AI is a life-threatening disorder that can result from primary adrenal failure or secondary adrenal disease due to impairment of the pituitary gland. It is the clinical manifestation of deficient production or action of glucocorticoids, with or without deficiency in mineralocorticoids and adrenal androgens [1]. The cardinal clinical symptoms of AI – as first described by Thomas Addison in 1855 – include weakness, fatigue, anorexia, abdominal pain, nausea, weight loss, orthostatic hypotension, and salt craving; characteristic hyperpigmentation of the skin occurs with primary adrenal failure. AI was invariably fatal until 1949, when cortisone was first synthetized and glucocorticoid replacement treatment became available.

AI may be primary when the adrenal is directly affected, which can occur via several mechanisms (immunity, infections, ischemia, congenital metabolic diseases such as adrenal leukodystrophy, etc.) or secondary when the pituitary gland has lost its capacity to secrete ACTH.

Secondary AI has become the most frequent etiology of AI due to the widespread use of exogenous corticosteroids in the therapy of many disease states (COPD, asthma, lupus, etc.). Chronic use of corticosteroids (using any route, PO, IV, nasal instillation, inhalation) leads to suppression of ACTH release. The lack of ACTH stimulation on the adrenal glands leads not only into suppression of cortisol secretion but also a decrease in actual glandular tissue. Thus the clinical spectrum of AI has changed since the original description by Addison and hence physicians need to raise their suspicion for AI in patients with nausea/vomiting with or without body weight and think of AI as a possible etiology for these symptoms. Some alerts are raised by the history: (a) Patients who have been (or are) treated chronically with corticosteroids, (b) thin individuals with a history of fatigue and chronic nausea/vomiting and/or abdominal pain, and (c) hyperkalemia and/or hyponatremia specially if patient has low blood pressure [1]. Regardless of the cause of AI, the outcome is a decrease in secretion of cortisol (primary and secondary) and mineralocorticoids (primary only) and therefore the diagnostic approach is aimed at demonstrating low levels of cortisol and decreased responsiveness of the adrenal gland to ACTH.

As a screening test for AI, a blood sample for cortisol and ACTH at around 8:00 am is recommended. This timing often poses a challenge for many ambulatory patients, and also for inpatients. Consequently, we recommend a full ACTH stimulation test, which is considered the current “gold standard” rather than a random cortisol level. The test can be performed in hospital settings and in ambulatory patients, is easy to do, and can be completed in 1 h. A basal sample is taken for measurement of ACTH and cortisol. After a dose of 250 mcg of ACTH 1–24 (Consyntropin) is given, blood samples for cortisol are taken 30 and 60 min later. The interpretation of results from the ACTH stimulation test is presented in Table 6.2.

Both hyper- and hypothyroidism are associated with nausea and vomiting; however, this is not the usual clinical manifestation that brings patients to the hospital. The mechanisms of nausea and vomiting in hyper- and hypothyroidism have not delineated. Hyperthyroidism is associated with increased number of bowel movements and in some cases diarrhea. Excess thyroid hormone increases the cellular response to catecholamines and this could decrease the intestinal transit time by increasing peristalsis [2]. We did not find data on the effects of thyroid hormone excess on gastric neuromuscular function, but thyroid hormone excess may cause tachygastria, which is associated with nausea and vomiting. Hypothyroidism is associated with decreased gastrointestinal transit time and classically the clinical presentation is constipation. In very advanced cases of hypothyroidism, nausea may be a prominent symptom associated with delayed gastric emptying [3–5]. Diagnostic tests for thyroid function are relatively simple. We recommend ordering levels of TSH and free thyroxine if there is suspicion for hyper- or hypothyroidism in patients with chronic nausea and vomiting. Furthermore, gastric emptying tests should not be ordered until thyroid function has been proven normal or normal thyroid levels have been achieved with treatment in patients with known hypo- or hyperthyroidism.

Gastroparesis [6] has received much attention recently due to the severity of nausea and vomiting, effects on glucose control, and scarcity of effective treatments [7, 8]. When gastroparesis (GP) afflicts patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM), the consequences are particularly severe and usually poorly responsive to treatments [9]. Symptoms associated with GP such as early satiety, prolonged fullness, nausea, and vomiting of undigested food do not only reduce the quality of life but also impede good control of blood glucose levels which may lead to frequent visits to the emergency room and multiple hospitalizations [10–12]. In patients with diabetes complicated by GP, ingested food is not emptied in a predictable time period; thus, the anticipated nutrient absorption is unpredictable. Consequently, in those patients treated with insulin, the selected dose and timing of insulin therapy to control postprandial glucose may be inappropriate. In many patients with GP and diabetes, the erratic postprandial glucose levels result in swings from hypoglycemia to severe hyperglycemia. A vicious cycle exists in diabetes complicated with GP since hyperglycemia itself elicits gastric dysrhythmias and slows gastric emptying in normal and diabetic individuals [13–16].

