COPD-Guidelines-2

According to ACP/ACCP/ATS/ERS, when to use combination therapy instead of monotherapy has not been clearly established. The evidence is insufficient to support a strong recommendation for the broad use of combination therapy, and clinicians should weigh its potential benefits and harms on a case-by-case basis. Taking this into consideration, the guideline suggests that clinicians may administer combination inhaled therapies (LAAC, LABA, or ICS) for symptomatic patients with stable COPD and FEV₁ < 60% predicted.

GOLD recommends against regular use of antitussives, immunoregulators, mucolytic agents, antioxidant agents, AAT augmentation therapy (for COPD that is unrelated to AAT deficiency), and vasodilators. GOLD is the only guideline developer to address phosphodiesterase-4 inhibitors, specifically roflumilast. According to GOLD, roflumilast can reduce exacerbations treated with oral or systemic glucocorticosteroids, and these effects are seen when it is added to long-acting bronchodilators. Note that ACP/ACCP/ATS/ERS provided no guidance in this area.

Other points made in recommendations:

GOLD also says that treatment for very severe COPD can be administered in 3 ways: long-term continuous therapy, during exercise, and to relieve acute dyspnea. 

UMHS points out that in patients with very severe COPD, long-term oxygen therapy has been shown to improve the following outcomes:

• Mortality
• Quality of life
• Cardiovascular morbidity (ie, pulmonary hypertension)
• Depression
• Cognitive function
• Exercise capacity
• Frequency of hospitalization

Virtually no adverse effects occur with long-term oxygen therapy.

Appropriate patient education topics cited by GOLD and UMHS include: information about the nature of COPD, including pathophysiology, triggers, and risk factors; smoking cessation; advance directives and end-of-life decisions; exacerbation recognition and self-management; strategies to help minimize dyspnea; and appropriate usage of inhalers, oxygen, and medications.

GOLD describes bullectomy as an older surgical procedure for bullous emphysema. Removal of a large bulla that does not contribute to gas exchange decompresses the adjacent lung parenchyma. Bullectomy can be performed thoracoscopically. In carefully selected patients, this procedure is effective in reducing dyspnea and improving lung function. Note: ACP/ACCP/ATS/ERS did not provide guidelines for surgery.

GOLD notes that in appropriately selected patients with very advanced COPD, transplantation has been shown to improve quality of life and functional capacity. UMHS adds that consideration of transplantation potential requires comanagement with a pulmonary specialist for detailed assessment of baseline pulmonary physiology and potential contraindications.

ACP/ACCP/ATS/ERS did not provide guidelines for surgery.

COPD: Guideline-1

What they say about spirometry:
ACP, ACCP, ATS, and ERS recommend that spirometry should be obtained to diagnose airflow obstruction in patients with respiratory symptoms. Spirometry should not be used to screen for airflow obstruction in individuals without respiratory symptoms.

GOLD: For the diagnosis and assessment of COPD, spirometry is the gold standard as it is the most reproducible, standardized, and objective way of measuring airflow limitation. The presence of a postbronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity < 0.70 confirms the presence of airflow limitation that is not fully reversible.

UMHS: Spirometry is the diagnostic "gold standard" because it is the most reproducible, standardized, and objective way of measuring airflow limitation. Spirometry should be ordered with bronchodilator and the postbronchodilator values used to assess both the presence of airflow obstruction and severity.

Areas of Difference in Clinical Presentation and Spirometry

What they say about spirometry to screen for airflow obstruction in asymptomatic patients, including those with current or past exposure to risk factors for COPD:

GOLD: A clinical diagnosis of COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors for the disease.

UMHS: Consider COPD in any patient with dyspnea, chronic cough or sputum production, and/or a history of inhalational exposures known to be risk factors.

ACP/ACCP/ATS/ERS: Spirometry should not be used to screen for airflow obstruction in individuals without respiratory symptoms. There is no difference in the annual rate of FEV₁decline or prevention of symptoms in these individuals with treatment. No evidence from randomized controlled trials supports treating asymptomatic individuals, with or without risk factors for airflow obstruction, who do not have spirometric evidence of airflow obstruction. In addition, evidence does not show any independent benefit of obtaining and providing spirometry results on success rates in smoking cessation.

