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Lisa Klimas

I'm a 35 year old microbiologist and molecular biologist with systemic mastocytosis, Ehlers Danlos Syndrome, Postural Orthostatic Tachycardia Syndrome, Adrenal Insufficiency, and an assortment of other chronic health issues. My life is pretty much a blast.

Naturally occurring mast cell stabilizers: Part 2

As discussed in the previous post, many flavonoids can modulate mast cell responses.  Luteolin, a flavone, has been studied for its powerful effects on inflammatory cells.  With prophylactic administration of this molecule, activation of mast cells and T cells can be prevented in a disease model for multiple sclerosis. Luteolin can also inhibit IgE-triggered degranulation as well as production of various mediators.  It is found in many foods, including celery, carrots, and chamomile tea.

Genistein, an isoflavone, prevents IgE-induced degranulation and histamine release.  It is a natural tyrosine kinase inhibitor, mostly activate against EGFR. It can be extracted from Genista tinctoria, also called dyer’s broom.  Several structurally related molecules also have mast cell modulating effects. Amentoflavone, from Ginkgo biloba and St. John’s Wort, decreases histamine release by mast cells. Ginkgetin, derived from Ginkgo biloba leaves, inhibits phospholipase A2, a mast cell mediator, and inhibits production of PGD2 by interfering with the COX-2 enzyme and of LTC4 by interfering with 5-lipoxygenase.

Emodin is an anthraquinone with a long history of use in herbal medicine traditions.  It boasts an array of anti-allergic activity and can inhibit the following IgE induced effects: mast cell degranulation; production of TNF, PGD2 and LTC4; and secretion of TNF and IL-6. It is under investigation for use in type II diabetes, where it can decrease the activity of glucocorticoids in obese animals and may treat insulin resistance.  Emodin can be found in rhubarb, frangula bark and other plants.

A number of other natural molecules also have mast cell stabilizing effects. Epigallocatechin gallate, found in higher quantities in white and green teas, as well as apples, onions and hazelnuts, can inhibit mast cell degranulation and LTC4 secretion.  Xanthones found in the juice and fruit of the purple mangosteen, Garcinia mangostana, decreased histamine release as well as PGD2, LTC4 and IL-6 from mast cells.

 

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct; 31(10): 1303-11.

Kritas SK, et al. Luteolin inhibits mast cell-mediated allergic inflammation. J Biol Regul Homeost Agents 2013 Oct-Dec; 27(4): 955-959.

Theoharides TC, Kempuraj D, Iliopoulou BP. Mast cells, T cells, and inhibition by luteolin: implications for the pathogenesis and treatment of multiple sclerosis. Adv Exp Med Biol 2007; 601: 423-30.

Son JK, et al. Ginkgetin, a biflavone from Ginkgo biloba leaves, inhibits cyclooxygenases-2 and 5-lipoxygenase in mouse bone marrow-derived mast cells. Biol Pharm Bull 2005 Dec; 28(12): 2181-4.

Lu Y, et al. Emodin, a naturally occurring anthraquinone derivative, suppresses IgE-mediated anaphylactic reaction and mast cell activation. Biochem Pharmacol 2011 Dec 1; 82(11): 1700-1708.

Kim DY, et al. Emodin attenuates A23187-induced mast cell degranulation and tumor necrosis factor-a secretion through protein kinase C and IkB kinase 2 signaling. Eur J Pharmacol 2014 Jan 15; 723: 501-506.

Naturally occurring mast cell stabilizers: Part 1

Warning: Naturally occurring molecules can interfere with medications or adversely affect disease state.  Please consult with your managing provider before adding supplements or drastically changing diet.

Flavonoid is a broad term used to describe certain plant derived metabolites. It can be used to refer to a variety of molecules, including isoflavonoids, neoflavonoids and anthoxanthins, which are categorized based on structure.  A number of flavonoids have been shown experimentally to modulate mast cell behavior and function as mast cell stabilizers.

Homoisoflavonone decreases production of PGD2 and leukotrienes B4 and C4 by downregulating COX-2 and 5-LO, the enzymes that make these molecules from arachidonic acid. It also interferes directly with the manufacture of IL-6 and TNF in mast cells stimulated by IgE (the traditional allergy pathway).  Homoisoflavonone can be isolated from bulbs of Cremastra appendiculata, which is commonly called Chinese tulip despite being an orchid.  Chinese tulip is commonly used in Chinese medicine.  Related homoisoflavonoids, extracted from the tuber of Ophiopogon japonicas, mondograss, are anti-inflammatories, possibly by interfering with COX-2 and 5-LO.

