Diabetic Gastroparesis

Etiology

Hyperglycemia (blood glucose greater than 200 mg/dL), commonly seen in poorly controlled diabetes, has been associated with diabetic gastroparesis resulting from neuropathy in the setting of chronic hyperglycemia and does not resolve with improved glycemic control. Acute hyperglycemia, on the other hand, though it can also result in delayed gastric emptying, is often reversible with improved glycemic control.[5][6][7]

Gastric emptying requires coordination of fundal tone and antral phasic contraction with simultaneous inhibition of pyloric and duodenal contractions. This coordination also requires interactions between the enteric and autonomic nervous systems, smooth muscle cells, and the stomach's specialized pacemaker cells (myenteric interstitial cells of Cajal; ICCs). The gastric motor dysfunction that is encountered in the setting of diabetes may occur as a result of autonomic neuropathy (both sympathetic and parasympathetic), enteric neuropathy (both excitatory and inhibitory neurons), ICC abnormalities (intrinsic neuropathy), acute blood glucose fluctuations, use of incretin-based medications, or psychosomatic factors. As a result, most patients with diabetes tend to have dysfunction at multiple points in the process of gastric emptying. This includes abnormal postprandial proximal gastric accommodation and contraction, as well as abnormalities in antral motor function.

Epidemiology

Although idiopathic gastroparesis is the most common form of gastroparesis, diabetes is the most common disease associated with the condition. Upper gastrointestinal symptoms are reported in 11% to 18% of patients with diabetes, most of which are associated with delayed gastric emptying. Gastroparesis is seen in approximately 4.8% of individuals with type 1 diabetes, 1% of those with type 2 diabetes, and 0.1% of those without diabetes. Although there is a stronger association between type 1 diabetes and gastroparesis, the incidence of type 2 diabetes is much greater, and therefore, gastroparesis associated with type 2 diabetes is seen more frequently. Additionally, incretin mimetics are used to treat patients with type 2 diabetes, and these medications pose an additional risk factor for developing gastroparesis.[8]

Signs and symptoms of delayed gastric emptying are seen more frequently in individuals with type 1 versus type 2 diabetes and typically in those who have had the disorder for at least five years. It has been observed that gastroparesis typically occurs in patients with a diagnosis of diabetes of at least ten years and is therefore seen more commonly in older individuals with type 2 diabetes.

Pathophysiology

Diabetic gastroparesis occurs as a result of dysfunction in the autonomic and enteric nervous systems. Chronically high levels of blood glucose (or inefficient glucose uptake) lead to neuronal damage resulting in abnormal myenteric neurotransmission (e.g., vagus nerve), impaired inhibitory (nitric oxide) neuronal function, and dysfunctional smooth muscle and pacemaker (interstitial cells of Cajal) cells. Altogether, this dysfunction results in a combination of fewer contractions of the antrum, uncoordinated antro-duodenal contractions, and pyloric spasms, ultimately resulting in delayed gastric emptying (gastroparesis).

Delayed gastric emptying in patients with diabetes, particularly of solids, may also occur in the setting of abnormal small bowel motility, which is thought to occur by a similar mechanism as that which is described in the stomach. Some patients with diabetes may additionally experience changes in gastric compliance, both increased or decreased, which may also contribute to delayed gastric emptying.[9]

In addition to this, serum (postprandial) glucose levels have a direct relationship with gastric emptying. In the setting of diabetic autonomic neuropathy, acute hyperglycemia stimulates gastric electrical activity.  In patients with diabetes (without neuropathy) and healthy controls, acute hyperglycemia will instead relax the proximal stomach and suppress gastric electrical activity (e.g., reduced the frequency, propagation, and contraction of the antrum) in both fasting and post-prandial conditions, thereby slowing gastric emptying.

Acute hyperglycemia has also been associated with increased sensitivity in the gastrointestinal tract. This may be responsible for the postprandial dyspepsia (e.g., early satiety, nausea, vomiting, heartburn, bloating, and pain) frequently experienced by patients with diabetic gastroparesis.

Carbohydrate absorption is highly dependent on the speed of gastric emptying through the release of peptides such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, in which slower gastric emptying results in a higher level of carbohydrate absorption. Therefore, a higher serum glucose level due to delayed gastric emptying can itself lead to the worsening of gastroparesis.

Histopathology

Histopathology does not routinely help in diagnosing a patient with diabetic gastroparesis. However, the findings seen on animal models and studies involving human pathology specimens have helped us understand the disease process better. Full-thickness biopsies, which are needed to diagnose changes in the deeper layers of the stomach wall, are not practical to be used as a diagnostic tool. In special studies done using full-thickness gastric biopsies, the findings included an inflammatory infiltrate, a reduction in the number of nerve cell bodies and ICCs in the myenteric plexus, and fibrosis.[10][11][12] Recent studies have pointed at the role of macrophages in the pathogenesis of diabetic gastroparesis.[13]

History and Physical

Nausea is the most common symptom in gastroparesis. Other common symptoms include vomiting, early satiety, postprandial fullness, and bloating. Vomitus often contains undigested chewed food. Both weight loss and weight gain can occur. Wide glycemic fluctuations can also happen in gastroparesis.[14][15] The timing of the symptoms relative to meals is important. Physical examination is usually nonspecific. However, neuropathy, abdominal distension, and halitosis can present in patients with diabetic gastroparesis.

Factors that may trigger an exacerbation of diabetic gastroparesis include uncontrolled blood glucose levels, medication noncompliance or intolerance, adrenal insufficiency, and infection.