What GOLD and UMHS said about imaging use for COPD (Note: ACP/ACCP/ATS/ERS did not provide recommendations):

GOLD: An abnormal chest x-ray is seldom diagnostic in COPD unless obvious bullous disease is present, but it is valuable in excluding alternative diagnoses and establishing the presence of significant comorbidities such as cardiac failure. CT of the chest is not routinely recommended. However, when there is doubt about the diagnosis of COPD, high-resolution CT scanning might help in the differential diagnosis. In addition, if a surgical procedure such as LVRS is contemplated, a chest CT scan is necessary.

UMHS: Routine chest x-ray may suggest a diagnosis of COPD, particularly if it demonstrates hyperinflation. However, a chest x-ray should not be considered diagnostic of the disease. Current evidence is not sufficient to recommend routine chest CT in early or moderate COPD. In patients with severe disease, high-resolution CT is required to evaluate the appropriateness of therapies such as LVRS or transplant.

What GOLD and UMHS said about AAT deficiency screening (Note: ACP/ACCP/ATS/ERS did not provide recommendations):

GOLD: In white patients who develop COPD at a young age (< 45 years) or who have a strong family history of the disease, it may be valuable to identify coexisting AAT deficiency. This could lead to family screening or appropriate counseling. A serum concentration of AAT below 15%-20% of the normal value is highly suggestive of homozygous AAT deficiency.

UMHS: Assess for deficiency in settings of clinical suspicion: age < 45 years, absence of other risk factors or severity of disease out of proportion to risk factors, prominent basilar lucency, family history, or bronchiectasis

What GOLD and UMHS said about other investigations (Note: ACP/ACCP/ATS/ERS did not provide recommendations):

GOLD: In advanced COPD, measurement of arterial blood gases while the patient is breathing air is important. The inspired oxygen concentration ... should be noted, a particularly important point if patient is using an O₂-driven nebulizer... [Twenty] to 30 minutes should pass before rechecking the gas tensions when the FiO₂ has been changed ... Adequate pressure must be applied at the arterial puncture site for at least 1 minute, as failure to do so can lead to painful bruising.

UMHS: In patients with a room air resting oxygen saturation between 89% and 93%, a 6-minute walk test with oxygen saturation should be considered to rule out ambulatory desaturation (see indications for supplemental oxygen therapy in the original guideline document).

GOLD and UMHS agree that pharmacologic therapy should proceed in a stepwise progression based on disease severity, recommending a short-acting beta agonist when needed for all stages of COPD, long-term treatment with a long-acting beta agonist (LABA) for patients with FEV₁ 50%-79% predicted, and addition of an ICS for patients with frequent exacerbations and FEV₁ < 50% predicted. The groups further agree that inhaled bronchodilators are preferred to theophylline, and maintenance treatment with oral corticosteroids is not recommended in COPD.

What else they said:
For patients with FEV1 between 60% and 80% predicted, ACP/ACCP/ATS/ERS suggest that treatment with inhaled bronchodilators may be used, noting that there is limited and conflicting evidence of health benefits resulting from initiation of inhaled bronchodilators (anticholinergics or LABA) in this patient population.

With regard to selection of an inhaled bronchodilator (LABA or long-acting anticholinergic [LAAC]), ACP/ACCP/ATS/ERS and GOLD recommend the choice be made on the basis of availability, patient preference, cost, and adverse effects. UMHS differs from the other 2 groups in that it recommends a LAAC (specifically tiotropium) be considered the first-line agent for baseline bronchodilator control.