Flavonols have been noted for their anti-allergic activity for a number of years.  Morin is a flavonol found in natural sources like Maclura pomifera (Osage orange) and Psidium guajava (guava).  Morin prevents mast cell degranulation and manufacture of cytokines like TNF and IL-4, as well as suppressing IgE activation almost completely at higher doses (please note the study on this used mice so it’s not clear what those dose would be in humans).  Other mast cell active flavonols include quercetin, myricetin, rutin, fisein and kaempferol.

Quercetin downregulates the expression of histidine decarboxylase, the enzyme that modifies histidine, an amino acid, to histamine.  Quercetin also inhibits release of histamine, prostaglandins and leukotrienes.  Additionally, it decreases production and release of IL-1b, IL-6, IL-8 and TNF.  Quercetin was reported to be stronger and more effective at inhibiting mediator release than cromolyn when taken prophylactically, although this has not yet been judged as true by any regulatory body.  Quercetin is found naturally in a number of foods, such as red onion, sweet potato, kale, and many others.  It is also found in small quantities in teas made with Camellia sinensis.  Rutin is a derivative of quercetin, found in citrus fruits, apples, cranberries and others.

Fisetin, kaempferol, myricetin, quercetin and rutin inhibited IgE mediated histamine release and prevented increased concentration of calcium inside mast cells, which is necessary for degranulation.  Fisetin, quercetin and rutin all decreased production of IL-1b, IL-6, IL-8 and TNF. Fisetin, myricetin and rutin all decreased action of NF-kB, which controls the pathway regulating production of cytokines. Myricetin is a particularly effective mast cell stabilizer.  It decreased degranulation and release of TNF and IL-6, but not IL-1b or IL-8.

Flavonols have been evaluated for other medicinal properties aside from mast cell modulation.  Myricetin has been suggested as a treatment for many diseases, including diabetes, while kaempferol affects many molecular pathways, including estrogen signaling.  These molecules occur naturally in a number of plants, including walnuts, onions and red grapes for myricetin; apples, onions, persimmons, strawberries and cucumbers for fisetin; and potatoes, squash, cucumbers, peaches and Aloe vera for kaempferol.

 

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Weng Z., et al. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity inhumans. PLoS One. 2012; 7(3): e33805.

Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct; 31(10): 1303-11.

Lee, YS, et al. Homoisoflavonone prevents mast cell activation and allergic responses by inhibition of Syk signaling pathway. Allergy 2014; 69: 453-462.

 

 

 

 

Role of sex hormones in hereditary angioedema

Sex hormones are well known for influencing symptoms of immune mediated conditions. Estrogen can affect cell proliferation and activation. Menses, pregnancy, menopause, and use of oral contraception are known to affect hereditary angioedema (HAE) but it is not yet clear how.

One hypothesis is that estrogen may activate the kallikrein-kinin system, thereby increasing production of bradykinin. Another hypothesis is that estrogen can affect the expression of the FXII gene, which produces the initiating molecule in the bradykinin pathway. Estrogen may also regulate the B2 receptors that bradykinin binds to. While all of these ideas are possible, there have not yet been any definitive findings.

In female patients, onset of HAE often correlates with the start of puberty. Menses, pregnancy and delivery also correlate with flare ups of HAE. Puberty makes HAE attacks more frequent and severe in 56.7% of cases; menses does the same in 35.3%; ovulation, 14%. Use of estroprogestin contraceptives irritate and worsen HAR in 63-80% of HAE women. The first trimester of pregnancy is known to be a difficult time for HAE women, as circulating estrogen is particularly high and many women discontinue maintenance therapy out of safety concerns for the fetus.

In patients with type III HAE in whom a Factor XII mutation has been identified, episodes occur almost exclusively during periods of high estrogen. This initial observation led to type III to be called “estrogen dependent HAE”, but this only refers to a subset of patients and has fallen out of use. Estrogen levels do not affect symptoms in other type III HAE patients (without the Factor XII mutation) and in many acquired angioedema patients.

