Gastroparesis is a syndrome marked by slow gastric emptying and symptoms such as nausea, vomiting, bloating, early fullness and abdominal pain. Although long associated with type 1 diabetes and now, increasingly, with type 2, the cause in many cases remains unknown.
But gastroenterologist Gianrico Farrugia, M.D., stresses that in the last few years, scientists at Mayo Clinic and elsewhere have made marked progress in understanding the pathological mechanisms underlying the disorder. Much of the current research focuses on the interstitial cells of Cajal (ICC), which are needed for normal stomach emptying.
"The ICC act as intestinal pacemakers for smooth muscle function," he says. ''They also amplify neuronal signals, act as mechanosensors and set the smooth muscle membrane potential gradient. Both human and animal models demonstrate loss of these cells in diabetic and idiopathic gastroparesis."
Normal gut function requires a balance between processes that injure ICC and processes that generate and maintain them. In people with diabetic gastroparesis, the balance shifts toward factors that damage ICC, including relative insulinopenia and deficiency of insulin-like growth factor-1 (IGF-1), both of which can cause smooth muscle atrophy.
Dr. Farrugia says a critical factor is oxidative stress resulting from low levels of heme oxygenase-1 (HO-1), an important protector against oxidative injury.
"When the mechanisms that normally counteract oxidative stress are impaired, especially upregulation of heme oxygenase-1, ICC are lost and gastric emptying is delayed. In mouse models, restoring HO-1 prevents and even reverses these cellular changes and restores normal gastric function."
In the stomach wall, HO-1 expression occurs in a particular subset of macrophages — CD206-positive M2 macrophages — whose cytoprotective effect on ICC appears related to the production of small amounts of carbon monoxide.
Dr. Farrugia says, "When the upregulation of HO-1 is lost, M2 macrophages are replaced by proinflammatory M1 macrophages. These cells, which do not produce carbon monoxide, are associated with ICC damage and the development of delayed stomach emptying. Thus, the upregulation of HO-1 in M2 macrophages seems critical to the prevention of diabetes-related gastroparesis."
In mouse studies, hemin, a biological product of red blood cells, has been shown to boost the production of HO-1, thereby reducing oxidative stress, allowing repair of the ICC network and normalizing gastric function. Now, Dr. Farrugia and colleague Adil E. Bharucha, MBBS, M.D., are recruiting patients for the first randomized controlled clinical trial to determine whether intravenous hemin therapy is equally beneficial for people with gastroparesis.
"The hope is that this clinical trial may lead to an effective medication for gastroparesis — one that doesn't just manage symptoms as prokinetics do, but that actually targets the cause of the disease."
The need for better treatments is especially critical now, Dr. Farrugia says, because the incidence of gastroparesis is increasing. The number of hospitalizations for the disorder grew by nearly 158 percent from 1995 to 2004. "The vast majority of patients are young women of childbearing age. This disease causes tremendous disruption in patients' lives and in the lives of their families, and none of the treatments we have are ideal."