Systemic Effects of Inhaled Corticosteroids

Abstract

Purpose of review:Although inhaled corticosteroids (ICSs) are the mainstay of therapy in asthma, their use raises certain safety concerns. We review the articles appearing in the last year which have addressed the safety of ICSs when used in the treatment of asthma and chronic obstructive pulmonary disease (COPD).

Recent findings: Recent studies suggest that patients with asthma as opposed to COPD do not experience an excess risk of pneumonia with ICS use. Patients with respiratory diseases are at increased risk of developing active tuberculosis and this excess risk is exacerbated by the use of high doses of ICSs. ICSs have systemic effects and one result appears to be an increase in the risk of diabetes onset and progression, especially at high doses of ICSs. When examining cases of glaucoma requiring therapy, there was no increase in risk with ICSs even at high current and cumulative doses. Finally, use of even high doses of ICSs during pregnancy does not appear to affect foetal adrenal function.

Summary ICSs are a highly effective therapy in asthma and have an excellent safety profile at the low doses usually required in asthma. Adverse effects appear mostly at higher doses.

Introduction

Inhaled corticosteroids (ICSs) are the mainstay of asthma therapy at all ages. Their broad anti-inflammatory activity controls the airway inflammation underlying airway hypersensitivity to viral infections, allergens and irritants. ICSs are the only asthma medication that has been shown to reduce mortality and the risk of hospitalization over the long term.^[1] Most of the therapeutic benefit is obtained at low doses such as fluticasone 200mg/day or the equivalent,^[2] whereas adverse effects increase with increasing dose in an apparently linear fashion.^[3] It is therefore important to use the lowest effective dose possible and to attempt to reduce the dose further in patients whose asthma has been well controlled for several months. Such dose lowering is made safer by providing patients with an effective action plan to increase the dose for a short period of time if symptoms worsen.

Pharmacologic Considerations

Although the various ICSs available are all therapeutically effective, certain products present safety advantages worth considering. Budesonide has the most evidence for safety during pregnancy and is therefore the drug of choice for women considering having children.^[4] Ciclesonide has substantially less systemic activity than other available ICSs, such that it may be preferred in patients requiring higher doses or in children in whom growth retardation is of significant concern.^[5,6•] Furthermore, ciclesonide appears to be associated with fewer upper airway adverse effects such as hoarseness and pharyngeal candidiasis than other ICSs of similar potency such as fluticasone.^[7]

 

ICSs are metabolized via the cytochrome P450 system, which is involved in biotransformation of the vast majority of all drugs currently available.^[8,9] Therefore, patients often find themselves taking several medications competing for the same enzymes, which are required for their biotransformation into inactive compounds, which can then be excreted. The cytochrome P450 enzyme most commonly involved in drug metabolism is the CYP3A4 isozyme, which is responsible for the first-pass metabolism by the liver of the commonly used ICSs. Inhibition of this metabolism of ICSs can be temporary and concentration dependent (competitive inhibition) or irreversible through formation of a stable metabolic intermediate through permanent binding of the inhibiting drug with the P450 enzyme. Irreversible inhibitors are of particular relevance because they can decrease the first-pass clearance and functional catalytic activity of drugs that are cleared by CYP3A4 until new enzyme can be manufactured.^[10] Examples of commonly used irreversible inhibitors of CYP3A4 are clarithromycin, erythromycin, isoniazid, carbamazepine, tamoxifen, ritonavir, verapamil and fluoxetine.^[10] Such interactions may be of particular relevance to patients with chronic obstructive pulmonary disease (COPD), as systemic inflammation appears to be a common accompaniment to COPD^[11] and inflammation and infection are associated with a further downregulation of cytochrome P450 enzymes.^[12] Severe adrenal insufficiency is now a well recognized adverse outcome of concomitant use of the ICS fluticasone and the potent cytochrome P450 inhibitor ritonavir.^[13,14] Macrolide antibiotics (clarithromycin and erythromycin) and the quinolone ciprofloxacin (a strong competitive inhibitor of cytochrome P450 enzymes^[15]) are commonly used in patients with respiratory disease. Although less potent inhibitors of cytochrome P450 than ritonavir, the repetitive use of such medications may plausibly be related to an increased risk of adverse effects seen with ICSs.