Reflex sympathetic dystrophy (Sudeck's osteodystrophy)

Reflex sympathetic dystrophy:

A constellation of changes involving the sympathetic nervous system, which has been known under many names (causalgia, Sudeck's osteodystrophy, posttraumatic osteoporosis, algodystrophy, shoulder hand syndrome). This syndrome can be precipitated by any neurally related visceral, musculoskeletal, neurologic or vascular condition. Frequently, however, a cause is not identifiable. Trauma, cerebrovascular disorders, degenerative disease of the cervical spine, discal herniation, postinfectious states, calcific tendinitis, vasculitis and neoplasm have all been associated with reflex sympathetic dystrophy.
Various theories have been advanced to explain the pathogenesis; the most widely held explanation involves the existence of an "internuncial pool." In this theory an injury or lesion is assumed to produce painful impulses that travel via afferent pathways to the spinal cord, where a series of reflexes are initiated that spread via the interconnecting pool of neurons. The lateral and anterior tracts are stimulated, which provokes efferent pathways to the peripheral nerves, producing the local findings of reflex sympathetic dystrophy.

Patients may exhibit variable symptoms and signs, often in the shoulder and hand. Stiffness, pain, tenderness and weakness may be associated with swelling, vasomotor changes, hyperaesthesia and disability. Glenohumeral joint periarthritis may be accompanied by a shoulder hand syndrome.

Radiographically, soft tissue swelling and regional osteoporosis are the most important features (Fig.1). Metaphyseal bone resorption leads to periarticular osteoporosis; subperiosteal bone resorption resembles that seen in patients with hyperparathyroidism; intracortical bone resorption produces excessive striation or tunnelling in cortices; endosteal bone resorption causes initial scalloping of the endosteal surface, with subsequent widening of the medullary canal; and subchondral and juxta-articular erosion may lead to small periarticular erosions. The extensive involvement and the severity of the bone resorption may lead to the radiographic appearance of rapid and severe osteopenia. However, the preservation of the joint space in this syndrome cannot be overemphasized as a characteristic feature of reflex sympathetic dystrophy

Scintigraphy of the bones and joints also shows increased accumulation of radionuclide agents in joints and bones, which may be related to an increased blood flow. Although the disease is bilateral, the abnormalities are much more marked on one side than on the other. Some patients reveal a segmental pattern affecting only a portion of an extremity.

Diabetes Management Protocols

AACE/ACE Diabetes Algorithm for Glycemic Control, HbA_1c 6.5% to 7.5%


The AACE/ACE algorithm considers the incretin-based forms of therapy -- dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists -- as possible first-line agents to be used as monotherapy. Both are efficacious in terms of reduction of HbA1c. Both have extremely good safety profiles in terms of low risk for adverse events and hypoglycemia. These agents are highly recommended for monotherapy when metformin is contraindicated. GLP-1 receptor agonists require injections (twice daily for exenatide, once daily for liraglutide, or once weekly for exenatide QW).

Basal insulin may be associated with hypoglycemia in patients with HbA1c values in this range (<7.5%). Insulin is almost always associated with weight gain and occasionally fluid retention.

Sulfonylureas such as glimepiride may result in hypoglycemia and weight gain. The potential for hypoglycemia is of particular concern in this HbA1c range (≤7.5%). There is also the possibility that sulfonylureas could result in acceleration of the loss of beta-cell function compared with other agents, as was suggested by results from the UKPDS. In contrast to most other algorithms, including the recent 2012 American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) position statement, the AACE/ACE algorithm does not include sulfonylureas as an option for monotherapy, in view of the risk of hypoglycemia, limited durability of effectiveness, and the likelihood of weight gain.

Intensification of treatment is indicated to try to achieve a target HbA1c of 6.5% in patient with recent-onset diabetes and no diabetic complications. Because the major factor contributing to the elevation of HbA1c in this range of HbA1c is postprandial excursion, agents such as DPP-4 inhibitors and GLP-1 receptor agonists that improve postprandial hyperglycemia are preferred (target < 140 mg/dL).

