Beyond Lab Consulting

Potassium: A Proper Level Does a Heart Good

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By Cat Troiano

Monitoring potassium levels is an important step in providing care to patients, particularly those who are taking antihypertensive medications as well as those with kidney disease or gastrointestinal conditions.

What is Potassium?   

Potassium is a macromineral that acts as an electrolyte to facilitate communication between nerves and muscles, and transportation of nutrients to cells and of wastes from cells. Potassium plays in essential role in cardiac function. While skeletal muscles, the ones that endure those resistance-training workouts, are voluntary and require the efforts of the exerciser in addition to the biochemical reactions that take place in the body with the onset of physical activity, cardiac muscle is involuntary and must work continuously and efficiently to maintain blood perfusion and sustain life. Potassium aids in ensuring that nerve signals reach all of the body’s muscles, including those heart muscles so that they keep pumping.  Potassium, along with sodium, which is another electrolyte, helps to regulate the amount of fluid maintained in and around the cells throughout the body. If a patient is dehydrated, the blood viscosity increases and the blood volume decreases, putting a strain on the heart as is beats faster to pump out the blood into circulation.

How Are Potassium Levels Maintained?

Potassium levels are maintained by aldosterone, which is a hormone that is produced in the adrenal glands. Aldosterone limits urinary sodium excretion from the body. Vasopressin, a hormone that is produced in the pituitary gland, acts as an antidiuretic to reduce urinary water excretion from the body. When the body is at risk for becoming dehydrated, such as when an individual sweats through his or her exercise workout, the adrenal gland and pituitary gland increase their secretions of these hormones in an effort to combat the loss of fluid and sodium as the heart rate and stroke volume increase to deliver more nutrient-rich blood to the active muscle cells. This is a normal metabolic reaction to exercise, and all of these levels return to normal after a workout has concluded. Conversely, when fluid levels become elevated, such as when drinking excessively high volumes of water in one sitting, the proportion of electrolytes becomes diluted, which is a potentially fatal condition known as hypernatremia. However, there are also health conditions that can lead to potassium imbalances, and individuals with these conditions must be closely monitored.

Which Patients Should Have Potassium Levels Monitored?

Patients who are being treated for hypertension should have their potassium levels evaluated periodically. Many of the medications used to treat hypertension act as diuretics, resulting in increased urination. Potassium levels should also be monitored in:

  • Patients with kidney disease
  • Patients with diabetic ketoacidosis
  • Patients who present with muscle weakness
  • Patients who present with cardiac arrhythmias

A blood serum potassium level is included as part of a basic metabolic profile as well as of an electrolyte panel. An electrolyte panel evaluates the level of potassium as well as those of sodium, chloride and bicarbonate.

The normal reference range for a blood potassium level 3.5 to 5.0 mEq/L

It is important to note that any ruptured blood cells within the sample collection tube will release potassium into the blood sample, which can result in a falsely elevated result. For this reason, all abnormally high potassium results should prompt a repeat test to verify the result. When initial potassium level tests yield either abnormally high or abnormally low results, ordering an evaluation of urine potassium levels is recommended as well.

The normal reference range for a urine potassium level in an adult patient is 25 to 125 mEq/L

What Does an Elevated Blood Potassium Level Indicate?

An abnormally high blood potassium level is diagnosed as hyperkalemia. The most common cause of hyperkalemia is advanced kidney disease. As the kidneys degenerate, renal insufficiency prevents adequate filtration of excess potassium from the blood to be excreted through urination. Thus, the potassium level in the blood increases as the kidney disease advances.

Other causes of hyperkalemia include:

  • Type 1 diabetes
  • Addison’s disease, a condition that compromised adrenal gland function
  • Rhabdomyolysis, a potentially life-threatening muscle injury that can result in renal failure
  • Tissue trauma, such as burns or surgical procedures
  • Beta blocker medications
  • Angiotensin-converting enzyme inhibitors
  • Nonsteroidal anti-inflammatory drugs
  • Angiotensin II receptor blockers
  • Calcium channel blockers
  • Overuse of potassium supplementation
  • Some anticoagulant drugs, such as heparin
  • Cyclosporine
  • Tacrolimus

Signs and symptoms of hyperkalemia include:

  • Muscle weakness
  • Muscle fatigue
  • Decreased appetite
  • Nausea
  • Paralysis
  • Cardiac arrhythmias

Treatment for mild to moderate cases of hyperkalemia typically include changing a medication that may be the cause of the condition, discontinuing potassium supplementation, reducing dietary intake of potassium-rich foods or use of medications, including diuretic drugs, insulin or potassium binders to help the body eliminate potassium from the gastrointestinal tract prior to absorption.

What Does a Low Blood Potassium Level Indicate?

An abnormally low blood potassium level is diagnosed as hypokalemia, which tends to occur more commonly in female patients and in older individuals. Causes of hypokalemia include:

  • Dehydration
  • Diarrhea
  • Vomiting
  • Insulin overdose
  • Diabetic ketoacidosis
  • Diuretic drugs
  • Certain corticosteroid drugs
  • Certain antibiotic drugs
  • Decongestants
  • Beta-adrenergic bronchodilators
  • Chemotherapy drugs
  • excessive alcohol consumption
  • Use of laxatives and enemas
  • Folic acid deficiency

Signs and symptoms of hypokalemia include:

  • muscle weakness
  • muscle cramps
  • cardiac arrhythmias
  • fatigue
  • constipation

Treatment for mild to moderate cases of hypokalemia include treating the underlying cause of diarrhea and vomiting, treating dehydration, discontinuing drugs that may be causing the condition or recommending the increased dietary intake of potassium-rich foods.