Inhaled Corticosteroids and Pneumonia

The TORCH (Toward a Revolution in COPD Health) trial, comparing the effect of fluticasone, salmeterol or their combination versus placebo on mortality in COPD patients, was the first to report an excess of pneumonia in patients receiving the ICS fluticasone.^[16] In a large observational study of over 175 000 patients identified using health administrative databases from the province of Quebec, we confirmed this excess.^[17] Patients with COPD who had a current prescription for an ICS were 70% more likely to be hospitalized with a primary diagnosis of pneumonia: relative risk (RR) 1.70, 95% confidence interval (CI) 1.63–1.77. The risk was greatest for those receiving the highest doses equivalent to fluticasone 1000 mg/day, RR 2.25, 95% CI 2.07–2.44. An excess of pneumonia was also confirmed in a meta-analysis of clinical trials of ICSs in COPD.^[18] Surprisingly, a meta-analysis of individual patient data restricted to clinical trials of budesonide in patients with COPD did not find an excess of pneumonia.^[19] Whether or not there is an excess in mortality resulting from pneumonia contracted by patients with COPD who are prescribed ICSs appears to be controversial. In the large observational study we carried out in Quebec, we found that ICS was associated with a 53% (95% CI 30–80%) excess in pneumonia hospitalization ending in death within 30 days.^[17] Inhospital mortality was not different between those prescribed and not prescribed ICS before the event. No excess in total mortality was found in the metaanalysis of clinical trials of ICSs in COPD.^[18] This may reflect the younger, healthier clinical trial populations and the lack of information on causespecific mortality. In a reanalysis of the TORCH study, a greater number of pneumonia deaths was seen in the group assigned to fluticasone alone, although no firm conclusion could be made because of the small number of events.^[20] A recent report from the Veterans Administration in the USA found that among patients with a listed diagnosis of COPD hospitalized for pneumonia, those who had been prescribed ICSs as outpatients actually had a lower in-hospital mortality.^[21] This is ikely due to differences in type and severity of respiratory disease in patients prescribed ICSs. Specifically, such patients are more likely to have an asthmatic component to their obstructive lung disease and this is associated with a better prognosis. Recently, Singanayagam et al. ^[22•] carried out a careful study of community-acquired pneumonia in patients with COPD confirmed by spirometry and found no difference in mortality after a hospitalization in relation to prior ICS use, whether alone or combined with a beta-agonist bronchodilator. Thus, although in-hospital mortality is likely unrelated to prior treatment with ICSs, the risk of severe pneumonia is increased and therefore, at least in our study, there is a clear excess of pneumonia mortality with ICSs.

It is easy to conceive that ICSs might be associated with an excess in pneumonia, given the chronic bacterial colonization found in many patients with COPD. Furthermore, there is evidence that corticosteroids reduce local defences in peripheral airways of patients with COPD.^[23] One would expect that patients with asthma might behave differently. O'Byrne et al. ^[24•] carried out a metaanalysis of clinical trials of budesonide compared to placebo or to fluticasone among patients with asthma. There was no excess of pneumonia reported as a severe adverse event with budesonide and there was no difference in the risk of pneumonia between budesonide and fluticasone in patients with asthma. When including milder events, budesonide was actually protective. This protective effect is likely explained by a reduction in asthma exacerbations associated with mucus plugging and atelectasis that might be reported as pneumonia radiographically.

