Complete Nurse's Guide to Diabetes Care, 3rd Edition

Chapter 31:

Common Comorbidities

Marjorie Cypress, PhD, MSN, RN, C-ANP, CDE,1 and Geralyn Spollett, MSN, C-ANP, CDE2

2Cypress is an adult nurse practitioner and certified diabetes educator in Albuquerque, NM. 2Spollett is an adult nurse practitioner and associate director at Yale Diabetes Center, New Haven, CT

Diabetes can be associated with other disorders, particularly an excess or deficiency of endocrine hormones through a shared etiological mechanism. This can occur in three ways:

• In type 1 diabetes (T1D), an autoimmune process that destroys β-cells also may affect other endocrine cells, leading to adrenal, gonadal, thyroid, or parathyroid disease.

• β-Cell function may be disrupted through an infiltrative process that also damages other endocrine or metabolic tissue.

• Insulin resistance and associated hyperinsulinemia may be at the root of the associated endocrinopathy.1

The effects of the “other” endocrine diseases may cause a destabilization of diabetes control, resulting in either hypoglycemia or hyperglycemia. Most of these disorders are related to pituitary adenomas that secrete excessive amounts of counterregulatory hormones or to the administration of exogenous hormone therapy. The main conditions associated with diabetes or glucose intolerance are acromegaly, Cushing’s syndrome, pheochromocytoma, and glucagonoma.2 Autoimmune diseases associated with diabetes include thyroid disease, Addison’s disease, celiac disease, and pernicious anemia. Other diseases that sometimes are associated with diabetes or result in unstable diabetes control include fatty liver disease and cystic fibrosis (see Chapter 33, Cystic Fibrosis–Related Diabetes). Lipodystrophy is recognized as a characteristic distribution of areas of lipoatrophy and to some degree other areas of lipohypertrophy. It is the association of metabolic abnormalities including diabetes, hypertriglyceridemia, and heart disease.



Acromegaly is a condition caused by excess growth hormone, usually caused by a pituitary microadenoma. Growth hormone causes hyperglycemia because of its effects on peripheral insulin resistance and hepatic glucose production as it is an insulin antagonist. The incidence of diabetes in acromegaly is estimated to be 13–32%, and the incidence of glucose intolerance in acromegaly is 60%. People who receive exogenous growth hormone (e.g., children with short stature) also can develop glucose intolerance or overt T2D and can suffer the microvascular and neuropathic complications often associated with chronic suboptimally controlled diabetes.2 Signs and symptoms of acromegaly in adults include excessive growth of hands and feet (with rapid increase in shoe and glove size), protruding jaw, enlarged tongue, coarse facial features, fatigue, weakness, acanthosis nigricans, hypertension, weakness, excessive growth of skin tags, and headaches.3 Acromegaly also is highly associated with cardiovascular complications: 40% of people with acromegaly also have hypertension and most have cardiomyopathy.4 Sleep apnea is noted to be common in people with acromegaly.5 The treatment for diabetes in those with acromegaly is the same as those without diabetes and lowering of glucose levels will improve insulin sensitivity.

Laboratory findings may include elevated serum growth hormone levels at fasting and after oral glucose. In healthy individuals, glucose will suppress growth hormone, but in those with acromegaly, growth hormone levels will increase.6 Other laboratory findings include elevated prolactin levels and elevated blood glucose levels. Magnetic resonance imaging (MRI) of the head may reveal a pituitary tumor in 90% of cases. Treatment consists of surgical excision of the tumor and has varying effects on glucose metabolism.

Cushing’s Syndrome

Cushing’s syndrome is the result of excessive cortisol secondary to either exogenous therapy or an endogenous cortisol-secreting pituitary adenoma, which may be either benign or malignant. Some people develop Cushing’s syndrome after taking glucocorticoids like prednisone for asthma, rheumatoid arthritis, lupus, or other inflammatory diseases. High cortisol levels can cause increased insulin resistance, increased gluconeogenesis, and decreased peripheral glucose uptake, which subsequently leads to glucose intolerance or overt T2D. Many of the features of Cushing’s syndrome closely resemble those associated with metabolic syndrome or cardiometabolic risk. Certain other conditions that may increase cortisol levels include strenuous exercise, sleep apnea, pain, alcoholism, depression, pregnancy, stress, and uncontrolled diabetes. Because some of these conditions are reversible with treatment, it is important to evaluate patients to distinguish those who may have Cushing’s syndrome versus those with possible pseudo-Cushing’s syndrome. If Cushing’s is suspected, a thorough workup should be conducted to look for a tumor if no other cause can be found. If a tumor is found, surgery may be an option.

The clinical picture of an individual with Cushing’s syndrome includes truncal obesity, hypertension, glucose intolerance, facial rounding (typical moon face), osteoporosis, abdominal striae, hirsutism, acanthosis nigricans, depression or emotional lability, and menstrual irregularity.2,3,7 Individuals with Cushing’s syndrome may go on to develop atherosclerosis and cardiovascular disease (CVD), which often are associated with insulin resistance and conditions associated with cardiometabolic risk. It is not clear to what extent Cushing’s syndrome is common or uncommon. Some believe that Cushing’s syndrome may be more common than previously thought because it often resembles the metabolic syndrome and further evaluation may not be performed. In addition, its features are similar to those of polycystic ovary syndrome, and the diagnoses of polycystic ovary syndrome or Cushing’s syndrome can be mistaken for each other.