Female HAE patients of reproductive age, who are not using oral contraceptives, often have polycystic or multifollicular ovaries. Ovulation is a complex multistep process in which two steps are controlled by C1INH.

 

 

References:

Zuraw, B. L., et al. A focused parameter update : Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol 2013; 131(6); 1491-1493e25.

Kaplan AP, et al. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammation pathway. Adv Immunol 2014; 121:41-89.

Kaplan AP, et al. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol 2010 Aug; 47(13):2161-9.

Firinu, Davide, et al. Characterization of patients with angioedema without wheals: the importance of F12 gene screening. Clinical Immunology (2015) 157, 239-248.

Ohsawa, Isao, et al. Clinical manifestations, diagnosis, and treatment of hereditary angioedema: survey data from 94 physicians in Japan. Ann Allergy Asthma Immunol 114 (2015) 492-498.

 

 

 

 

Gastroparesis: Idiopathic gastroparesis (Part Seven)

Gastroparesis occurring in the absence of any known trigger, such as diabetes, surgery, medication or disease related onset, is classified as idiopathic gastroparesis.  In most series that include patients with multiple forms of gastroparesis, idiopathic gastroparesis (IGP) is the most common, affecting 35-67% of GP cases.  As with most forms of GP, IGP affects about three times more women than men, particularly young and middle-aged women.  IGP in particular affects young women who are overweight or obese.

In a study including 243 patients with IGP, 88% were female.  34% reported frequent nausea, 23% abdominal pain and 19% vomiting.  28% had severely delayed gastric emptying, here defined as more than 35% retention of contents four hours after consumption.  46% were overweight.  When compared to patients with diabetic GP, IGP patients more often reported feeling too full after eating and that their hunger was sated by smaller meals.  IGP patients demonstrated more severe gastric retention than type I diabetic GP patients.

Moderate/severe upper abdominal pain was found to be more frequent in IGP, and correlated with GP severity, decrease in quality of life, depression and anxiety.  Having pain as the predominant symptom causes quality of life impairment equivalent with nausea and vomiting.

Bloating is a common GP symptom.  Severe bloating was present in 41% of patients, and was more common in overweight female patients.  It also corresponded with severe nausea, fullness, distention, abdominal pain and notable bowel dysfunction.  Quality of life and other measures of wellbeing decrease as bloating becomes more severe.

Idiopathic GP is treated similarly to other types, but diagnosis may be delayed due to the lack of a known trigger.  Medications that have been reported as helpful but have not been studied in larger populations include sildenafil, paroxetine, cisapride, tegaserod, clonidine and buspirone.

References:

Sarosiek, Irene, et al. Surgical approaches to treatment of gastroparesis: Gastric electrical stimulation, pyloroplasty, total gastrectomy and enteral feeding tubes.  Gastroenterol Clin N Am 44 (2015) 151-167.

Pasricha, Pankaj Jay, Parkman, Henry P. Gastroparesis: Definitions and Diagnosis. Gastroenterol Clin N Am 44 (2015) 1-7.

Parkman, H. P. Idiopathic Gastroparesis. Gastroenterol Clin N Am 44 (2015) 59-68.

Nguyen, Linda Anh, Snape Jr., William J. Clinical presentation and pathophysiology of gastroparesis.  Gastroenterol Clin N Am 44 (2015) 21-30.

Bharucha, Adil E. Epidemiology and natural history of gastroparesis. Gastroenterol Clin N Am 44 (2015) 9-19.

Camilleri, Michael, et al. Clinical guideline: Management of gastroparesis. Am J Gastroenterol 2013; 108: 18-37.

 

The only constant

Summer is over.  Maybe astronomically speaking it’s not, but it is.  When you close your eyes on August 31, warm windy days and bathing suits and beach towels and eating outside are all packed away by summer faeries and pushed to the back of the closet.  When you open your eyes on September 1, it is fall.

I had an amazing summer.  I could never have imagined that I would have a summer like this again.  I went swimming in the ocean and went to a water park and got sunburnt and walked around in the sunshine. I worked a lot and took the train and ate solid food and exercised.  I still have mast cell disease and it will never go away and no, my GI tract does not work well.  But I feel better in a lot of ways.  I feel better than I thought I would ever feel again.