Inhaled Corticosteroids and Tuberculosis

Oral corticosteroids are a recognized risk factor for the development of active tuberculosis. Our group investigated whether the risk of tuberculosis was also increased in users of ICSs using the Quebec healthcare administrative databases.^[25•] We identified a cohort of 427 648 patients treated with respiratory medications who were on average 52 years of age (±27 years) at cohort entry. Overall, the risk of active tuberculosis amongst this population of patients with respiratory disease was nearly four times that of the general population. Current users of ICSs were slightly more likely to develop tuberculosis, RR 1.33, 95% CI 1.04–1.71. This risk was confined to patients who had not received oral corticosteroids in the prior year, such that ICSs did not confer an additional risk to that of oral corticosteroids. Amongst patients who had not been dispensed oral corticosteroids in the last year, the risk of active tuberculosis was increased almost twofold with higher doses of ICSs equivalent to 1000μg or more per day of fluticasone (RR 1.97, 95% CI 1.18–3.30).

Inhaled Corticosteroids and Diabetes

Studies from the 1990s did not find an association between the use of ICSs and risk of diabetes.^[26] Lower doses of ICSs were being used at that time and these medications were used less extensively in elderly patients with COPD who are at greater risk of diabetes. We therefore re-examined the risk of diabetes onset and progression in a large cohort of patients prescribed respiratory medications followed up to the end of 2007.^[27•] Amongst 388 584 patients without prior treatment for diabetes, there was a 34% increase in the risk of newonset diabetes (RR 1.34, 95% CI 1.29–1.39). Risk was greatest at higher doses of ICSs equivalent to 1000 μg or more per day of fluticasone (RR 1.64, 95% CI 1.52–1.76). Amongst 30 167 patients who developed diabetes during follow-up, 2099 progressed from oral agents to insulin. The risk of such a progression was also higher amongst patients dispensed ICSs (RR 1.43, 95% CI 1.17– 1.53).

Inhaled Corticosteroids and Glaucoma

Glaucoma is the leading cause of blindness worldwide. Raised intraocular pressure is a risk factor for glaucoma and ocular and systemic corticosteroids increase intraocular pressure. Whether or not ICSs raise intraocular pressure is less clear. An earlier study by Garbe et al. ^[28] found an increased risk of glaucoma among users of ICSs. Nearly half of the glaucoma cases were not associated with any therapy, however, thus putting into question the validity and importance of these diagnoses. Furthermore, this earlier study was carried out before the availability of the newer more potent ICSs such as fluticasone. We therefore carried out a large observation cohort study based on the health administrative databases of the Province of Quebec [29•]. Cases were chosen from amongst 196 964 patients 66 years of age or older dispensed respiratory medications. Cases were patients who had visited an ophthalmologist in the prior 90 days and who had been dispensed medication for glaucoma or underwent surgery for this condition. Controls were patients who had visited an ophthalmologist within the same time period but who did not receive a glaucoma diagnosis or treatment for this condition. Therewas no difference in the use of ICSs between the 2991 cases and the 13 445 controls (RR1.05,95%CI 0.91–1.20).Noexcess riskcouldbe demonstrated at the highest doses of ICSs equivalent to 1000 μg or more per day of fluticasone, nor when limiting the analysis to patients who had or had not been dispensed oral corticosteroids. We also examined the effect of cumulative dose of ICSs and found no increase in risk of glaucoma. Therefore, ICSs may be used without incurring an increase in risk of glaucoma requiring therapy. This is in contrast to the increased risk of cataractswhich is seen even with low doses of ICSs in the elderly.^[30,31]

Inhaled Corticosteroids and Pregnancy

Poorly controlled asthma is associated with poor pregnancy outcomes including preeclampsia, preterm birth and low birth weight.^[32] These can be prevented with regular use of ICSs,^[33] and therefore ICSs during pregnancy are recommended in current guidelines. Despite this, there is lingering concern regarding the safety of ICSs during pregnancy. As an illustration, a recent report linked the use of high doses of ICSs dispensed in the first trimester of pregnancy to an increase in the risk of congenital malformations.^[34] An earlier report from the same group had not found an excess risk at lower doses of ICSs.^[35] A report published this year examined the effect of ICSs use during pregnancy and maternal and foetal hormone levels.^[36•] Although a dosedependent suppression of maternal hormone levels was seen (cortisol, osteocalcin), there was no effect on foetal adrenal function even at high maternal doses of ICSs.