Patients whose potassium levels are revealed to be less than 3.0 or greater than 6.0 must pursue immediate care, as such numbers may be life-threatening. Excessively high or low potassium levels can result in cardiac arrhythmias and cardiac arrest. Such cases require intravenous fluid therapy and hospitalization to restore normal electrolyte balances.

Dietary Potassium

Unlike most vitamins, most minerals are found in the body as well as taken in through food. Potassium, as well as sodium, chloride, fluoride and iodide, have a high level of bioavailability, meaning that higher proportions of these minerals are readily absorbed and utilized by the body to carry out their metabolic functions.

Foods that are rich in potassium include:

  • Sweet potatoes and potatoes
  • Beets and beet greens
  • Bananas
  • Oranges
  • Dried fruits, such as raisins or dried apricots
  • Spinach
  • Yellowfin tuna
  • Avocados
  • White beans
  • Pumpkin

The daily adequate intake of potassium for healthy men and healthy nonpregnant, nonbreastfeeding women is 4,700 milligrams.

Testing, and monitoring when necessary, blood potassium levels is a crucial key in preserving critical cardiac, muscle and nerve functions in your patients. 

Joint Effort: Symptoms and Tests Together Can Diagnose Rheumatoid Arthritis

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Did you know that there are numerous different types of arthritis? Arthritis is a collective term that covers more than 100 conditions characterized by longterm joint inflammation that can result in permanent joint damage. Some of the more commonly known forms include osteoarthritis, gout, rheumatoid arthritis, psoriatic arthritis and fibromyalgia. Rheumatoid arthritis, or RA, is the third most prevalent form of arthritis, affecting 1.3 million Americans. This debilitating condition affects quality of life and can reduce a patient’s lifespan. Early intervention with treatment protocols can greatly improve these factors once assessment of a patient’s risk factors and symptoms and proper testing to diagnose the condition has been performed.

How Is RA Different from Osteoarthritis?

RA is a chronic inflammatory condition that targets the joints. Unlike osteoarthritis, which is also known as degenerative joint disease, remains the most commonly diagnosed form of arthritis and is characterized by reduction in bone mass and an increase in susceptibility to fractures, RA affects the synovial lining of the joints. This weakens the tendons and ligaments, the connective tissues which attach muscle to bone and bone to bone, respectively, resulting in restricted joint stability and mobility, pain, and deformity as the joint capsule erodes. The damage doesn’t stop there, however. Over time, the inflammation of RA can damage other tissues in the body, including those of the lungs and heart. Unlike osteoarthritis, which results from aging and wear and tear, RA is categorized as an autoimmune disorder, which is defined as a condition in which the body’s immune cells attack the body’s own healthy tissues. Lupus, multiple sclerosis, Crohn’s disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, Graves’ disease, celiac disease and type 1 diabetes are all other examples of autoimmune disorders.

RA’s disease progression varies from patient to patient. In some, the disease advances rapidly, while in others, it progresses more slowly. Many patients experience remission periods in which their symptoms abate, and then these durations of relief end with a return of the symptoms. When this occurs, the patient is said to be experiencing a disease flareup. A few lucky patients will experience a permanent remission.

What Are the Risk Factors of RA?

The exact cause of RA remains unknown, but several potential risk factors have been identified. These risk factors include:

Family history. Although there are patients who are diagnosed with RA without any known family history of the disease, if an individual who does have a first-degree relative, such as a parent, who has been diagnosed with RA, then that individual is at an estimated four times greater risk than someone without the family history for developing the condition.

Gender. Roughly 75 percent of individuals stricken with RA are women. This may be due in part to hormonal shifts that occur during perimenopause, as age appears to present another potential risk factor.

Age. RA can affect individuals at any age, but the condition is most prevalent in those aged 45 years and older.

Smoking and environmental hazards. Smoking appears to not only increase one’s risk for developing RA, but it may also heighten the severity of the condition. Exposure to certain hazardous materials, such as asbestos, is also suspected to increase the risk of RA development.

Obesity. Individuals who are overweight or obese may carry a greater risk for developing RA.

Again, these are potential risk factors. Since the cause of RA remains a bit of a mystery, these risk factors must be considered in addition to the patient’s symptoms before suspecting RA.

What Are the Symptoms of RA?

At the early stage of RA, joints in the fingers and toes are affected, presenting with swelling and discomfort. The joints maybe warm to the touch, and redness may be observed. Patients may experience stiffness in the joints upon awakening and following periods of inactivity. As RA advances, these symptoms gradually extend to the wrists, ankles, elbows, knees, shoulders and hips. One of the factors that typically differentiates RA from osteoarthritis us that in RA patients, affected joints are usually symmetrical, meaning that the same joint on both sides of the body are affected. For example, a patient may be experiencing discomfort in the left hand as well as in the right hand.

While localized joint pain and inflammation is the initial complaint, additional symptoms of RA may include:

  • Chronic fatigue
  • Decrease in appetite and weight loss
  • Fever
  • General malaise
  • Depression

When four or more joints are affected, a patient complains of experiencing these symptoms for a duration of six months or longer or has any of the risk factors mentioned above in addition to their presenting symptoms, the diagnostic process should include testing for RA.

Which Tests Can Screen for RA?

Once an evaluation of a patient’s symptoms and history has been performed, laboratory tests are ordered to determine whether or not the patient’s arthritis is specifically RA. This determination can often be made through a combination of two laboratory tests: the rheumatoid factor screening test and the anti-cyclic citrullinated peptide test.