Laboratory evaluation is somewhat problematic in that several tests can have false-negative or some false-positive results. A current recommended laboratory evaluation, which appears to be more specific and reliable, is evening salivary cortisol level.7 Because cortisol levels peak in the early morning hours, an evening level should be lower. Other more commonly used tests include a 24-h urine-free cortisol level. This test should include a urine creatinine level to help evaluate whether the urine collection was properly done (normal urine creatinine in 24 h is ~1 g and should not fluctuate more than 10%). The overnight dexamethasone suppression test involves administration of 1 mg dexamethasone at 11:00 p.m., with serum levels of cortisol drawn in the morning. In Cushing’s syndrome, the cortisol level fails to be suppressed. This test, although commonly performed, also can have false-positive results, and questionable test results should be referred to an endocrinologist.7 Further evaluation may include an MRI to look for a pituitary tumor. Treatment focuses on surgical excision of the adenoma, which can result in a reversal of the metabolic abnormalities.

Pseudo-Cushing’s syndrome presents with some of the same clinical features with mildly elevated urinary free cortisol and sometimes an abnormal dexamethasone suppression that corrects with treatment of the underlying condition. Several studies have found relationships between high cortisol profiles (although still in the normal range) and elevated fasting blood glucose, postprandial blood glucose, A1C levels, and blood pressure. Whether the elevated cortisol levels are a result of chronic stress of hyperglycemia or enhanced hypothalamic-pituitary-adrenal axis activity with T2D is unknown. When the hyperglycemia or weight loss are treated, however, the clinical features of Cushing’s diminish.8,9


A pheochromocytoma is an adenoma or less commonly a malignant tumor that secretes excessive amounts of the catecholamines epinephrine, norepinephrine, and dopamine. Catecholamines normally are secreted in response to hypoglycemia and counter the effects of insulin by increasing glucose production through glycogenolysis. Therefore, the symptoms associated with glucose intolerance and symptoms of hypoglycemia are present and include headache, excessive diaphoresis, and palpitations that can last from minutes to hours. Acute attacks also may include pallor, nausea, and panic attacks that may last several minutes and resolve spontaneously. Another insidious sign of pheochromocytoma is new-onset T2D.10

Laboratory evaluation is conducted through urine catecholamine levels. Symptoms are controlled through α- and β-blockade, but resolution of pheochromocytoma is accomplished only through tumor removal.2Postoperative follow-up is critical to assess for hypoglycemia from hyperinsulinemia (24 h postop), which may be masked because of impaired gluconeogenesis and glycogenolysis.10


A glucagonoma is a rare and often-malignant tumor that secretes excessive amounts of the hormone glucagon. Increased gluconeogenesis and glycogenolysis result in glucose intolerance. Other associated symptoms are weight loss, glossitis, rash, and anemia.2 Treatment may consist of somatostatin therapy or surgical removal of the tumor.

Hypogonadism and Low Testosterone in Men with Diabetes

Men with T2D have higher rates of testosterone deficiency than those without diabetes. Some studies have found that 33–42% of men with diabetes have low testosterone as measured by free testosterone levels.11,12 Other studies have demonstrated a strong association between conditions associated with the metabolic syndrome (i.e., insulin resistance, dyslipidemia, visceral obesity, and glucose intolerance).13 In short-term studies, replacement therapy has demonstrated improvements in insulin sensitivity, visceral obesity, and lipids.13

Clinical symptoms of low testosterone include a decrease or loss of libido, decreased strength of erections, fatigue, decreased physical strength, and mood changes. Androgen Deficiency in the Aging Male14 is a short questionnaire that assesses the clinical symptoms associated with low testosterone. Biochemical evaluations generally consist of free testosterone, and sex hormone–binding globulin, although follicle-stimulating hormone and luteinizing hormone sometimes are used to differentiate between a primary or secondary hypogonadism. Because testosterone is secreted in a circadian rhythm with peak levels in the morning, testosterone levels should be measured in the morning.

Treating low testosterone with replacement therapy may consist of injections, patches, gels, mucoadhesive material applied to the teeth, or oral tablets. Each has its risks and benefits and should be discussed with a health-care professional familiar with these therapies.

Unfortunately, some health professionals and patients are reluctant to discuss issues related to sex and erections. Nurses should be aware of the high prevalence of low testosterone among men with T2D. Explaining how common these symptoms are among men with T2D can make it easier to ask patients whether they are experiencing any of these symptoms. Nurses should refer patients for evaluation and treatment.


Nonalcoholic steatohepatitis (NASH) is a common, often silent, liver disease. It may resemble alcoholic liver disease, but it occurs in people who drink little or no alcohol. Nonalcoholic fatty liver causes no signs and symptoms and no complications in most people. NASH is a common explanation for abnormal or elevated aminotransferase levels in up to 90% of cases once other causes of liver disease are excluded. NASH has been found to be common in people with T2D and is associated with a higher prevalence of cardiovascular disease, including coronary heart disease, peripheral vascular disease, and cerebrovascular disease.15,16

In some people with nonalcoholic fatty liver disease, however, the fat that accumulates can cause inflammation and scarring in the liver. At its most severe, nonalcoholic fatty liver disease can progress to liver failure.