Incretin-based agents are usually associated with minimal risk of hypoglycemia. The DPP-4 inhibitors are weight-neutral; the GLP-1 receptor agonists are generally associated with significant weight loss and occasionally (especially in the morbidly obese patient) with major weight loss. The DPP-4 inhibitors and the GLP-1 receptor agonists have the advantage that they stimulate beta cells to secrete insulin in a glucose dependent manner. This means that as the plasma glucose falls into the normoglycemic range, the effect of the incretin-based medication is reduced or turns off. Thus, as glucose decreases from an elevated level (eg, 150 mg/dL) to a normal or near-normal value (eg, 90 mg/dL), the enhancement of insulin secretion by the incretin-based therapy is reduced. Similarly, inhibition of glucagon secretion by the pancreatic alpha cells turns off as glucose levels fall to normal or low levels, so that glucagon counter-regulation comes back into play when needed.

The extended-release and branded forms of metformin may have better gastrointestinal tolerability than generic metformin.

Intensification of therapy with an insulin secretogogue, such as glipizide or basal insulin, increases the risk of hypoglycemia and weight gain. These agents may also hasten the decline of beta-cell function.

The ADA recommends the use of MNT as an important tool for helping patients with type 2 diabetes achieve therapeutic goals, although it can be a complex intervention for patients. Therefore, patients require educational programs, such as those provided by a CDEs; these clinicians can help patients become active participants in their disease management.
Several studies have evaluated the implementation of MNT and demonstrated that their use results in reductions in A1c and low-density lipoprotein (LDL) cholesterol. As little as a 5% reduction in weight decreases insulin resistance, improves glycemia and lipemia, and reduces blood pressure.
Studies have also shown that diet alone, diet and exercise, and meal replacement can result in sustained weight loss of 4.8% to 8% in patients with type 2 diabetes. The lack of a strict adherence to interventions is a major barrier to achieving recommended goals. Even a 10% decrease in total adherence to therapy with metformin has been shown to produce an increase of 0.14% in A1c.
The DAWN study showed that only 16.2% of patients with type 2 diabetes report being compliant with all the instructions provided by their healthcare providers.

Glycemic Recommendations for Non-pregnant Adults With Diabetes.

A1c	< 7.0%
Preprandial capillary plasma glucose	70-130 mg/dL (3.9-7.2 mmol/L)
Peak postprandial capillary plasma glucose	< 180 mg/dL (<10.0 mmol/L)
General Comments Goals should be individualized, based on: Duration of diabetes Age/life expectancy Comorbid conditions Known cardiovascular disease or advanced microvascular complications Hypoglycemia unawareness Individual patient considerations More or less stringent glycemic goals may be appropriate for individual patients. PPG may be targeted if A1c goals are not met despite reaching preprandial glucose goals.

Specific methods for improving adherence include:

• Verifying patient recall and comprehension of the treatment plan
• Clarifying potential treatment benefits
• Simplifying regimens
• Electronic monitoring
• Minimizing costs
• Discussing adverse events
• Minimizing diabetes-related depression or emotional distress

The ADA and European Association for the Study of Diabetes (EASD) consensus guidelines recommend the addition of insulin in patients whose A1c remains further from the target value of greater than 8.5% or who have symptoms related to hyperglycemia, following the use of oral therapy and lifestyle modification. Therapy should be individualized and insulin can be initiated earlier in the course of disease, as appropriate to lower A1c. The role and rationale for injection therapy was discussed with TC in an earlier visit and barriers to injection were addressed. Other injection therapies, such as the GLP-1 receptor agonists, may help promote weight loss.