Conclusion

ICSs are a highly effective therapy in asthma and have an excellent safety profile at the low doses usually required in asthma. Adverse effects appear mostly at higher doses which can usually be avoided by using combinations of different therapeutic classes and decreasing the dose of ICSs once asthma control has been achieved. If high doses of ICSs are required for prolonged periods, consideration should be given to using an ICS with less systemic activity such as ciclesonide.

Sidebar

Key Points

• In contrast to patients with chronic obstructive pulmonary disease, patients with asthma prescribed inhaled corticosteroids (ICSs) do not appear to be at increased risk of pneumonia.
• High doses of ICSs increase the risk of reactivation of tuberculosis, although this is not additive to the risk of oral corticosteroids.
• High doses of ICSs increase the risk of clinically overt diabetes and the progression to insulin therapy.
• ICSs, even at high doses, do not seem to increase the risk of glaucoma requiring therapy.

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1. Papers of particular interest, published within the annual period of review, have been highlighted as:
   •of special interest
   ••of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp.93-94).

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Abnormal Urine Color

Ryan D. Aycock, MD, MS; Dara A. Kass, MD

Posted: 01/31/2012; South Med J. 2012;105(1):43-47. © 2012 Lippincott Williams & Wilkins

Abstract

A change in urine color can be distressing for patients and physicians alike. Many of the causes of abnormal urine color are benign effects of medications and foods; however, a change in urine color may be a sign of an underlying pathological condition. The good news is that in many cases the diagnosis can be determined from a thorough history and urinalysis. This article presents many of the conditions physicians may encounter and will help them form a narrow differential diagnosis and treatment plan.

Introduction

Abnormal urine color can be distressing to patients, their family members, and clinicians alike. Patients expect an explanation for any alterations in the color of their urine, and rightfully so. Unfortunately, little original research exists regarding urine discoloration. Much of the information comes from case reports. Further complicating the issue is that there is no objective, standardized way to describe urine color.^[1] One author may use the term "dark" to describe findings without fully defining the term to mean either a bolder shade of yellow, muddy brown, orange, or even a crimson red.^[2]
 

More than 20 years ago, the Southern Medical Journal published a review article on the differential diagnosis of various urine colors.^[3] Although useful at that time, clinicians are unlikely to perform benchtop chemistry tests such as adding hypochlorite bleach to urine samples to determine the presence of aminosalicylic acid. The present review attempts to list many of the conditions physicians may encounter and help them form a narrow differential diagnosis and treatment plan. The Fig. lists many of the potential causes of different urine colors that are described in detail in the review.

  Figure 1.  Differential diagnosis of disorders and ingestions that can lead to abnormal urine colors.

Red Urine

The first problem we encounter with word "red" is that the term is broad enough to encompass the colors pink, shades of red, orange, brown, or black, depending on which clinician views the sample.^[4] Whenever a patient develops red urine, the physician should always order a urine dipstick and urinalysis to look for the presence of red blood cells or hemoglobin. If blood is truly present, then the differential is broad and includes disorders of the renal collecting system^[5] and hematologic system,^[6,7] and contamination from menstrual blood. Additional workup will be guided depending on the patient's history and physical examination. A computed tomography scan may elucidate an anatomical problem such as entrapment of the left renal vein between the superior mesenteric artery and the aorta, also known as Nutcracker syndrome.^[8] A transfusion reaction, glucose-6 -phosphate dehydrogenase deficiency,^[9,10] sickle cell anemia, or thalassemia can lead to a hemolytic anemia and darken the urine to a deep reddish color.