Rheumatoid factor (RF) is an immunoglobulin-M protein autoantibody which is present in roughly 80 percent of patients who have RA, indicating an inflammatory state and autoimmune condition. The normal reference range for an RF test is less than 20 u/ml. However, there are other conditions that can yield an elevated RF level, including other autoimmune disorders, cancer, diabetes, some chronic infections, some vaccines and even the normal aging process. It is also important to note that approximately 20 percent of patients who have RA will have normal RF levels. Therefore, it is important to order an anti-CCP test in conjunction with the RF test.

Anti-cyclic citrullinated peptide (anti-CCP) is another autoantibody that is present in 60 to 70 percent of RA patients. When a patient’s RF and anti-CCP tests both yield positive results, the diagnosis is known as seropositive RA. The normal reference range for an anti-CCP test is less than 20 u/ml.

The remaining percentage of symptomatic patients whose RF and anti-CCP tests both yield negative results are diagnosed with seronegative RA. These patients may yield results on other laboratory screenings that are indicative of inflammation.

Although not specific to RA detection, the erythrocyte sedimentation rate (ESR) test and the C-reactive protein tests, both of which indicate the presence of inflammation, can be helpful in diagnosing RA in that elevated levels in these two tests are typical results in RA patients, but not in patients with osteoarthritis. These tests can also be useful in monitoring the condition’s level of activity as the disease progresses and when patients experience RA flareups.

The ESR test evaluated the rate at which erythrocytes, or red blood cells, settle into the bottom of the test tube apart from the plasma portion of the blood. When there is an increased level of acute phase reactant proteins, such as C-reactive protein, the erythrocytes drop to the bottom of the tube at a faster rate. A higher than normal level of C-reactive protein, and thus a higher sedimentation rate, occur in the presence of inflammation. The normal reference ranges for these two tests are:

ESR

Men less than 50 years of age: 0 to 15 mm/hr. to 0 to 20 mm/hr.

Women less than 50 years of age: 0 to 20 mm/hr. to 0 to 30 mm/hr.

Normal results tend to be higher in patients who are 50 years of age and older.

C-reactive protein

Less than 1.0

The ESR and C-reactive protein tests alone cannot be used to attain a definitive diagnosis of RA, however, since other factors, such as advanced age, the presence of infection or obesity, can cause elevated results in both tests.

If the above tests yield results that do not facilitate a confident diagnosis of RA, then diagnostic imaging tests, such as radiographs and magnetic resonance imaging, will come into play to visualize the condition of the affected joints, allowing physicians to rule out other causes of discomfort, make the diagnosis and assess the severity of the disease. These imaging tests, along with the ESR and C-reactive protein tests, may also be utilized to monitor the disease progression. The RF and anti-CCP tests are not particularly helpful in monitoring disease progression in that a patient who had elevated levels at the time of diagnosis will continue to have elevated levels, even during periods of disease remission. Complete blood counts and metabolic profiles should be ordered periodically to monitor for potential RA complications as well as any side effects that can result from drug therapies used to treat the condition.

What Are Complications of RA?

As RA progresses, complications can come about. Some potential complications of RA include:

  • Rheumatoid nodules, which are firm subcutaneous lumps that typically form in close proximity to joints
  • Sjogren’s syndrome, an immune disorder that is characterized by dry mouth and dry eyes
  • Anemia
  • Carpal tunnel syndrome
  • Cardiovascular problems, including pericardial inflammation, arterial hardening and obstruction
  • Lung disease and respiratory compromises, such as COPD
  • Lymphoma
  • Increased infections

Frequent evaluations and longterm monitoring of patients with RA are imperative. Periodic laboratory and imaging tests are essential to track the disease’s progression as well as to identify complications and to treat accordingly.

What is the Treatment and Prognosis for RA Patients?

There is no cure for RA. Treatment goals are to reduce pain and inflammation and to retard the progression of the disease. Early treatment with disease-modifying antirheumatic drugs can slow the progression of a patient’s RA and increase the chances for remission. Other treatment options include:

  • Non-steroidal anti-inflammatory drugs
  • Corticosteroid drugs
  • Physical therapy
  • Exercise that improves joint stability and range of motion
  • Mind-body exercise, such as tai chi

When other methods of treatment are ineffective, surgical intervention to repair or to remove and replace damaged joints may be considered.

Patients who are referred to a board-certified rheumatologist to begin treatment at the earliest possible stage of the disease, before extensive joint damage has been sustained, have the best chance at living a full and active life.

Nature’s Contagious Terrorists: Tick-Borne Illnesses

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By Cat Troiano

With summer just around the corner, outdoor recreation beckons. While sun, surf and communing with nature provide enjoyment throughout the warmer months, the season also presents ticks, which pose serious health risks that can compromise quality of life. When we think about diseases that are spread via bites from ticks, Lyme disease typically comes to mind. While Lyme disease is the most commonly diagnosed tick-borne illness, these parasitic arachnids transmit a lengthy list of other maladies as well. Many of these illnesses present with similar signs and symptoms, which is why testing is important for attaining a diagnosis.

How Are Tick-Borne Illnesses Spread?

Once hosts, such as mice, deer, dogs and sheep, become infected, they harbor the disease pathogens. Depending on which tick-borne disease is infecting the host, such pathogens may be viral, bacterial or protozoan in nature. Some tick-borne diseases are rickettsial, meaning that they are caused by rickettsia, which are microorganisms that possess qualities of both viruses and bacteria. Rickettsia cannot thrive and reproduce outside of living cells.

Ticks are parasitic organisms. Once a tick feeds off of the blood from an infected host, the tick becomes a vector. The contracted pathogen is then carried by the tick and transferred into the next host off which it feeds.