Counseling Techniques for Challenging Barriers to Insulin Therapy

Patient Statement	Clinician Response	Technique
"High blood sugar doesn't make me feel tired."	"I would like to know more details about how you feel. For instance, what is it like for you when you get up in the morning?"	Acceptance Questioning Clarification
"I just don't want to use insulin."	"I respect your feelings about that. Can you tell me why it bothers you so much?" Or "I wonder if you would do a short-term experiment to see what insulin does for you. Then you can make an informed decision about insulin."	Acceptance Questioning Negotiation Empowerment
"Well I tried it. Now what?"	"Congratulations. I'm impressed that you were willing to try something new. What you did --taking insulin -- has normalized your blood sugars. I bet you can apply this success to your other efforts-diet and exercise."	Esteem-building Cognitive framing Empowerment
"Having to use insulin must mean I'm getting worse"	"I can understand how you could conclude that. What's happening to you is actually quite normal for people who have had diabetes as long as you have. The purpose of insulin is prevention, not progression."	Acceptance Verification Normalization Positive reframing
"Can't I just try a stronger pill?"	"I know it would be easier if you could. Unfortunately, we don't have any stronger pills. I want to reassure you that insulin is what your body needs at this time. Can you try thinking of insulin as the most appropriate medication at this time to give your body?"	Validation Acceptance Support and information Positive reframing

DPP-4 Inhibitors
One approach to incretin-based therapy involves blocking the degradation of endogenous incretins through the inhibition of dipeptidyl peptidase-4 (DPP-4). The DPP-4 inhibitors include sitagliptin, saxagliptin, and linagliptin, which are currently approved for the treatment of T2DM, as well as the investigational agents vildagliptin and alogliptin. DPP-4 inhibitors can be taken orally without regard to meals.



The efficacy and safety of DPP-4 inhibitors have been well studied in patients with T2DM. Saxagliptin added to metformin reduces HbA1c (P < .0001), fasting plasma glucose (P < .0001), and postprandial glucose (P < .0001) after 24 weeks compared with metformin alone. Linagliptin significantly reduces HbA1c by -0.5% to -0.7% when given as single-agent therapy or when added to metformin; thiazolidinedione (TZD); sulfonylurea; and metformin and sulfonylurea. In a head-to-head trial, sitagliptin added to metformin showed similar glucose-lowering effects after 52 weeks of treatment compared with glipizide added to metformin, but with a more favorable effect on body weight (1.5 kg weight loss vs 1.1 kg weight gain; P < .001) and a reduced risk of hypoglycemia (4.9% vs 32.0%).


GLP-1 Receptor Agonists (RAs)
GLP-1 RAs are indicated for the treatment of T2DM as an adjunct to lifestyle modifications including diet and exercise. Currently available agents include twice-daily exenatide, once-weekly exenatide, and once-daily liraglutide. GLP-1 analogs improve glycemic control in patients with T2DM by enhancing glucose-dependent insulin secretion and reducing postprandial glucagon secretion. The GLP-1 RAs also slow gastric emptying, resulting in increased satiety, reduced food intake, and weight loss. However, decreased gastric emptying may also lead to nausea, vomiting, and diarrhea for some patients.

Table 4. Properties of GLP-1 Agonists




Liraglutide is a long-acting subcutaneous GLP-1 analog that is administered once daily. The LEAD-6 (Liraglutide Effect and Action in Diabetes) trial compared liraglutide 1.8 mg once daily and exenatide 10 µg twice daily in patients with poorly controlled T2DM despite treatment with metformin and/or a sulfonylurea. Add-on treatment with liraglutide provided a greater reduction in HbA1c compared with add-on exenatide (1.1% vs -0.8%; P < .05) and a greater reduction in fasting plasma glucose (-29.0 mg/dL vs -10.8 mg/dL; P < .05). Moreover, more patients in the liraglutide group than in the exenatide group reached the treatment goal of HbA1c < 7.0% (54.0% vs 43.0%; P < .05). Both agents were well-tolerated, and liraglutide and exenatide promoted similar levels of weight loss (-3.24 kg vs -2.87 kg).[33]

Newer formulations with reduced administration frequency may help improve patient adherence to antidiabetes therapy. The DURATION-1 (Diabetes Therapy Utilization: Researching Changes in A1c, Weight and Other Factors Through Intervention with Exenatide Once Weekly) trial evaluated long-term treatment with different formulations of exenatide in patients with T2DM. Patients were randomly assigned to treatment with exenatide 2 mg once weekly or exenatide 10 μg twice daily for 30 weeks, followed by 1.5 years of exenatide 2 mg once weekly for all patients. Compared with twice-daily exenatide, treatment with once-weekly exenatide provided a greater reduction in mean HbA1c (-1.5% vs -1.9%). The DURATION-5 trial compared exenatide twice daily with exenatide once weekly over 24 weeks in 252 patients with T2DM. The once-weekly formulation provided superior glycemic control compared with standard twice-daily dosing. The mean reduction in HbA1c was -1.6% in the exenatide once-weekly group and -0.9% in the exenatide twice-daily group (P < .0001).