Even without the presence of blood, dark red urine could be an ominous sign. The classification of diseases collectively known as porphyria can present with dark urine,^[11] abdominal pain, photosensitive rashes, or neuropsychiatric complaints.^[12] The disease is difficult to detect because it is rare. In addition, many hospital laboratories are ill equipped to perform porphyrin analysis on urine, further delaying treatment.

A relatively new development in US toxicology practice is the use of hydroxocobalamin for cyanide poisoning.^[13] The traditional treatments for cyanide poisoning—amyl nitrite, sodium nitrite, and sodium thiosulfate—can induce methemoglobinemia, further reducing the oxygen-carrying capacity of red blood cells. Hydroxocobalamin works by combining with cyanide to form cyanocobalamin (vitamin B^[12]).^[14] An unintended yet benign consequence of its administration is to color the skin and urine red.^[15] The effects usually wear off after a few days.^[16]
 
Other medications associated with red urine development include warfarin,^[17] phenazopyridine,^[18] rifampin,^[19] ibuprofen, and deferoxamine.^[20] Certain foods such as carrots (carotene),^[21] blackberries, and beets can occasionally cause red urine.^[22,23] Curiously, beeturia seems to be linked to the co-ingestion of oxalate-containing foods such as rhubarb, spinach, and oysters.^[24]
 
Finally, a patient with factitious disorder may present with red urine from adding blood or another red-colored material directly to his or her sample.^[25–27] These patients may present with otherwise nonspecific complaints and will undergo an extensive but futile workup. Malingering is difficult to diagnose and may require repeat urine samples obtained under direct observation to finally uncover the disorder.

Orange Urine

Continuing along the spectrum of red disorders, orange urine may be a manifestation of one of the above-named conditions or ingested substances such as high-dose riboflavin,^[28] phenazopyridine,^[29] and isoniazid. According to one study, 50% of isoniazid users will notice discoloration, making the finding common but insensitive when checking for compliance.^[30] The discovery is harmless and requires no further workup if there are no additional complaints.
Curiously, one case report mentions an infant with orange urine caused by a urinary tract infection.^[31] The apparent cause was a Gram-negative bacillus that produces indole from tryptophan. The conclusion reached by the authors is peculiar in that indole reactions usually produce blue, green, or purple urine.

Brown Urine

As red urine becomes darker, some clinicians may interpret the color as brown. As a result, any of the disorders or ingestions listed above should be considered whenever a sample is thought to be brown. In the 1980s, a case series on acetaminophen overdose demonstrated that in addition to hepatorenal failure, three patients developed brown urine because of the buildup of the metabolite p-aminophenol.^[32]
 
Brown urine could be a sign of melanocytes in the urinary system. Metastatic melanoma can lead to a rare condition called diffuse melanosis, causing dark skin, distant lesions to the internal organs, and brown or black urine.^[33] One case report mentions a patient with acute kidney injury from melanin accumulation in the tubular system.^[34] The prognosis is poor at this point.

Black Urine

Black urine rounds out the discussion of causes of reddish urine discoloration. Many of the conditions listed above can present with black urine if the discoloration is dark enough; however, several of the conditions listed below are dangerous enough that the presence of black urine requires additional workup. Example causes include metronidazole,^[35] nitrofurantoin, cascara or senna laxatives, methocarbamol, sorbitol, and the phenol derivative cresol,^[36] a common disinfectant ingested by alcoholics, which often is debilitating and leads to severe systemic toxicity.^[37] Intramuscular iron injections are also associated with black urine as a benign effect of the medication.

Patients in this case simply need reassurance.^[38] The presence of melanin in the urine can cause brown discoloration, as discussed above, or with a black tint. >-Methyldopa and L-dopa can induce urinary melanin in alkalotic urine, which is a known adverse effect of these medications.^[39] Alcaptonuria is a rare hereditary disease in which the body has a weakened ability to catabolize tyrosine, leading to an accumulation of homogentisic acid in the body.^[40] It presents clinically with arthritis and darkening of the skin and urine.^[41] The diagnosis is made by measuring homogentisic acid in the urine.^[42] There is no cure, however, and treatment consists of high-dose vitamin C and limiting protein intake.