What Are the Most Common Tick-Borne Illnesses?

According to the Centers for Disease Control and Prevention, the number of confirmed and probable cases of Lyme disease exceeded 42,000 in 2017 and remains the most frequently reported tick-borne illness in the United States. Lyme disease is transmitted by the black-legged leg, which is commonly known as the deer tick, throughout the northeast, northern Midwest and mid-Atlantic states. It is also transmitted by the western black-legged tick in northern California and up the Pacific coast. You can read more about Lyme disease and its test interpretations here. Additional tick-borne illnesses, their vectors and geographic prevalence include:

Rickettsial Diseases:

  • Anaplasmosis, transmitted by the black-legged tick in the northeastern and northern midwestern regions and by the Western black-legged tick in northern California and along the Pacific coast
  • Ehrlichiosis, transmitted by the Lone Star tick throughout the eastern states and by the American dog tick along the Pacific coast and in areas east of the Rocky Mountains.
  • Rocky Mountain spotted fever, transmitted by the American dog tick east of the Rocky Mountains and along the Pacific coast
  • Rickettsia parkeri rickettsiosis, transmitted by the Rocky Mountain wood tick throughout the Rocky Mountain region

Non-rickettsial Diseases:

  • Babesiosis, transmitted by the black-legged tick in the northeastern and northern midwestern regions and by the Western black-legged tick in northern California and along the Pacific coast
  • Tularemia, transmitted by the Lone Star tick throughout the eastern states, by the Rocky Mountain wood tick throughout the Rocky Mountain region and by the American dog tick along the Pacific coast and in areas east of the Rocky Mountains
  • Powassan virus, transmitted by the black-legged tick in the northeast as well as in the states of Virginia and Wisconsin
  • Borrelia miyamotoi disease, transmitted by the black-legged tick in the northeastern and northern midwestern regions and by the Western black-legged tick in northern California and along the Pacific coast
  • Tick-borne relapsing fever, transmitted by the orinthodoros soft tick in the western states
  • Colorado tick fever, transmitted by the Rocky Mountain wood tick throughout the Rocky Mountain region
  • Heartland virus, transmitted by the Lone Star tick in midwestern and southern states

Some ticks can harbor multiple diseases, and coinfection from one tick bite is a possibility. It is also important to note that some of these illnesses can be contracted internationally, and a number of additional tick-borne diseases have been identified in other nations. Novel tick-borne illnesses can also emerge, such as the recently identified Long Island tick rhabdovirus, which is transmitted by the ambloyomma americanum tick, and 364D rickettsiosis, transmitted by the Pacific Coast tick and recently discovered in the state of California.

Signs of Tick-Borne Illnesses

The signs and symptoms of many tick-borne illnesses are not unique to these illnesses, and they present with most of the tick-borne diseases. These influenza-like symptoms typically include:

  • Fever
  • Headache
  • Muscle aches
  • Joint pain
  • General malaise

Some illnesses may progress with the presentation of symptoms of serious complications, such as neurological deficits, kidney or liver failure, or compromised cardiorespiratory function. Some diseases, such as Lyme disease, may present with a characteristic rash, but it is crucial to note that these rashes do not emerge on all infected patients.

On the rise in recent years is the incidence of red meat allergies caused by the bite of the Lone Star tick. Galactose is a monosaccharide, a simple sugar that is found in some foods, often in combination with glucose to form the disaccharide lactose. However, the Lone Star tick produces another galactose compound known as galactose-alpha-1,3-1 galactose, or alpha-gal, in its gastrointestinal tract. When the tick bites its host, this sugar is injected, and it renders the host allergic to red meats. This condition is known as alpha-gal syndrome. Some affected individuals will suffer from anaphylactic shock after consuming beef, pork, lamb and other red meats, and the reaction may occur three to six hours after they have eaten the red meat. 

Another tick-borne condition is tick paralysis, a rare phenomenon that primarily affects children. Tick paralysis is transmitted by various tick species, including the American dog tick, and it results when a biting tick deposits a neurotoxin into its host. Signs of tick paralysis include flaccid weakness, changes in voice, respiratory difficulty and neurological symptoms of paralysis ascend up the body from the lower extremities. Unlike other tick-borne illnesses, the condition typically resolves rapidly and completely once the infected tick is extricated from the host, but if the tick is not discovered and the condition continues to progress, respiratory failure and death can result.

So many diseases and symptoms! How are physicians to make specific diagnoses under these conditions? Laboratory tests are available for detecting antibodies for several of the most common tick-borne illnesses.

Diagnostic Testing

Laboratory testing to identify a particular tick-borne disease should be pursued for any patient who presents with these symptoms and meets any one of the following criteria that increases his or her risk for exposure:

  • The patient found a tick attached on their body.
  • The patient resides in a geographic location in which any tick-borne disease(s) is prevalent.
  • The patient has recently traveled to a geographic location where tick-borne illnesses are prevalent.
  • The patient has recently spent time in an area where ticks are endemic – i.e. camping in a wooded area.

Abnormal laboratory findings on a complete blood count in a patient with tick-borne illness may include low hematocrit, platelet and white blood cell counts and an elevated reticulocyte count. Abnormal findings on a metabolic profile may include elevated liver enzymes and elevated renal values, which include creatinine and blood urea nitrogen levels. Elevated protein may be detected on a urinalysis.