Evaluation

The first step in evaluating patients who present with the symptoms above would be to exclude mechanical obstruction and peptic ulcer disease. All patients should undergo an upper gastrointestinal endoscopy. This should be followed by either a CT scan with oral and intravenous contrast or other imaging such as a small bowel follow-through to exclude obstruction beyond the duodenum. Retained food is seen on endoscopy without mechanical obstruction, and in rare cases, bezoars suggest gastroparesis.

The conventional test that is cost-effective and widely used for gastroparesis diagnosis is measuring gastric emptying by scintigraphy, which is considered the gold standard by many.[16] Solid-phase emptying is usually used to evaluate for gastroparesis. Liquid-phase emptying is not well demonstrated for diagnosing gastroparesis and is more widely used to assess dumping syndrome after gastric surgery. Most centers use a 99 mTc sulfur colloid labeled egg white sandwich as the test meal.[17] Standard imaging is performed at 0,1,2,4 hours postprandially. A four-hour study is more sensitive and accurate in diagnosing gastroparesis, and clinicians should avoid shortened 2- and 3-hour studies.[18][19][16] Medications such as opiates and anticholinergics can slow gastric motility, whereas prokinetics and other medications can hasten gastric emptying. Hyperglycemia is known to slow gastric motility, and it is worthwhile to try and achieve euglycemia before performing the test if that is an option.[16] 

Breath testing is another validated study for gastroparesis. Most commonly, 13C-labelled octanoate, a medium-chain triglyceride, is bound to a solid meal and ingested. After emptying from the stomach, it is absorbed by the small intestine and metabolized to 13CO2, which is expelled from the lungs during respiration. Currently, it has limited penetrance into the clinical practice and is performed for clinical research and pharmaceutical studies.[16]

Electrogastrography and gastroduodenal manometry are other tests based on myoelectrical activity that are potentially helpful but are not yet available for widespread clinical use.

Treatment / Management

The first step in the treatment of symptomatic gastroparesis is often lifestyle modifications. Optimal glycemic control in patients with diabetes will minimize the effects of hyperglycemia, causing delayed gastric emptying. Smaller, more frequent meals with minimizing carbonated beverages, increasing the liquid content, reducing fats and fiber content are common recommendations.[20] Alcohol and smoking should be discouraged, as they can worsen the symptoms.[21][22]

Antiemetics are often the first step in gastroparesis patients as they help with the common symptoms of nausea and vomiting. Serotonin (5-HT3) receptor antagonists like ondansetron, phenothiazines (dopamine receptor antagonists) like prochlorperazine and promethazine are commonly used. Side effects include sedation and extrapyramidal effects, and therefore, these are usually used on an as-needed basis.[16]

The cornerstone of pharmacologic therapy in diabetic gastroparesis consists of prokinetic agents.

Metoclopramide, a 5-HT4 receptor activator and dopamine receptor antagonist in the stomach with weak 5-HT3 receptor antagonism in the nervous system, is a commonly used medication that increases the contraction amplitude of esophageal fundic and antral musculature. It is effective for treating gastroparesis for several weeks, but long-term dosing has shown inconsistent results.[23]

Erythromycin binds to the motilin receptors responsible for the initiation of the MMC in the upper gut.[24][25] Like metoclopramide, erythromycin works well in the short term, but the long-term loss of response is common.(B3)

Domperidone is a dopamine (D2) agonist with effects similar to metoclopramide but is much less likely to cause extrapyramidal side effects as it does not cause the blood-brain barrier. Symptomatic patients with diabetes have reported improved domperidone therapy, but again, the effect could be lost in about six weeks.[26][27][28] Domperidone was associated with cardiac arrhythmias in the past and is not FDA approved in the United States. Cisapride is a 5-HT4 agonist that might have effects that last up to 1 year, but unfortunately, it was also associated with ventricular arrhythmias, including torsades de pointes, and has been withdrawn from the US market. Both these drugs are available through select investigators as part of clinical trials with strict patient monitoring. In patients who do not respond well to the above therapies alone, combination prokinetic therapies can be tried. Symptomatic control of nausea using antiemetics is another option. Several studies have evaluated pyloric botulinum toxin injection, but these studies were often unblinded and had small numbers of patients.[16] (A1)

Gastric electrical stimulation has been studied, but so far, there has not been a significant reduction in symptoms noted consistently across various small studies. It was granted humanitarian approval from the FDA to treat chronic refractory nausea, but it is not available widely and is not routinely reimbursed.[16][29] (A1)

In refractory patients with severe symptoms, a gastrostomy tube for intermittent decompression by venting or suctioning may provide relief.[29] For patients who cannot maintain nutrition with oral intake, placement of a feeding jejunostomy can be effective in providing nutrition, fluids, electrolytes and reduce hospitalizations.[30][31] A trial of nasojejunal feeding can predict the response to a jejunostomy.[29](A1)

The last resort in refractory gastroparesis is surgery, including a partial gastrectomy with Roux-en-Y gastrojejunostomy and gastric resection. There is not enough data on surgical treatment at this time, and the decision to subject a patient to this should ideally be made by a motility expert.[16]

Differential Diagnosis

• Gastric outlet obstruction
• Rumination syndrome
• Functional dyspepsia
• Chronic pancreatitis
• Biliary colic

Prognosis

The outcomes of diabetic gastroparesis are not well defined. Prognosis depends on the adequate control of hyperglycemia and compliance with medications. It affects the quality of life and can have significant morbidity if left uncontrolled. Education regarding the need for lifelong management of this condition is essential to improve clinical outcomes. 

Complications

Malnutrition is an important complication of diabetic gastroparesis that often needs management with jejunostomy, parenteral nutrition, or surgery. Wide glycemic fluctuations can occur in diabetic gastroparesis, and this can lead to complications such as hypoglycemia and diabetic ketoacidosis or hyperosmolar hyperglycemic state. Nausea and vomiting can lead to aspiration pneumonia.