Blue and Green Urine

Blue urine most typically appears to be caused by ingestion of methylene blue.^[43,44] This substance is used in the United States for diagnostic tests, treatment of methemoglobinemia,^[45,46] or as a treatment for refractory hypotension.^[47] Outside the country, however, oral methylene blue may be found in medications and home remedies because it has antimicrobial properties.^[48,49] True blue urine seems to be exceedingly rare, possibly because blue pigments combine with urochrome, the major contributor to urine's normal yellow hue, to create a green color before urine's elimination. In that regard, there are many case reports in which methylene blue turns urine green.^[50–52]
 
Other medications associated with green urine may contain phenol groups and include promethazine,^[52] thymol,^[53] cimetidine,^[54] and propofol.^[55–58] The mechanism of action appears to be caused by phenol's conjugation by the liver and subsequent excretion by the kidneys.^[59,60] The strength of the green seems to be dose related.^[58] Curiously, propofol also is associated with pink^[61] and white urine.^[62]
 
Some nonphenol drugs noted to produce green urine are metoclopramide,^[63] amitriptyline,^[64] and indomethacin. In any event, the urinary findings of all of the above medications are benign effects and do not acquire further workup once urinalysis results are normal.

There are isolated case reports of parenteral absorption of tetrahydronaphthalene (Cuprex),^[65] a pesticide that was used in the 1980s as an over-the-counter treatment for lice, and ingestions of the herbicides mefenaceta and imazosulfuro producing green urine.^[66] A patient who has come in contact with these compounds should be treated as if he or she were poisoned and deserves full toxicology workup, stabilization, and possible admission to the intensive care unit.

In the critical care setting, patients receiving enteral tube feeds have on occasion been noted to produce green urine. The belief is that the food coloring additive Food Dye and Color Blue Number 1 (FD&C Blue No. 1) is absorbed from the gastrointestinal (GI) tract in high enough concentrations to cause dark green urine.^[67,68] In animal models, >1% of FD&C Blue No. 1 is found in rat urine.^[69] This finding is harmless and disappears with changes in tube feeds.

Not all causes of green urine are innocuous, however. Pseudomonas-causing bacteremia and urinary tract infections can present with green urine.^[60,64] In this case, the patient's history and physical examination should point to an infectious disorder and urine and blood cultures may make the diagnosis. Treatment is centered on clearing the infection rather than on urine color.

Bile pigments in the urine represent a rare but worrisome cause of discoloration. Upon discovering biliverdin, clinicians must take a careful and thorough history to determine the location of the leak. Radiographs or invasive imaging may even be required. A case report of an enterovesical fistula caused by pelvic radiation therapy provides one such source of bile.^[70] Other rarer causes of blue and green urine include conditions that impair amino acid absorption from the GI tract.

Blue diaper syndrome^[71] and Hartnup disease^[60] are autosomal recessive disorders in which tryptophan builds up in the GI tract, causing bacteria to metabolize it to indole, leading to a buildup of indican in the urine. The blue coloring by itself is not dangerous, but it does point to another underlying condition that requires investigation.

Purple Urine

The only known cause of purple urine is purple urine bag syndrome. This usually benign condition is thought to arise from a series of steps in which tryptophan in the GI tract is converted to indole,^[72] the indole is then metabolized by the liver and excreted by the kidneys, and the final product undergoes transformation by bacteria in the urine to create indigo (a blue pigment) and indirubin (a red pigment).^[73] These pigments combine to form purple urine that then stains the polyvinylchloride of a Foley catheter.^[74] Purple urine is associated with Gram-negative bacteruria and typically resolves after treatment with antibiotics and changing the catheter.^[75,76]

White Urine (Albinuria)

Albinuria has a wide differential diagnosis and requires a more thorough investigation beyond a simple urinalysis. Sediment from minerals in the urine such as hypercalciuria, phosphaturia, or hyperoxaluria occasionally can be discovered after centrifugation and analysis.^[77] Consultation with a nephrologist is recommended at this point because changes in dietary intake and medication initiation may be required. Severe urinary tract infection is one possible cause of white urine because purulent fluid may enter the bladder.^[78] In addition, caseous material from urinary tuberculosis also should be entertained. Careful urine culture is required, followed by antibiotic therapy.