The DURATION-6 trial compared once-weekly exenatide and daily liraglutide in 911 patients with T2DM. After 26 weeks, the mean reduction in HbA1c was 1.26% in the exenatide group and 1.48% in the liraglutide group (P < .05). Once-weekly exenatide was associated with fewer adverse gastrointestinal events than daily liraglutide, including less nausea (9.3% vs 20.4%), vomiting (3.7% vs 10.7%), and diarrhea (6.1% vs 13.1%). More than twice as many patients in the liraglutide group (5.3%) than in the exenatide group (2.6%) discontinued treatment due to adverse events. Patients in both groups had a modest reduction in body weight, with no significant differences between treatments.

Treatment Considerations

Nausea: Nausea and vomiting related to delayed gastric emptying are the most common adverse events associated with GLP-1 RAs. Nausea is mostly mild-to-moderate, and is most common at initiation of therapy; it tends to decrease with continuing treatment. In 1 prospective study, the frequency of nausea was similar during weeks 26 to 52 of treatment for patients treated with liraglutide 1.8 mg/d, liraglutide 1.2 mg/d, or sitagliptin 100 mg/d. In the LEAD-6 trial, the risk of nausea was significantly higher for patients treated with exenatide 10 µg twice daily compared with those treated with liraglutide 1.8 mg/d (P < .0001). In DURATION-6, nausea was less frequent among patients who received once-weekly exenatide (9.3%) than among those who received liraglutide (20.4%).

Weight loss: In a meta-analysis of GLP-1 RAs, the magnitude of weight loss was similar for exenatide once weekly (mean: -2.8 kg; 95% CI: -5.2 to -0.3 kg), exenatide twice daily (mean: -2.8 kg; 95% CI: -2.9 to -2.7 kg), and liraglutide (mean: -2.8 kg; 95% CI: -3.5 to -0.9 kg). Several studies have demonstrated that the weight loss associated with GLP-1 RA treatment is sustained for at least 2 years.

Use in patients on insulin therapy: Twice-daily exenatide has also been evaluated as add-on therapy in patients treated with glargine insulin. In the prospective trial, 259 patients who were taking glargine insulin were randomly assigned to add-on therapy with placebo or twice-daily exenatide. Compared with placebo, exenatide was associated with a greater reduction in HbA1c (-1.0% vs -1.7%), more favorable effects on body weight (+1.0 kg vs -1.8 kg), and a smaller increase in glargine dose (20 units vs 13 units). Patients had a similar risk of hypoglycemia regardless of treatment group. However, more patients in the exenatide group than in the placebo group dropped out of the study (13 vs 1).

Use in patients with comorbid renal impairment: Renal impairment appears to impact the clearance of exenatide in patients with T2DM, but does not affect the metabolism of liraglutide.This is because exenatide is eliminated predominantly via glomerular filtration, whereas no specific organ serves as the major route of elimination for liraglutide. Table 5 summarizes the recommended dosing for exenatide and liraglutide for patients with T2DM and comorbid renal impairment.

Table 5. GLP-1 Receptor Agonist Dosing in Patients with Renal Impairment

^*Hypovolemia due to nausea/vomiting may worsen renal function
CrCl = creatinine clearance; ESRD = end-stage renal disease

Safety Considerations

Pancreatitis: In 2008, the Food and Drug Administration (FDA) issued an alert to healthcare professionals regarding the risk of pancreatitis with incretin-related drugs. The FDA report described several issues with incretin agents including:

• Reports of pancreatitis in liraglutide clinical trials.
• Postmarketing reports of pancreatitis in patients taking exenatide, including cases of hemorrhagic/necrotizing pancreatitis that resulted in patient deaths.