NASH usually causes no signs and symptoms. When it does, they may include the following:

• Fatigue

• Pain in the upper right abdomen

• Weight loss

The major feature in NASH is fat in the liver, along with inflammation and damage. Most people with NASH feel well and are not aware that they have a liver problem. Nevertheless, NASH can be severe and can lead to cirrhosis, in which the liver is permanently damaged and scarred and no longer able to work properly.17

NASH is becoming increasingly common, possibly because of the greater number of Americans with obesity. In the past 10 years, the rate of obesity has doubled in adults and tripled in children. It is a common disease that often occurs in people who are overweight or obese, including those with T2D.18 Obesity also contributes to diabetes, high triglycerides, and low HDL cholesterol, which can further complicate the health of someone with NASH. Diabetes and high blood cholesterol also are becoming increasingly common among Americans.18

NASH is usually a silent disease with few or no symptoms. Patients generally feel well in the early stages and only begin to have symptoms—such as fatigue, weight loss, and weakness—once the disease is more advanced or cirrhosis develops. The progression of NASH can take years, even decades. The process can stop and, in some cases, reverse on its own without specific therapy. Or NASH can slowly worsen, causing scarring or fibrosis to appear and accumulate in the liver. As fibrosis worsens, cirrhosis develops; the liver becomes seriously scarred, hardened, and unable to function normally. Not every person with NASH develops cirrhosis, but once serious scarring or cirrhosis is present, few treatments can halt the progression. A person with cirrhosis experiences fluid retention, muscle wasting, bleeding from the intestines, and liver failure. Liver transplantation is the only treatment for advanced cirrhosis with liver failure, and transplantation increasingly is performed in people with NASH. NASH ranks as one of the major causes of cirrhosis in America, behind hepatitis C and alcoholic liver disease.


Currently, no specific therapies for NASH exist. The most important recommendations given to people with this disease are as follows:

• Reduce their weight (if obese or overweight)

• Follow a balanced and healthy diet

• Increase physical activity

• Avoid alcohol

• Avoid unnecessary medications

These are standard recommendations, but they can make a difference. They are also helpful for other conditions, such as heart disease, diabetes, and high cholesterol.19

A major attempt should be made to lower body weight into the healthy range. Weight loss can improve liver tests in patients with NASH and may reverse the disease to some extent. Research at present is focusing on how much weight loss improves the liver in patients with NASH and whether this improvement lasts over a period of time.

Experimental approaches under evaluation in patients with NASH include antioxidants, such as vitamin E, selenium, and betaine. These medications act by reducing the oxidative stress that appears to increase inside the liver in patients with NASH. Whether these substances actually help treat the disease is not known, but the results of clinical trials should become available in the next few years.18

Another experimental approach to treating NASH is the use of newer antidiabetic medications—even in people without diabetes. Most patients with NASH have insulin resistance, meaning that the insulin normally present in the bloodstream is less effective for them in controlling blood glucose and fatty acids in the blood than it is for people who do not have NASH. The newer antidiabetic medications make the body more sensitive to insulin and may help reduce liver injury in patients with NASH. Studies of these medications—including metformin, rosiglitazone, and pioglitazone—are being sponsored by the National Institutes of Health and should answer the question of whether these medications are beneficial in NASH.


In recent years, more interest and research has focused on lipodystrophies. Lipodystrophies are a heterogeneous group of diseases that are characterized by the complete or partial loss or absence of subcutaneous adipose tissue. Although some lipodystrophies are congenital and evident at birth, others manifest later in childhood, adolescence, or even in adulthood. Lipodystrophies often are associated with the metabolic abnormalities, including those seen in the metabolic syndrome. In its consensus statement, the American Association of Clinical Endocrinologists list a number of characteristics that should increase suspicion of lipodystrophy in patients. These include the following:

• Loss of subcutaneous body fat that typically occurs or is noticed late in childhood or around puberty

• Affects the distal extremities or gluteal regions

• Accumulation of fat in face, neck, and intra-abdominal area

• Diabetes with severe insulin resistance (>200 units/day)

• Ketosis-resistant diabetes

• Polycystic ovarian syndrome (PCOS) or metabolic reproductive syndrome

• Severe hypertriglyceridemia >500 mg/dL

• History of pancreatitis associated with elevated triglycerides

• Evidence of non-alcoholic fatty liver disease

• Extreme hunger and complaints of constant hunger, needing to eat

• Amenorrhea and secondary hypogonadism in men19

Recent research has identified the hormone leptin, produced by adipose tissue that regulates a number of physiological processes and behaviors, including appetite, body weight, neuroendocrine functions, and glycemia.20Those with lipodystrophy have low levels of leptin. Currently, the treatment for lipodsyrophy includes diet and exercise, fibrates for hypertriglyceridemia, antihyperglycemic medications, and in some cases, the use of U-500 insulin in those with severe insulin resistance. Leptin replacement therapy has been shown to improve some metabolic abnormalities associated with lipodystrophy,20 and the drug metreleptin currently is under review by the U.S. Federal Drug Administration for treatment.19 Nurses may see patients with some of these metabolic abnormalities and can support and counsel patients in terms of lifestyle change, and the importance of taking medications to improve their current and future health status.