Chyluria is another possible diagnosis. It arises from abnormal communication between the lymphatics to the urinary tract, most commonly as a result of filariasis,^[78] but also can be the result of a lymphatic fistula.^[79] Antiparasitic drugs are of no benefit because the urine is usually sterile by this point. Referral to a urologist is necessary because the patient may require intervention to close the communication.

Conclusions

A change in urine color can be distressing for patients, their family members, and clinicians alike. This article presented many of the potential causes of urine discoloration. Luckily, many of these causes are benign effects and can be elucidated from a detailed history. At a minimum, however, physicians should order a urinalysis when confronted with an abnormal urine color because potential pathologies do exist.

Key Points

• Diagnosing the cause of abnormal urine color usually can be made using a patient's history alone.
• When encountering abnormal urine color, a physician must, as the first step, order a urinalysis.
• Treating the underlying condition leads, in general, to resolution of urinary symptoms.

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Bydureon: An Easy, Effective New Treatment for Type 2 Diabetes

Hi. I am Dr. Anne Peters, and today I am going to talk about long-acting exenatide (Bydureon™; Amylin Pharmaceuticals; San Diego, California). Bydureon is basically short-acting exenatide (also known as Byetta^®) that is incorporated into microspheres that make it very long-acting. Therefore, you only have to give it once a week. Bydureon is "once-a-week Byetta." Many things about this drug are very similar to Byetta. Byetta is a GLP-1 agonist. These drugs work like GLP-1 in the body: They improve insulin secretion, they lower blood glucose levels, they lower glucagon levels, and they help patients lose weight.

Bydureon is perhaps even a little more effective than Byetta. You get a somewhat greater reduction in A1c and maybe a slightly greater weight loss. Results, as you well know, vary based on the individual patient, but overall the drug seems to be well tolerated and effective in clinical trials. In terms of side effects, as with all of the GLP-1 agonists, the most common side effects are gastrointestinal, and the most common is nausea. Bydureon causes less nausea than with the shorter-acting Byetta, perhaps because it is much more slowly absorbed and patients get used to it and are able to tolerate the dose. You don't dose-adjust Bydureon; you start out with 2 mg per week, and that is what a patient continues on. They are not changing the dose over time.

In terms of other side effects, there is a black box warning for medullary thyroid carcinoma, because in rodents there is an increase in C-cell tumors, both malignant and benign, with this agent. It is not known if this occurs in humans, but because of the rodent data, there is a black box warning. This drug should not be used in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia (MEN) syndrome. There is also a warning about pancreatitis, and as we know from other GLP-1 agonists on the market, pancreatitis has been reported with these agents. We don't know for sure whether these agents cause pancreatitis, but because of these reports, it is in the label and we need to warn patients to look for signs and symptoms of pancreatitis. If they develop them, they need to come to medical attention to be diagnosed and treated appropriately.

Otherwise, most of the warnings and indications are similar to what you are used to, although this drug has an interesting indication: It can be used as monotherapy (but not as first-line monotherapy), which basically means that after diet and exercise are not effective, patients are started on metformin. If metformin isn't tolerated, then they can take Bydureon as a second-line monotherapy. It is also approved for use with other oral agents with sulfonylurea agents, thiazolidinediones, and metformin, but it is not currently approved for use with insulin or in children.