In addition to ordering a complete blood count and metabolic profile, there are numerous individual laboratory tests available to diagnose particular suspected tick-borne diseases. Depending on the test that is selected, diagnosis is achieved through the following various methods:

  • Microscopic visualization and identification of the pathogen in blood cells
  • Enzyme-linked immunosorbent assay (ELISA) to detect specific antibodies
  • Immunofluorescent assay (IFA) to detect particular IgG or IgM antibodies
  • Polymerase chain reaction to identify pathogen DNA
  • Immunoblot technique, such as the Western blot test
  • Culture to identify bacterial pathogens

The newest addition to the arsenal of tests for diagnosing tick-borne diseases is the TBD Serochip, which is a real-time polymerase chain reaction method screening. The advantage of this particular test is that it evaluates one blood sample to detect antibodies of eight of the most common tick-borne pathogens found in the United States. This alone makes this test valuable in that it can pinpoint a specific infection when generalized symptoms might otherwise require multiple individual tests, and it also has the capability to identify coinfections. The eight diseases that can be diagnosed with this test include Lyme disease, anaplasmosis, babesiosis, ehrlichiosis, Rocky Mountain spotted fever, Heartland virus, Powassan virus and borrelia miyamotoi.

An alpha-gal IgE test is available for determining if a patient who has suffered an allergic reaction after consuming red meat has contracted alpha-gal syndrome.

There is no laboratory test for tick paralysis. However, if a patient presents with symptoms, physicians should seek out a tick that is attached on the patient as well as order testing to rule out Guillain-Barre syndrome, an autoimmune disorder that presents with similar signs, including paralysis.

Treatment and Prevention

Tick-borne diseases, some of which can progress rapidly, should be treated as early as possible in symptomatic patients, which often means administering treatment even before test results become available. Most tick-borne diseases are treated with antibiotic therapy, typically with doxycycline or tetracycline.

There is no treatment for alpha-gal syndrome, and patients are strongly advised to avoid all red meat and food products containing meat-based ingredients. In some cases, allergy symptoms can abate over time if the patient does not sustain another bite from a tick that injects alpha-gal.

To reduce the risk of contracting tick-borne diseases, patients should be advised to take preventative measures, which includes adopting the following practices:

  • When venturing outdoors where there is an inherent risk of exposure to ticks, don light-colored clothing so that ticks are easy to spot, and wear long sleeves and pants. Tucking the bottoms of the pant legs into white socks will help to prevent ticks from migrating to the legs, and they will be easy to find on white socks.
  • Apply a tick repellent spray that contains DEET to both outer clothing and exposed skin.
  • Campers should spray the outer surfaces of tents and other gear with insecticidal products that contain permethrin.
  • When hiking, remain on cleared trails, and avoid straying off course into areas with tall grasses, brush and weeds.
  • Pet owners should apply topical tick preventative products as prescribed by their veterinarians to dogs and to cats that go outdoors.
  • Clothing should be stripped immediately upon returning indoors and placed directly into the dryer for 10 minutes to kill any ticks that were missed when inspecting the apparel. Patients should then shower and wash their hair, and conduct a thorough inspection of their skin from head to toe, removing any ticks immediately.
  • Outdoor home property should be maintained and kept free of all brush and debris to eliminate areas that small wild animals, the primary hosts for ticks, may find hospitable. Trees, lawns and shrubs should be sprayed regularly with insecticide products.

To help physicians to rule out some of the tick-borne disease possibilities, patients should be advised to deposit any ticks that they extricate from their bodies into a sealed jar or a Ziploc bag. If symptoms of illness develop, bringing the tick along to the doctor’s appointment can facilitate a visual identification of the tick, which helps to guide in antibiotic and test selection for more timely success with treatment.

Details Matter: Multiple-Phase Testing for Cushing’s Syndrome

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by Cat Troiano

Hypoadrenocorticism, more commonly known as Cushing’s syndrome, is an endocrine disorder that is characterized by hypercortisolism, which is an abnormally high level of the hormone cortisol in the blood. Between 10 and 15 million individuals in the United States are diagnosed with this condition each year. Diagnosing Cushing’s syndrome can be challenging due to the fact that some of its presenting symptoms mimic those of other conditions as well as to the fact that there are a number of potential causes of hypercortisolism.

What Is Cortisol?

Often coined the stress hormone, cortisol is produced in the adrenal cortex, which is the outer layer of the adrenal glands, which are situated just superior to the kidneys. Cortisol is secreted in response to stressful conditions to prepare the body to function optimally during such times. Similarly, the slow-acting hormone is also released in response to imposed physical demands during exercise. Regulatory functions of cortisol include:

  • Maintains blood pressure
  • Prompts glucose synthesis in the liver
  • Decreases the rate of glucose utilization by the cells
  • Stimulates free-fatty acid mobilization from adipose tissue
  • Reduces inflammation
  • Regulates the body’s hydration level

Multiple glands are responsible for the normal production of cortisol. First, the hypothalamus produces corticotropin-releasing hormone. This hormone stimulates the pituitary gland, which is a pea-sized gland that sits at the base of the brain, just below the hypothalamus. The pituitary gland produces another hormone, called adrenocorticotropic hormone (ACTH) in addition to other hormones, including growth hormone and vasopressin. ACTH is the hormone that stimulates cortisol production in the adrenal glands.

Hypercortisolism Causes and Risk Factors

Both genders can develop Cushing’s syndrome, but it is most commonly diagnosed in women between the ages of 30 and 50. Longterm uncontrolled hypertension and longterm high blood glucose levels in diabetics are risk factors for developing Cushing’s syndrome. There are several causes of high cortisol levels:

Pituitary adenoma, which is a benign tumor on the pituitary gland, promotes an overstimulation of ACTH hormone, which in turn stimulates excess cortisol production from the adrenal gland. The specific name for this condition is Cushing’s disease, and it accounts for more than half of all hypoadrenocorticism cases.