Practical Point

Managing people with diabetes involves not only attention to blood glucose, blood pressure, and lipid control, but also awareness of other endocrine diseases that can be associated with diabetes. Nurses and other health-care professionals need to maintain a high index of suspicion when treating patients with diabetes, as many of the other endocrine diseases can present with mild symptoms. A thorough review of symptoms can help with early detection and treatment for some of these problems.


Autoimmune-mediated diabetes (T1D) is associated with other autoimmune diseases, most notably thyroid disease, celiac disease, Addison’s disease, and pernicious anemia. In addition to islet cell antibodies in autoimmune-mediated diabetes, antithyroid peroxidase, adrenal, and antigastric parietal autoantibodies are often present. These autoimmune diseases are probably higher than noted. In one study of 491 children with T1D, 32.6% had at least one nonislet autoantibody.21

Diabetes and Thyroid Disease

The prevalence of thyroid disease in individuals with diabetes is much higher than in the general population. The prevalence of autoimmune thyroid dysfunction varies in the population with T1D within racial groups, age-groups, and geographic regions. Although there are no statistics for the U.S. population, a study conducted in Scotland showed that of the 13.4% of people diagnosed with thyroid disease, the highest incidence (31.4%) was found in women with T1D and the lowest (6.8%) in men with T2D, suggesting that those with T1D are more susceptible to thyroid disease. In this group, the most common thyroid dysfunction was subclinical hypothyroidism.22

In T1D, Graves’ disease is the most common autoimmune thyroid disease leading to hyperthyroidism. Most often diagnosed in young women, this disease has clear links to the human leukocyte antigen markers. Thyrotoxicosis disrupts glucose control by causing an increase in glucose absorption, utilization, and production. The increased production of thyroid hormone and its subsequent effect on metabolism results in accelerated gluconeogenesis by the liver and an increase in peripheral tissue uptake of glucose. The increased glucose production and disposal stimulated by the thyroid hormones occurs independent of insulin levels. In addition to these mechanisms, increased thyroid hormone also can cause insulin resistance and promote an increase in insulin clearance rates. To compensate for the lack of circulating insulin, more insulin must be secreted. In previously undiagnosed patients, hyperthyroidism may unmask impaired glucose tolerance and diabetes.

For patients with T1D with undiagnosed hyperthyroidism, the rapid disposal of insulin results in hyperglycemia and can lead to ketoacidosis. Because this is a life-threatening acute complication, the importance of screening for thyroid disease in T1D cannot be underestimated. Conversely, if a patient has thyrotoxicosis, a screening test for latent diabetes should be done.

The presentation of clinical signs and symptoms of hyperthyroid disease (see the box “Symptoms of Hyperthyroidism”) warrants thyroid function evaluation. The thyroid-stimulating hormone (TSH) blood test is the best way to screen for thyroid function. If the levels of TSH are suppressed, then the amount of thyroid hormone being produced is excessive, indicating a hyperthyroid state. A free thyroxine index or free T4 level will help determine the extent of the hyperthyroid problem. If the laboratory results do not match the clinical presentation, further workup by an endocrinologist may be necessary to determine the cause for the hyperthyroidism and subsequent treatment.

In Graves’ disease, therapeutic options include ablation by radioactive iodine, justified surgical removal of the gland, or medical control with thionamides. If the patient has tachycardia or tremors, the use of β-adrenergic-blocking agents can ameliorate these symptoms, but also may decrease the patient’s ability to recognize hypoglycemia and impair the counterregulatory response to hypoglycemia.1 If using radioactive iodine (as is preferred in the U.S.), a pregnancy test must be administered before the treatment. Patients should be informed of side effects of antithyroid drugs and the importance of contacting their provider immediately if they develop a pruritic rash, jaundice, dark urine, arthralgias, abdominal pain, nausea, fatigue, fever, or pharyngitis. Fever and pharyngitis are symptoms suggestive of agranulocytosis.23

Lymphocytic thyroiditis, another cause of hyperthyroidism, particularly in young postpartum women, can spontaneously revert to hypothyroidism. Although the disease usually resolves, a percentage of women have permanent hypothyroidism. Careful monitoring of thyroid function must be done throughout the disease process to determine appropriate treatment and make the necessary adjustments in therapy. The changeable course of this condition further complicates diabetes control.

During the initial phases of treatment for hyperthyroidism, insulin needs still are increased, but as the patient becomes euthyroid, or in some cases hypothyroid, previous medication dosages may be excessive. Frequent self-monitoring of blood glucose and a flexible insulin regimen may be the best course of action to compensate for fluctuations in the insulin requirement.


In hypothyroidism concomitant with diabetes, the most common cause is an autoimmune thyroid dysfunction, Hashimoto’s disease. It occurs in T1D but also has an increased prevalence in T2D unrelated to autoimmunity factors.