Later, an analysis from the FDA Adverse Event Reporting System (AERS) reported:

• A 6-fold increase of pancreatitis with sitagliptin or exenatide compared with other antidiabetes medications, including rosiglitazone, nateglinide, repaglinide, and glipizide.
• An increase in the reporting rate of pancreatic cancer in patients treated with sitagliptin or exenatide.

Despite the value of these safety warnings, the AERS has limitations for understanding true pancreatitis risk, including potential reporting bias. In addition, the AERS reporting system did not collect information on BMI, a known risk factor for pancreatitis.

Healthcare professionals should consider the following precautions related to pancreatitis when treating patients with incretin-based therapies.

• Adhere to label warnings
• Observe patients for symptoms of acute pancreatitis (persistent severe abdominal pain that may be accompanied by vomiting)
• Discontinue drug if pancreatitis is suspected
• Do not restart drug if pancreatitis is confirmed
• Consider other antihyperglycemic therapies in patients with a history of pancreatitis

Thyroid cancer: Liraglutide and once-weekly exenatide carry boxed warnings for thyroid C-cell tumors based on data from rodent models of T2DM. Clinical trials and postmarketing data show conflicting results regarding the effects of GLP-1 analogs on calcitonin levels, with small increases in calcitonin levels in some studies and reduced levels in others. To date, no definitive cases of medullary thyroid carcinoma related to liraglutide have been detected. No cases of thyroid cancer have been reported in the exenatide clinical trials.

Renal impairment: Postmarketing reports have also tracked renal outcomes in patients treated with GLP-1 RAs. To date, no evidence indicates that GLP-1 RAs are directly toxic to kidney cells. However, renal impairment may occur in patients who have experienced nausea, vomiting, diarrhea, and dehydration. In some cases, renal impairment has been observed in patients who are taking concurrent medication known to affect renal function or hydration status (eg, angiotensin-converting enzyme [ACE] inhibitors, nonsteroidal anti-inflammatory drugs [NSAIDs], or diuretics). In addition, cases of patients requiring hemodialysis or transplantation have also been reported. Impaired renal function has also been observed in patients without known underlying renal disease.

In many cases, treatment-emergent renal impairment is reversible with supportive treatment and discontinuation of potentially causative agents. Current labeling includes a warning against GLP-1 RA use in patients with severe renal impairment or end-stage renal disease (ESRD). Furthermore, GLP-1 RAs should be used with caution in patients with a history of renal transplantation (exenatide and exenatide once weekly), and when initiating or escalating exenatide doses in patients with T2DM and comorbid renal impairment (exenatide, exenatide once weekly, and liraglutide).

BIPOLAR DISORDER

Bipolar disorder is a condition in which people go back and forth between periods of a very good or irritable mood and depression. The "mood swings" between mania and depression can be very quick.

Bipolar disorder affects men and women equally. It usually starts between ages 15 - 25. The exact cause is unknown, but it occurs more often in relatives of people with bipolar disorder.

Types of bipolar disorder:

• People with bipolar disorder type I have had at least one manic episode and periods of major depression. In the past, bipolar disorder type I was called manic depression.
• People with bipolar disorder type II have never had full mania. Instead they experience periods of high energy levels and impulsiveness that are not as extreme as mania (called hypomania). These periods alternate with episodes of depression.
• A mild form of bipolar disorder called cyclothymia involves less severe mood swings. People with this form alternate between hypomania and mild depression. People with bipolar disorder type II or cyclothymia may be wrongly diagnosed as having depression.