Glucocorticoid drug use over the longterm, such in the treatment of such conditions as asthma and autoimmune disorders as well as injectable formulations used to relieve joint pain and administration of such drugs following organ transplants, is another common cause of hypoadrenocorticism. This exogenous form is referred to as iatrogenic Cushing’s syndrome.

Adrenal tumors, which may be benign or malignant, develop on the adrenal gland and prompt cortisol production. Cancerous adrenocortical carcinomas are the least common cause of hypoadrenocorticism.

Ectopic ACTH-producing tumors overproduce ACTH, which in turn triggers the production of cortisol by the adrenal gland. Such tumors are not located in the pituitary or adrenal glands. Instead, they develop in other parts of the body, such as in a lung, or other glands, such as the thyroid or the pancreas. This form of hypoadrenocorticism is referred to as ectopic Cushing’s syndrome)

While most cases of hypoadrenocorticism are not hereditary, there are incidences of familial Cushing’s syndrome in which younger individuals carry a genetic mutation that predisposes them to develop cortisol-producing tumors on one or more glands of the endocrine system.

Symptoms and Complications of Cushing’s Syndrome

The list of signs and symptoms that present with Cushing’s syndrome is lengthy. These indicators include:

  • weight gain around the trunk
  • Fatty accumulations superior to the clavicle bone
  • Round appearance of the face
  • Thin limbs
  • muscle weakness
  • Fatigue
  • Easy bruising
  • Thinning of the skin
  • Facial redness
  • Striae, or purple stretch marks, on the axillary region of the body
  • Acne
  • Excess facial and body hair growth and thinning hair on the scalp in women
  • Amenorrhea in women
  • Decreased libido
  • Impotence and/or infertility in men
  • Depression, anxiety or mood swings

Cushing’s syndrome is usually curable. However, when left untreated, complications ensue, some of which can have fatal repercussions. Complications of longterm hypercortisolism include:

  • Myocardial infarction
  • Stroke
  • Hyperlipidemia
  • Insulin resistance, prediabetes, type 2 diabetes
  • Hypertension
  • Osteoporosis
  • Venous thromboembolism

Such complications emphasize the importance of testing all individuals who present with a physical appearance that may be indicative of hypoadrenocorticism in order to make a diagnosis and design a treatment plan. Patients who have hypoadrenocorticism may generate abnormal findings on general laboratory screenings, including elevated white blood cells and neutrophils on a complete blood count, hypokalemia on a metabolic profile or impaired function on a glucose tolerance test. Specific tests for Cushing’s syndrome must then be performed to make a diagnosis.

Diagnosing Cushing’s Syndrome

All tests for Cushing’s syndrome have limitations in that a number of factors can generate false-positive results. One such factor is the condition known as pseudo-Cushing’s. Pseudo-Cushing’s is a state in which an individual produces abnormally high levels of cortisol, but often does not present with the aforementioned physical attributes that are associated with Cushing syndrome. The causes of these elevations differ from those with true Cushing’s syndrome, and they include:

  • Alcoholism
  • Anorexia nervosa
  • Chronic illnesses, such as acquired immunodeficiency syndrome
  • Depression
  • Obesity
  • Pregnancy
  • Polycystic ovarian syndrome

Pseudo-Cushing’s can affect the results of many Cushing’s tests, as can the use of certain drugs, such as oral contraceptives, and other medical conditions, such as hyperthyroidism.

To complicate matters further, as mentioned above, there are multiple potential causes of Cushing’s syndrome, and it is crucial to determine not only whether or not a patient actually has Cushing’s syndrome, but to determine the cause of their condition as well. Fortunately, there are multiple tests for diagnosing Cushing’s syndrome, and a testing sequence is the recommended method for attainting a diagnosis. First, one or more initial tests are performed to detect abnormal cortisol levels. Once abnormal levels are confirmed, then secondary tests are performed to determine the cause of the abnormal results.

Initial Tests:

24-Hour Urinary Free-Cortisol Test

The 24-hour urinary free-cortisol test provides a measurement of how much cortisol a patient’s body produces over the course of a 24-hour duration. This is typically the initial test performed to determine if a patient has hypoadrenocorticism. The normal reference range for the 24-hour urinary free-cortisol test is less than 40 to 50 ug/d. A result that exceeds this range is suggestive of Cushing’s syndrome. However, patients with early or mild cases may generate normal results on the 24-hour urinary free-cortisol test.

Low-Dose Dexamethasone Suppression Test

The low-dose dexamethasone suppression test evaluates how the cortisol-producing adrenal glands respond to the ACTH hormone. The testing procedure requires that the patient receives one milligram of dexamethasone, which is a synthetic glucocorticoid drug, in the evening, followed by a blood draw on the next morning. Normally, the dose of dexamethasone should suppress the production of ACTH during the overnight hours, resulting in a low morning serum cortisol level. However, if a patient does indeed have Cushing’s syndrome, then this normal response does not kick in, and thus their morning cortisol level will be abnormally high. A test result of 1.8 ug/dL or greater is a positive result. It is important to note that patients who slept poorly, who are currently under excessive emotional or physical stress or those who are obese may generate false-positive results on this test.

Late-Night Salivary Cortisol Test

The late-night salivary cortisol test measures cortisol levels in 1 mL of a patient’s saliva over the span of one hour, typically between 11 p.m. and midnight when cortisol production is low in patients without Cushing’s syndrome. A result that exceeds the normal reference range of 0.10 to 0.15 ug/dL is suggestive of Cushing’s syndrome.

If any of these initial tests generate positive results, repeat testing should be ordered to rule out false-positive results before proceeding to the secondary phase of testing. The secondary tests are performed to discern the cause of hypercortisolism.