Hypothyroidism slows the absorption of glucose from the gastrointestinal tract, reduces glucose uptake by the peripheral tissues, and decreases gluconeogenesis. In response to prolonged insulin half-life, endogenous insulin secretion may be reduced. Although these changes in glucose metabolism may not produce clinical symptoms in a person without diabetes, they have a substantial impact on glucose control in the person with diabetes. Overall glucose control deteriorates and episodes of hypoglycemia increase. As with hyperthyroidism, TSH is the most accurate method to evaluate primary hypothyroidism. The level of TSH will be elevated in response to the decrease in thyroid hormone production. Most hypothyroidism is related to primary thyroid failure. In some instances, however, the hypothalamus or pituitary gland will be the cause of the hypothyroidism, and in such cases, the TSH may not be elevated. Further evaluation by an endocrinologist is needed to determine the cause. Regardless of etiology, the presenting clinical picture for hypothyroidism remains consistent. As hypothyroidism resolves with treatment, an increase in insulin dosage will be needed to meet the increased metabolic need.24

If a person with T1D presents with unexplained changes in weight, lipid profile, insulin dosage requirements, and glycemic control and has a family history of thyroid disease, careful assessment for thyroid disease is warranted.

Treatment for hypothyroidism relies on the replacement of L-thyroxine. The usual dose of levothyroxine is 75–125 µg. In elderly patients and those at risk for atherosclerotic heart disease, the initial dose should be reduced to 50 µg. CVD is prevalent in T2D; therefore, these therapeutic guidelines should be considered in patients with diabetes.

Further adjustments in therapy are made based on the results of TSH testing done every 4–8 weeks. Because certain medications, malabsorption syndromes, and specific dietary intake can interfere with the absorption of L-thyroxine, it is recommended that it be taken on an empty stomach 60 min before breakfast or at bedtime, 4 h after the last meal.25 A recent study demonstrated a significant interaction between levothyroxine and iron, calcium, proton pump inhibitors, and estrogen. All four drugs increased TSH levels, indicating a reduction in the effectiveness of levothyroxine. A decrease in serum TSH was statistically significant in patients on statin therapy. Glucocorticoids, H2 receptor antagonists, or disease-modifying antirheumatic drugs did not alter the TSH levels.26

Dyslipidemia can result from the metabolic changes associated with hypothyroidism. As thyroid function approaches normal levels, the lipid profile also will improve. With the persistence of unrecognized hypothyroidism or untreated subclinical hypothyroidism, however, the risk of CVD increases.27 Many patients with T2D have features of the metabolic syndrome as well as dyslipidemias that are slow to respond to treatment. If the underlying cause is hypothyroidism and it is not treated, lipid levels will have limited clinical improvement. This underlines the need for annual screening for thyroid disease in the population with diabetes.

Nursing Implications

Thyroid disease is the most common autoimmune disease seen in those with diabetes. The increased prevalence of thyroid disease particularly among women with T1D as well as among those with a positive family history of thyroid disease supports the need for screening and increased vigilance for signs or symptoms of hypo- or hyperthyroidism. The destabilization of glucose control in thyroid disease requires an intensification of diabetes management, particularly self-monitoring of blood glucose and adjustments in medication therapy. Nursing must focus on maintaining a continuity of care and coordination of therapies. Patient education regarding the interface of thyroid disease and diabetes and the ways to distinguish between the causes of clinical symptoms (e.g., hypoglycemia versus hyperthyroidism) is a nursing priority. To achieve and maintain the euthyroid state, the nurse needs to educate the patient on thyroid replacement therapy. Knowledge regarding the proper timing and possible medication interactions are essential for positive therapeutic outcome. Uncontrolled thyroid disease places the patient at further risk for CVD.

Symptoms of Hyperthyroidism


Increased sweating

Heat intolerance

Nervousness and anxiety


Muscle weakness

Palpitations and tachycardia



Weight loss

Symptoms of Hypothyroidism

Dry, coarse skin and hair

Cold intolerance


Facial edema

Slow speech and mentation

Poor concentration


Weight gain

Lower-extremity edema


Weakness and lethargy


Practical Point

Thyroid disease is frequently seen in individuals with both T1D and T2D. The ADA recommends providers screen patients with T1D for autoimmune thyroid disease soon after diagnosis and at any time the patient presents with symptoms suggestive of thyroid disease. Those already diagnosed with thyroid disease need to be monitored periodically by lab tests and physical examination. It is important that nurses advise patients of the potential for other medical and psychological complications when thyroid levels are not adequately controlled.

Celiac Disease in T1D

Celiac disease is an often overlooked and underdiagnosed problem associated with T1D. The symptoms may mimic other gastrointestinal problems and may be misdiagnosed. First noted in the late 1960s, celiac disease associated with T1D has a prevalence rate of ~4–6%.28 More recent estimates of celiac disease in people with T1D are as high 1 in 20 people.27 Celiac disease has been noted in other organ-specific autoimmune conditions, such as thyroid disease and Addison’s disease.30

Pathophysiology of Celiac Disease

A genetically mediated disease of the small bowel, celiac disease may present in infancy and early childhood and then again later in life (>60 years of age). It most commonly is seen in people of European descent and has a 95% genetic predisposition. Viral exposures may trigger an immune response in individuals predisposed to the disease, resulting in the onset of active disease.