The estimates of prevalence of GP in DM vary widely. Although in tertiary centers, up to 40 % of patients with T1DM are reported to have GP [17], surveys in Olmsted County, Minnesota indicated a prevalence of 5 % in T1DM and 1 % in T2DM [18]. Our own data from an analysis of more than 40 million medical records is much closer to the Olmsted County estimate supporting a prevalence of GP in diabetes of less than 5 % [19]. Thus, GP in diabetes is not so common but it has a large negative impact on the lifestyle of patients and intensively increases the use of hospital resources by these patients. Although good control of glycemia prevents or delays many of the chronic complications of T1DM [20–22], the effect of good glucose control on the onset or progression of GP in DM is unknown. Compared with T2DM, T1DM patients with GP are younger, thinner, and tend to have more severe delays in gastric emptying [9]. Mortality is increased in patients with diabetes when they develop GP and is usually related to cardiovascular events.

The normal stomach performs a series of complex neuromuscular activities in response to the ingestion of solid foods [23]. First, the fundus relaxes to accommodate the volume of ingested food (Fig. 6.1). Normal fundic relaxation requires an intact vagus nerve and is mediated by enteric neurons containing nitric oxide. The relaxation of the fundus allows food to be accommodated without excess stretch on the fundic walls. Secondly, the corpus and antrum produce recurrent peristaltic waves that mix or triturate the ingested solids into fine particles termed chyme.

Thirdly, emptying of chyme into the duodenum begins when the ingested solid foods are sufficiently triturated. The peristaltic waves empty aliquots of chyme through the pylorus into the duodenum (Fig. 6.1). The emptying of food from the stomach is altered by the nature of the constituents (carbohydrate, protein, and fat) and the fiber and indigestible components. Finally, normal postprandial neuromuscular activity is associated with a sense of comfortable fullness. In contrast, patients with diabetes and GP have the ingestion of food elicits early, satiety, nausea, and epigastric discomfort or pain [24].

Full-thickness biopsies of the gastric corpus from patients with T1DM, T2DM, and GP indicate the disease is primarily a disease of gastric enteric neurons and interstitial cells of Cajal (ICC). Interestingly, these neurons are surrounded by an immune infiltrate composed primarily of type 2 macrophages, suggesting a role for the immune system [25–29]. The pathophysiological alterations in stomach function in GP include abnormal fundic relaxation results from loss of nitric oxide release from the vagus nerve. Dysfunction of the ICCs which are also stretch receptors may also have a role in poor fundic relaxation (Fig. 6.2). The depletion of ICCs and presence of abnormal enteric neurons are the mechanisms of gastric neuromuscular dysfunction associated with the presence of gastric dysrhythmias and loss of the normal 3 cpm myoelectrical rhythm. The pyloric sphincter also regulates gastric emptying. Relaxation of the pyloric sphincter to allow antroduodenal flow is mediated by nitric oxide released from enteric neurons. In a subset of patients with diabetic GP and normal 3 cpm gastric myoelectrical activity, pylorospasm (failure of pyloric relaxation in coordination with antral peristaltic waves) results in GP.

Symptoms associated with diabetic GP are early satiety, prolonged fullness, bloating, nausea, vomiting, abdominal discomfort, and pain. These are nonspecific symptoms. Approximately 20 % of patients develop these symptoms acutely. Nausea is the most bothersome and predominant symptom in patients with diabetes with GP. Vomitus frequently contains previously ingested chewed food. Prolonged stomach fullness and vague epigastric discomfort are common. Symptoms are similar in patients with T1DM and T2DM, although T2DM patients tend to have more fullness and bloating. In a minority of patients (20 %) with GP, abdominal pain is the predominant symptom [20]. The symptoms of GP range from periods of quiescence to periods of severe nausea and vomiting; the intensity of the latter frequently results in emergency room visits and hospitalization. Patients with uncontrolled nausea and vomiting may develop dehydration, hypovolemia, acidosis, and full-blown diabetic ketoacidosis (DKA).

GP is confirmed by nuclear medicine gastric scintigraphy. A standardized solid meal (Egg Beaters®) is ingested and then followed by 1-min duration scintigrams at each hour for a total of 4 h [30]. An upper endoscopy should be completed to rule out esophagitis, peptic ulcer disease, or mechanical obstruction. The gastric emptying test meal is usually not tolerated while the patient is ill and in hospital. This test is more reliably and consistently completed when the patient is a stable outpatient. An emerging technology is the Wireless Capsule Motility Test which measures intraluminal pH, pressure, and temperature. The capsule is swallowed during ingestion of a nutrient bar; no further food intake is allowed for 5 h. A sudden change from a low pH (acid) to a neutral or alkaline pH indicates exit of the capsule from stomach into duodenum. If the capsule does not empty from the stomach into the duodenum in 5 h, then delayed gastric emptying is confirmed.

Patients with DM and GP may develop these following medical emergencies:

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