Secondary Tests:

Corticotropin-Releasing Hormone Stimulation Test (CRH stimulation test)

This test measures the level of cortisol in the blood in response to the injection of a synthetic CRH. An initial blood sample is taken prior to the injection, and then additional blood samples are collected at intervals during the one to three hours that follow the injection. The result of this test helps the physician to determine the cause of a patient’s abnormal ACTH and cortisol secretion levels. As mentioned above, Cushing’s syndrome can result from pituitary adenomas or from ectopic tumors. The results of the CRH stimulation test can distinguish between pituitary adenoma, which will yield peaks in ACTH and cortisol levels on the CRH stimulation test, and ectopic Cushing’s syndrome, which will not exhibit these elevations.

High-Dose Dexamethasone Suppression Test

This test can also help to pinpoint the cause of a patient’s Cushing’s syndrome. The procedure for administering the high-dose dexamethasone test differs from that of the low-dose dexamethasone suppression test only in that the patient must take a higher dose – 8 mg – of dexamethasone. At this dose, patients whose test results reveal low morning serum cortisol levels may have pituitary tumors, whereas those with high morning serum cortisol levels may have adrenal tumors or ACTH-producing tumors elsewhere in the body, such as in the lungs.

Dexamethasone-Suppressed Corticotropin-Releasing Hormone Test

This test combines the dexamethasone suppression test with the CRH stimulation test with the goal of ruling out a pseudo-Cushing diagnosis. Patients with Cushing’s syndrome will have elevated cortisol levels, whereas those with pseudo-Cushing will not have elevated cortisol levels as a result of this test.

Petrosal Sinus Sampling Test

This invasive testing procedure is relegated only to patients for which a Cushing’s syndrome diagnosis has been confirmed. ACTH normally drains from the pituitary gland into the inferior petrosal sinus veins. For the petrosal sinus sampling test, blood samples are taken from these veins through a catheter. One sample is taken before the administration of corticotropin-releasing hormone, and then additional samples are taken at intervals over a short time span that follows the injection. The ACTH levels that are revealed in these samples are compared to those of samples that are taken from a peripheral vein. Higher ACTH levels in the samples taken from the petrosal sinus veins are indicative of pituitary adenoma. If the ACTH level in these samples is similar to that of the samples taken from the peripheral vein, then such a result is suggestive of ectopic Cushing’s syndrome.

Additional Screening Tests

Once a diagnosis of Cushing’s syndrome has been achieved, diagnostic imaging tests, such as magnetic resonance imaging, computed tomography and ultrasound, may be ordered to evaluate the patient’s lungs, abdominal organs and pituitary and adrenal glands for tumors, hyperplasia and other abnormalities.

Treatment for Hypoadrenocorticism

The treatment for hypoadrenocorticism depends upon the cause of the hypercortisolism. In the case of iatrogenic Cushing’s syndrome, a patient’s use of glucocorticoid drugs will likely need to be weaned down to the most minimal dose that can be sustained to effectively manage the condition for which he/she is taking the medication. Surgery to remove pituitary adenomas is the effective treatment method for patients with Cushing’s disease, and surgical removal is also performed when ACTH-producing tumors are diagnosed elsewhere in the body. Other treatment options for Cushing syndrome include radiation, chemotherapy and drug therapy to reduce the production of cortisol. Patients who are suspected to have Cushing’s syndrome are usually referred to an endocrinologist for testing, treatment and management plans.

Thanks to Johns Hopkins for the image.

Urine Sample: One Chapter of the Metabolic Story

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by Cat Troiano

Urination is one of the body’s ways of eliminating metabolic waste, which is why a urinalysis is an important diagnostic screening method. For something that is considered waste, one to two ounces of that waste can provide a wealth of information regarding the body’s metabolic efficiency. Is it enough to make a definitive diagnosis, or is it a valuable noninvasive first step?

Who Should Be Tested?

When the body expels urine, it is eliminating excess water and sodium. Perspiration and, to a much lesser extent, exhalation also rid the body of water. Urine, however, also rids the body of creatinine, uric acid, urea and other toxic compounds that the kidneys filter from the bloodstream. Other compounds can also be shed in the urine, and their presences serve as indicators of illness.

A urinalysis should be ordered along with a routine comprehensive metabolic blood panel and complete blood cell count to provide a complete metabolic health evaluation. Urinalyses are also performed to aid in diagnosing the following conditions:

• Urinary tract infections
• Chronic kidney disease
• Diabetes
• Liver disease

If a patient has any of these conditions, periodic urinalyses are ordered to monitor the illness so that changes in treatment protocols can be implemented as needed.

Urinalyses should be ordered at once when a patient presents with signs of urinary illness. Such signs include:

• persistent urge to urinate
• passing only minimal amounts of urine
• pain or burning sensation during urination
• blood seen in the urine
• fever
• pains in the back, side or abdomen

If a urinary tract infection is suspected, a urine culture should also be ordered.

While pregnancy can be diagnosed from a urine sample, the telltale hormone is not included in a urinalysis and must be detected in a separate test, which is the human chorionic gonadotropic urine test. However, routine urinalyses are ordered as part of an expectant mother’s prenatal examinations to screen for such conditions as gestational diabetes.

A urinalysis is also part of a pre-op screening to confirm that the kidneys are functioning optimally to process anesthetic agents and to alert physicians to the presence of diabetes or infection, which will need to be addressed prior to any surgical procedures.

Urinalysis: A Three-Step Process

A complete urinalysis is performed in three steps, which include a physical analysis, a chemical analysis and a microscopic analysis.