In celiac disease, also known as gluten-sensitive enteropathy, there is an abnormal T-cell response against gliadin, a part of wheat gluten and prolamins (derived from barley, rye, and possibly oats). The production of proinflammatory cytokines results in an immune reaction to gluten, the storage protein of wheat. This inflammatory environment causes an immune deregulation and loss of tolerance that activates CD8+ T-cells and B-cells in the intestinal epithelium.31The resulting pathophysiology affects the functioning of the villi of the small intestine and limits its ability to absorb nutrients. This inability to digest certain carbohydrates results in osmotic diarrhea, hypersecretion caused by crypt hyperplasia, and dysmotility caused by an inflammatory reaction.32

Gluten intolerance or gluten sensitivity (GS) should not be confused with celiac disease. They are two distinct diseases caused by different intestinal responses to gluten. Although both entities have a T-cell–mediated reaction to gluten, only celiac disease is associated with increased intestinal permeability. In gluten-sensitive individuals, tissue transgutaminase autoantibodies or autoimmune comorbidities are not present. Although those with GS cannot tolerate eating gluten and develop gastrointestinal symptoms, it does not lead to small intestinal damage. The diagnosis of GS is usually made through an elimination diet and a monitoring of response when the gluten-containing foods are reintroduced.33

In celiac disease, the usual clinical presentation is that of chronic diarrhea and failure to thrive or anorexia. Vomiting, bloating, and distention and constipation are part of the constellation of classic symptoms. Steatorrhea or fatty stools indicating impaired absorption may be present. Unexplained weight loss, muscle tenderness, and signs of immunological illnesses, such as atopic dermatitis and alopecia, also may be present. A papular-vesicular rash, dermatitis herpetiformis, may appear on the base of the scalp and on the elbows, knees, and trunk. Extreme itching and burning characterize the rash. Less typical presentations may include iron-deficiency anemia, vitamin deficiencies, osteoporosis or osteopenia, arthritis, alteration in teeth enamel, recurrent aphthous stomatitis, short stature, chronic hepatitis, depression, irritability, chronic fatigue, or neurological problems. Although some patients have profound symptoms, such as abdominal cramping, flatulence, and violent diarrhea, many others are unaware of the problem or are asymptomatic.34

Symptomatic patients find that once a gluten-free diet is followed for a period of time, they notice a reduction in gastrointestinal symptoms, improved general health, and an increase in energy and well-being. Epidemiological studies now indicate that the frequency of malignant complications associated with celiac disease is much lower than previously reported. The increase in fracture risk and reproductive problems is small when patients adhere to a gluten-free diet.35

Diabetes and the Effect of Celiac Disease

Two studies that focused on the effect of celiac disease on blood glucose control found little disruption in control. Amin et al.34 found no difference in metabolic control, as measured by hemoglobin A1c, in patients with T1D with or without celiac disease. No statistically significant change in insulin requirement was found. It was reported, however, that after starting a gluten-free diet, some celiac patients had an increased incidence of morning hypoglycemia. The second study, by Kaukinen et al.,37 found no difference in metabolic control in diabetes with the initiation of treatment for celiac disease.

Before diagnosis and treatment, patients with celiac disease have hypoglycemic episodes and reduced insulin needs that are assumed to be related to the malabsorptive state. Over time, treatment with a gluten-free diet can help reduce the incidence of hypoglycemia. Therefore, Schwarzenberg and Brunzell38 recommend closely monitoring insulin needs and blood glucose control during the early phase of treatment with a gluten-free diet, when changes in nutritional status may influence metabolic control.

Diagnosis of Celiac Disease

In people with a family predisposition to the disease, serological testing, used as a screening tool, may help discover atypical or silent celiac disease. In the past, most investigators advocated a profile of three antibody assays: 1) antigliadin immunoglobulin G (IgG), 2) antigliadin immunoglobulin A (IgA), and 3) either antiendomysial or an antitissue transglutaminase assay for diagnosis.36 A revision of the serologic testing by National Institutes of Health Consensus Development Congress on Celiac Disease, the American Gastroenterological Association Institute, and World Gastroenterology Organization now recommends serum tissue transglutaminase (tTG) IgA and endomysial antibody (EMA-IG) assays and does not advise the Anti-Gliadin Antibodies (AGA) use. When drawn together, the tTG IgA and EMA increase the overall sensitivity and specificity of the diagnosis of adult celiac disease.34

If the results of both assays are positive or the patient has symptoms but negative results, the patient should be referred to a gastroenterologist. Positive serological tests alone are not sufficient for diagnosis and the gold standard is a distal duodenal biopsy by endoscopy.34 A newer procedure, the capsule endoscopy, is minimally invasive and is used in higher-risk populations. A small camera is ingested that can take serial images of the intestinal villi and small bowel mucosa.39

Although no guidelines address continued screening of the at-risk population, many centers have adopted yearly testing for the first 3 years of diagnosed diabetes, and then screening every 3–5 years thereafter or whenever symptoms develop.38 ADA advises that consideration should be given for screening soon after diagnosis of T1D as well as screening those who have a first-degree relative with celiac disease or symptoms suggestive of celiac. 40