To get to the practical nitty-gritty, I am going to show you a picture of what a vial looks like. This is a 2-mg vial, and patients will use one of these weekly. As you can see, patients have to reconstitute this drug and they need to reconstitute it just before they use it. They cannot reconstitute in advance and then give later.

Bydureon will come in a box. This is the box, and in this box is everything the patient needs for reconstituting the agent. There are careful step-by-step instructions that patients are to follow to give this. It is a subcutaneous injection, but in the immediate term, they are going to need to do this preparation to give the drug. The manufacturer is working on a pen that will be much simpler.

From my own perspective, this is a lot like giving glucagon. My patients, at least those on insulin, know how to give glucagon. I am just going to show you how you mix up a glucagon injection, which is a lot like mixing up a Bydureon injection except that there are going to be more careful instructions. There is also an orange connector that connects the two. Inside the Bydureon box will be a syringe that has diluent in it. In essence, the patient will have to inject the diluent into the vial, mix it up, then pull out the solution and pull it back and give the injection. After the first time a patient does this they will find it pretty simple, but it is important to go through this with your patients and then refer them to appropriate resources in case they need to know anything more about giving the drug.

In terms of other practical features, this should be available in pharmacies in February, so pretty quickly patients will be able to use this. In terms of cost, if you just buy it over the counter it is going to cost a little bit more than Byetta and a little bit less than the maximal dose of liraglutide. In terms of formularies, we will see how that plays out. For some formularies, this is just going to be a line extension of Byetta, just a once-a-week form. They may accept it early. Others may take a while, but I am really excited that we now have another drug and perhaps a drug that for some patients will make adherence easier, because this is now just a once-a-week injection as opposed to giving injections more often. This is Dr. Anne Peters for Medscape.

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2012 Adult Immunization Schedule: The Key Changes

Dr. Sandra Fryhofer: Hello, I'm Dr. Sandra Fryhofer. Welcome to Medicine Matters. The topic is key changes in the 2012 adult immunization schedule, which was published in Annals of Internal Medicine.^[1,2]

Here is why it matters.

Vaccinations are vital to our nation's heath. The Advisory Committee on Immunization Practices (ACIP) has now adopted an evidence-based process for reviewing data and economic impact.

Human Papillomavirus

For specific recommendation changes, let's start with the human papillomavirus (HPV) vaccine, which is no longer just for girls. The new HPV recommendation: routine vaccination for males aged 11 through 21 years. (Routine vaccination for females is recommended for those aged 11 through 26 years). Female vaccination rates are now low, which makes male vaccination more cost-effective. Routine HPV vaccination in men who have sex with men is recommended through age 26 years; it is cost-effective, regardless of coverage rates in females.

Hepatitis B

Hepatitis B vaccination is now recommended routinely for adults with diabetes who are younger than age 60 years. Those with diabetes age 23 through 59 years have more than twice the risk for contracting hepatitis B compared with people without diabetes. Those with diabetes who are age 60 years or older may be vaccinated at physician discretion.

Tdap and Pertussis Protection

Recommendations for adult tetanus, diphtheria, and pertussis (Tdap) vaccination concern pertussis protection and, specifically, cocooning infants and young children by vaccinating family and household contacts, including those over age 65 years. The new change is when to vaccinate pregnant mothers, which should be during pregnancy, after 20 weeks' gestation. Timing the vaccination this way will allow the mother's antibodies to pass on to the fetus.

Influenza

In the latest recommendations, egg allergy is no longer a contraindication to the influenza vaccination, although egg-allergic patients must get the inactivated shot because that is what has been studied. In addition, the new intradermal influenza vaccine, with its microinjector apparatus and ultrafine needle, is an option for adults aged 18 through 64 years. Finally, everyone over 6 months old should be vaccinated for flu, and this includes healthcare workers.

Another heads-up: the American College of Physicians has just released the fourth edition of the Guide to Adult Immunization, and there is even a mobile app in the works. So please, keep vaccinating.

For Medicine Matters, I'm Dr. Sandra Fryhofer.

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