Physical Analysis:

Urine should be straw to pale yellow in color, and it should be clear, not cloudy. It should not have a particularly foul odor. Medications and foods can affect these physical aspects of urine. For example, have some beets for dinner tonight, and then see what color your urine appears when you visit the bathroom tomorrow. Rhubarb, blackberries and carrots can also alter the color of urine, asparagus can change the odor, and a high protein diet can make the urine appear cloudy. Even the extent to which a patient is hydrated can be evidenced in their urine’s appearance. Sneak a peek at your urine the next time you visit the bathroom. If your urine looks clear or a pale shade of yellow, then your body is properly hydrated. If your urine is bright yellow or darker in color, then you are not drinking enough water.

Ironically, some drugs that are used to treat urinary tract infections, such as phenazopyridine, can tint urine into an orange hue. Other medications that can alter any urinalysis results include, but are not restricted to:

• Certain antibiotics, such as metronidazole, rifampin and nitrofurantoin
• Sulfasalazine, a drug used to manage ulcerative colitis, rheumatoid arthritis and Crohn’s disease
• Propofol, an anesthetic agent
• Promethazine, a drug used to control asthma
• Certain vitamins and minerals, such as vitamin C and riboflavin
• Cimetidine, an antihistamine
• Levodopa, a drug used in the treatment of Parkinson’s disease
• Laxative preparations that contain senna
• Amitriptyline, an antidepressant
• Anticoagulant drugs
• Methocarbamol, a muscle relaxant
• Potassium citrate, which is used to treat kidney stones as well as gout
• Thiazide diuretics, which are antihypertensive drugs
• Sodium bicarbonate drugs used to treat acid indigestion

After a visual inspection for color and clarity, two laboratory screenings are performed to complete the urinalysis.

Chemical Analysis:

Acidity is represented as a pH level. Neutral pH has a value of 7. The normal pH reference range is 5.0 to 8.0. A result that is higher than this range, interpreted as an alkaline, or basic, level may be caused by urinary tract infection, urinary tract obstruction and renal failure, and can also result if a patient has been vomiting. A high pH level can also occur in patients with respiratory alkalosis. When the urine pH value is lower than the normal range, interpreted as an acidic level, this may be the result of diabetic ketoacidosis, dehydration, starvation and acidosis, and can also result if a patient is having diarrhea.

Bilirubin is a resulting by-product from the normal breakdown of red blood cells. It is normally passed along to the liver, where it is allocated into bile. Bilirubin should not be present in urine. If bilirubin is detected on a urinalysis, additional tests to evaluate liver function should be pursued.

Urobilinogen is a by-product of bilirubin. Urobilinogen is primarily excreted through defecation, but small amounts may be passed through urination. The normal reference range for urobilinogen is 0.2 to 1.0 mg/dL. If the test results exceed that range, then additional tests to evaluate liver function should be pursued.

Blood in the urine, known as hematuria, is not normal. Blood that is detected on a urinalysis can be indicative of kidney or bladder infection, kidney or bladder stones, renal cancer, bladder cancer or a blood disorder. Further tests will be necessary to achieve a specific diagnosis. Menstruation should be ruled out first in female patients.

Specific gravity reveals how efficiently the kidneys are able to concentrate the urine. The normal specific gravity reference range is 1.003 to 1.035. Results lower than the reference range are indicative of kidney disease. Results higher than the reference range can be a result of dehydration.

Glucose should not be detectable when performing a urinalysis. If the result is not negative, then further testing should be ordered to confirm a diagnosis of diabetes.

Ketones are the byproduct of the breakdown of fat and should not show up on a urinalysis. If the result is not negative, then further testing should be ordered to confirm a diagnosis of diabetes. Extreme low-carbohydrate diets can also lead to ketones in the urine.

Protein in the urine, or proteinuria, should be investigated further if the result exceeds a normal reference range of 0 to 20 mg/dL. Higher results can result from kidney disease, urinary tract or bladder infection, diabetes and dehydration, as well as hypertension or health conditions caused by eclampsia in pregnant women.

Nitrites are nitrogen compounds that can result when Gram-negative bacteria, including E. coli, release an enzyme that converts nitrates into nitrites. When nitrites are detected on a urinalysis, a urinary tract infection is the likely explanation.

Leukocyte esterase is produced by leukocytes, one of the five types of white blood cells in the body. As in the case of nitrites, if leukocyte esterase is detected on a urinalysis, a urinary tract infection should be suspected.

If any abnormalities are detected, the microscopic analysis will help to confirm the initial findings.

Microscopic Analysis:

• Leukocytes, or white blood cells
• Erythrocytes, or red blood cells
• Bacteria, which is a strong indicator of infection
• Casts, which are microscopic particles that can be made up of fat, protein or blood cells
• Crystals, the presence of which indicate bladder or kidney stones

Once the urinalysis is complete, the combined results provide more pieces of the diagnostic puzzle.
Putting the Tests Together

As informative as a urine specimen is, a urinalysis must be combined with additional tests to definitively rule out and confirm the causes of abnormal results. This is why a complete metabolic profile should accompany a urinalysis, as the metabolic profile will reveal specific values of renal and liver function as well as blood glucose levels. If crystals are seen on the microscopic analysis, additional tests and/or procedures should be performed to ascertain the size and number of stones as well as to determine if they are calcium oxalate, uric acid or struvite stones. In the case of a urinary tract infection, a urine culture will identify the offending bacteria and guide in the selection of the most effective antibiotic to combat the infection. If diabetes is suspected, further tests must be ordered so that an effective treatment plan for the patient’s disease management can be formulated.

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