Many affected patients have subclinical disease. Children in particular can benefit from early diagnosis and treatment. Undiagnosed celiac disease contributes to growth failure, low bone density, and potential neurological abnormalities. Freemark et al.41speculate that the treatment of celiac disease in T1D could reduce the risk of developing other autoimmune diseases, such as Graves’ disease or Addison’s disease or non-Hodgkin’s lymphoma of the small bowel.41 Although screening of children has potential issues—invasive testing with risks and psychological burdens—research has shown that the prevalence of celiac disease in children proven by biopsy is relatively high, with children who were <4 years of age at onset of T1D at highest risk.42

Treatment of Celiac Disease

The current recommendation for treatment is that a gluten-free diet be maintained for life. The most important reason to adhere strictly to the diet is to reduce the risk of small-bowel lymphoma associated with celiac disease. As nutritional status improves, patients note a positive change in energy. The malabsorptive state associated with celiac disease deprives the patient of important minerals, vitamins, and micronutrients. Adherence to the diet improves the absorption of these important nutrients and can reverse anemia, osteopenia, and other symptoms of vitamin deficiencies, such as cheilosis and neurological symptoms. After a period of time on the gluten-free diet, some patients become exquisitely sensitive to the smallest amounts of gluten, whereas others may find they can tolerate small amounts without experiencing diarrhea or cramping. Despite the reduction of symptoms in response to gluten ingestion, the harmful effects of eating foods containing gluten have been demonstrated by small-bowel biopsies showing ongoing mucosal damage.

The Gluten-Free Diet

Maintaining a gluten-free diet is difficult but not impossible. Obvious sources of gluten and prolamins, such as bread, cereals, processed cheese, and wheat-based snack foods, are easily recognized and avoided (see Tables 31.1 and 31.2). Gluten, however, also is used as a thickener, emulsifier, binder, or stabilizer in many products. Oats, amaranth, and buckwheat43currently appear on the list of gluten-free foods, but controversy persists over whether these foods are safe in large amounts over time. Even certain ground spices may contain gluten products. Other sources of prolamins, such as grain alcohol, postage stamps, cosmetics, lip balms, and mouthwashes, should be avoided. Patients must be encouraged to read the labels on all foods because sometimes ingredients on previously “safe” foods change. Foods that are gluten free may be contaminated in transport or by the cooking process. Restaurant eating can be particularly difficult, and the person with celiac disease must learn to ask many questions regarding food preparation and possible kitchen contamination by gluten foods.

Table 31.1—Starches, Grains, and Other Foods Appropriate for a Gluten-Free Diet

• Amaranth,* arrowroot, whole-bean flour, buckwheat,* corn, cornstarch, cornmeal, flax, millet,* nut flours, oats,* oat bran,* oat gum,* pea flour, potato, sweet potato and yam, potato flour, potato starch, quinoa,* rice and wild rice, rice bran, rice flour, sago, sorghum, soy, tapioca, teff*

• Fresh, frozen, or canned unprocessed fruits and vegetables

• Fresh meats, poultry, seafood, fish, game, eggs, some processed meats with gluten-free ingredients, tofu, dried peas, beans, and lentils

• Milk, yogurt, and cheese made with gluten-free ingredients

• Oils, tree nuts, seeds, natural peanut butter, and salad dressings and spreads with gluten-free ingredients

• Honey, sugar, pure maple syrup, corn syrup, jams, jellies, candy, and ice cream with gluten-free ingredients

• Pure spices and herbs, salt, wheat-free soy sauce, vinegar with gluten-free ingredients

• Coffee ground from whole beans, brewed tea, carbonated beverages, some root beer

This is only a partial listing. Patients are encouraged to read all labels and to seek comprehensive food and additive lists from celiac organizations and the American Dietetic Association.

*Recommendations about acceptability are inconsistent. Many physicians restrict these grains for the first 6 months after diagnosis or until patients are in full remission.

Source: Adapted from Schwarzenberg and Brunzell.38

Table 31.2—Grains and Other Foods/Ingredients Not Appropriate for a Gluten-Free Diet

• Barley, bran, bulgur, couscous, durum flour, farina, graham flour, hydrolyzed plant protein (HPP), hydrolyzed vegetable protein (HVP), kamut, malt, malt extract, malt flavoring, malt syrup, semolina, rye, spelt (dinkel), triticale, wheat, wheat bran, wheat germ, wheat starch

• Imported foods that are labeled “gluten-free” but that may contain wheat starch*

• Processed meats and luncheon meats containing HVP or HPP, breaded meats, meats with sauces or gravies, casseroles

• Fruits and vegetables with sauces, breading, or thickeners

• Flavored milk, yogurt, processed cheese, and spreads made with gluten-containing ingredients

• Canned soups, soup mixes, bouillon, miso

• Candy, snack foods, desserts, frozen yogurt, and ice cream with gluten-containing ingredients

• Ground spices, condiments, and soy sauce with gluten-containing ingredients

• Margarine, salad dressing, and dips with gluten-containing ingredients

• Instant coffee, instant tea, instant cocoa mixes, some root beer, grain alcohol

This is only a partial listing. Patients are encouraged to read all labels and to seek comprehensive food and additive lists from celiac organizations and the American Dietetic Association.