In most people with bipolar disorder, there is no clear cause for the manic or depressive episodes. The following may trigger a manic episode in people with bipolar disorder:

• Life changes such as childbirth
• Medications such as antidepressants or steroids
• Periods of sleeplessness
• Recreational drug use

The manic phase may last from days to months. It can include the following symptoms:

Easily distracted

Little need for sleep

Poor judgment

Poor temper control

Reckless behavior and lack of self control

            Binge eating, drinking, and/or drug use

            Poor judgment

            Sex with many partners (promiscuity)

            Spending sprees

Very elevated mood

            Excess activity (hyperactivity)

            Increased energy

            Racing thoughts

            Talking a lot

Very high self-esteem (false beliefs about self or abilities)

Very involved in activities

Very upset (agitated or irritated)

These symptoms of mania occur with bipolar disorder I. In people with bipolar disorder II, the symptoms of mania are similar but less intense.

The depressed phase of both types of bipolar disorder includes the following symptoms:

Daily low mood or sadness

Difficulty concentrating, remembering, or making decisions

Eating problems

Loss of appetite and weight loss

Overeating and weight gain

Fatigue or lack of energy

Feeling worthless, hopeless, or guilty

Loss of pleasure in activities once enjoyed

Loss of self-esteem

Thoughts of death and suicide

Trouble getting to sleep or sleeping too much

Pulling away from friends or activities that were once enjoyed

There is a high risk of suicide with bipolar disorder. Patients may abuse alcohol or other substances, which can make the symptoms and suicide risk worse.

Sometimes the two phases overlap. Manic and depressive symptoms may occur together or quickly one after the other in what is called a mixed state.

Treatment

Periods of depression or mania return in most patients, even with treatment. The main goals of treatment are to:

• Avoid moving from one phase to another
• Avoid the need for a hospital stay
• Help the patient function as well as possible between episodes
• Prevent self-injury and suicide
• Make the episodes less frequent and severe

The health care provider will first try to find out what may have triggered the mood episode. The provider may also look for any medical or emotional problems that might affect treatment.

The following drugs, called mood stabilizers, are usually used first:

• Carbamazepine
• Lamotrigine
• Lithium
• Valproate (valproic acid)

Other antiseizure drugs may also be tried.

Other drugs used to treat bipolar disorder include:

• Antipsychotic drugs and anti-anxiety drugs (benzodiazepines) for mood problems
• Antidepressant medications can be added to treat depression. People with bipolar disorder are more likely to have manic or hypomanic episodes if they are put on antidepressants. Because of this, antidepressants are only used in people who also take a mood stabilizer.

Electroconvulsive therapy (ECT) may be used to treat the manic or depressive phase of bipolar disorder if it does not respond to medication. ECT uses an electrical current to cause a brief seizure while the patient is under anesthesia. ECT is the most effective treatment for depression that is not relieved with medications.

Transcranial magnetic stimulation (TMS) uses high-frequency magnetic pulses to target affected areas of the brain. It is most often used after ECT.

Patients who are in the middle of manic or depressive episodes may need to stay in a hospital until their mood is stable and their behavior is under control.

MRI

Diffusion-weighted imaging (DWI) helps assess tissue cellularity and micro-structure by identifying changes in tissue water diffusion, eg, central nervous system (CNS) lymphoma.

apparent diffusion coefficient (ADC).[5] Lower ADC values correspond to well-organized tissue and high cellularity; higher ADC values correspond to low cellularity and not well-organized tissue. Thus high-grade or very cellular tumors (eg, lymphoma, Figure 4) may show lower ADC values. Similarly, increasing ADC values after treatment might indicate treatment response because tumor cell density decreases with cell death and leads to increase in the extravascular extracellular space (EES).



Positron emission tomography (PET) is a nuclear medical imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide (tracer), which is introduced into the body on a biologically active molecule. Three-dimensional images of tracer concentration within the body are then constructed by computer analysis. In modern scanners, three dimensional imaging is often accomplished with the aid of a CT X-ray scan performed on the patient during the same session, in the same machine.

Strawberry-Term associated with different disease

Strawberry tongue: Kawasaki ,Scarlet fever

Strawbery gingiva: Wegeners

Strawberry cervix: Trichomonas

Strawberry skull: Trisomy 18

Strawberry rectum: Spirochete

Strawberry gallbladder: Cholesterosis

Strawberry nasal mucosa: sarcoidosis

Strawberry nasal mass: rhinosporodiosis