*Foods produced in the U.S. or Canada and labeled “gluten-free” do not contain gluten or wheat starch.

Source: Adapted from Schwarzenberg and Brunzell.38

The addition of a gluten-free diet to the medical nutrition therapy recommended for diabetes presents a challenge and may be perceived as an additional burden. Referral to a registered dietitian can help educate and support the patient through this adaptive process. Patients who count carbohydrates need to know that gluten-free products may not contain the same number of carbohydrates as other starch products and that the digestion and glucose response may be quite different. For example, patients substituting rice or rice flour products for wheat-based ones may have a more rapid postmeal increase in glucose. Joining a support group or becoming active in celiac disease educational organizations will give the patient access to current information.

Psychosocial Issues

Having celiac disease in addition to T1D may present additional stress because of the nature of the symptoms, increased dietary restrictions, and serious consequences if untreated. Because the disease may go unrecognized for a long period, individuals who have multiple, recurring gastrointestinal complaints may be labeled as difficult patients. In addition, following a gluten-free diet is difficult in social situations in which food is a focus. Patients may feel uncomfortable and isolated. Although dietary education of the individual and family is central to the treatment, emotional support from the health-care team is equally important in treating this disease.


Supporting patients as they adapt to the dietary changes necessary to control celiac disease is critical for successful outcomes. Whether mild or severe enteropathy via endoscopy, patients benefit from strict adherence to a gluten-free diet. A patient assessment targeting possible vitamin deficiencies or iron deficiency anemia, thyroid, and liver dysfunctions as well as gluten-associated neurological symptoms should be done at each follow-up visit.

Nursing Implications

Like diabetes, celiac disease is a chronic condition that requires ongoing patient self-management. Assisting the patient in achieving positive outcomes in the management of both diseases is a challenge for the nurse. To be successful at managing both conditions, the patient must have a working knowledge of diabetes and the rudiments of medical nutrition therapy as well as a sophisticated understanding of the gluten-free diet and how it interacts with glucose control issues, such as hypoglycemia. Working as a team, the nurse and dietitian can educate the patient in the initial dietary changes and support the lifelong process of adaptation and readjustment.

Practical Point

Celiac disease is often missed as a diagnosis, and its symptoms often are attributed to other gastrointestinal diseases or poor adherence to the treatment regimen. Patients can become frustrated with their health-care team and health-care system. It is important that nurses be aware of the symptoms of this common disease and promote early detection.

Addison’s Disease

In Addison’s disease, autoimmune destruction of the adrenal glands results in adrenal insufficiency and the absence of cortisol. Because Addison’s disease can be treated effectively if diagnosed early, it is important to quickly evaluate for this disease to avoid fatalities. Clinical symptoms include weight loss; hyperpigmentation of the neck, elbows, and fingers; fatigability; muscle weakness; dehydration; increased craving for salt; and malaise. The risk of Addison’s disease is 1 in 250 in individuals with immune-mediated T1D. Therefore, individuals with immune-mediated T1D plus the presence of thyroid autoantibodies should be tested for the presence of adrenal 21-hydroxylase autoantibodies.44 Another laboratory evaluation for Addison’s disease is the adrenocorticotropic hormone cortisol-stimulation test, in which adrenocorticotropic hormone is administered intravenously and a cortisol level is drawn both 30 and 60 min later. If the cortisol level does not respond, the diagnosis of adrenocortical insufficiency, or Addison’s disease, is made. The lifelong treatment consists of oral hydrocortisone.

Pernicious Anemia

Another autoimmune disease associated with T1D is anemia. Both iron deficiency anemia and pernicious anemia can be autoimmune-mediated by parietal cell antibodies. The presence of antibodies to thyroid peroxidase and antigastric parietal cell antibodies and antiadrenal antibodies is four to five times as frequent in individuals with T1D as in the population without diabetes. In a study of individuals withT1D, 20.9% were found to be parietal cell antibody–positive; of those, 15.4% had iron deficiency anemia, and 10.5% had pernicious anemia.45 Parietal cell antibodies can inhibit the secretion of the intrinsic factor necessary for the absorption of vitamin B12, leading to latent and eventually overt pernicious anemia. B12 deficiency associated with metformin use is also seen in individuals with T2D. National Health and Nutrition Examination Survey data showed a biochemical B12 deficiency of 5.8% among those with diabetes using metformin compared with 2.4% in those with diabetes not using metformin and 3.3% without diabetes and not using metformin.46 The 2017 ADA Standards of Medical care recommend consideration of periodic screening of B12 levels and supplementation as needed for those taking metformin.40 Regardless of the etiology, if laboratory tests indicate a deficiency of this vitamin, treatment typically consists of monthly injections of vitamin B12, although some elderly patients with gastric atrophy receive oral supplements in addition to the monthly injections.


Many diseases can affect the level of glucose control that a person with diabetes achieves. These diseases cannot be overlooked in the treatment of diabetes. The metabolic changes that occur with the various disease states can make self-management of diabetes more difficult. Individuals who are coping with one or more chronic diseases will need nurses to provide additional patient education and psychological support to achieve positive outcomes.


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