Last week was a difficult week for me.  I have been pushing it the last few weeks, trying to do more than I probably should.  I started feeling gross again, burny hot skin, really bad nausea, more GI trouble than usual.  I started needing to sleep a lot longer.  It was so defeating.

I crawled into bed one day and lay awake, too tired to sleep, reliving the last several months.  I was scared.  I was scared that this was over.  I was scared that these three months were all I was going to get.  I was scared because it felt like I was finally living again and losing that would be too painful.  Because I was finally entertaining the thought that I could go back to school and travel and have fun without risking ending up in the hospital.

Last Friday, I realized I had a fever.  I was sick because I had a cold or something.  It hadn’t even crossed my mind that it was anything other than mast cell disease.  I slept most of this weekend and am getting better.

It only took a few days for my dreams to turn from school and travelling back to a stable accommodating job with good insurance.  You know.  My fall back dream.  The dream that I will retain the means to treat my myriad health issues and live independently in a clean, safe place.  That dream.  It sounds silly and narrow to people who have never been sick but let me tell you, it’s not silly to me.  Even when I am feeling better, even when I think I could do things I put aside long ago, even when I am embarrassed to admit it, this is my dream.  This is the dream that needs to come true for any other dream to be realized.

I like my life.  I have a great job.  I have an apartment I can afford in a convenient location.  I have a great support system.  I receive excellent health care.  I can walk my dogs at night.  I can pay my bills.  I am lucky.  I am so lucky.  And it feels wrong to risk losing all of these things to pursue another dream that could prevent me from getting the care I need.

So I push these thoughts aside and feel grateful for all that I have.  I focus on living the life I have now and try not to rock the boat.  I don’t make any changes.

There is this idea that by doing nothing, we can preserve our lives just the way they are.  That if we don’t change, we are guaranteeing the future provided by steadily travelling this same road.

It doesn’t work that way.  It never did.  Everything changes.  The only constant is you.

Yesterday I found out about some changes at work that will directly affect me and how I continue to do my job.  Maybe not in a bad way.  I went back to my desk and cried for a few minutes because I’m a crier and I get very attached to people.  Then I got up and got lunch and went back to work.  I was sad and anxious but also a little relieved and excited.

I don’t know the name of this feeling.  But I do know that I could choose to stay here in my little apartment with my job that I love close to my family and friends and doctors.  I could make that choice and it could all change anyway.

And I could make the choice to give all of this up and I could find myself without healthcare or money or a home.  Or I could find that I give it all up and succeed.

It feels like the stakes keep getting higher and higher.   But that doesn’t mean I shouldn’t try.

Gastroparesis: Autonomic nervous system and vagus nerve (Part Six)

Gastric emptying is facilitated by neurologic signals through the autonomic nervous system.  The autonomic nervous system controls many of the involuntary functions of the body, such as digestion.  The autonomic nervous system has two components: the parasympathetic nervous system, which manages activities pertaining to digestion, among other things; and the sympathetic nervous system, which mediates the fight-or-flight response.  Normally, upper GI function receives parasympathetic neurologic signals from the vagus nerve.  Sympathetic control is maintained by nerves originating at spinal T5-T10.

The vagus nerve sends signals the enteric neurons, nerve cells in the GI tract, to increase gastric motility.  The vagus nerve does not directly stimulate smooth muscle in the GI tract.  Signals from the vagus nerve help to relax the stomach to allow room for food, contract to move the food to the pyloric sphincter, and relax the pyloric sphincter to pass stomach contents to the small intestine.  These actions occur by coordinating the signals among the enteric neurons (GI nerve cells), interstitial cells of Cajal (which control smooth muscle contraction) and smooth muscle cells.

Normally, food passes through the esophagus and into the portion of the stomach closest to the esophagus.  The pressure of the food in this area causes other parts of the stomach to relax and allow food.  The stomach then contracts to break up food and push it towards the small intestine.

At any part of this process, dysfunction of the autonomic nervous system can inhibit proper digestion and gastric emptying.  Gastroparesis is a frequent complication of conditions affecting autonomic function, like orthostatic intolerance.  In some cases, treatment of the orthostatic intolerance can improve gastroparesis symptoms.

Vagotomy, an outmoded surgical treatment for ulcers that severs the vagus nerve, prevents the stomach from being able to relax to accept food.  It can trigger rapid movement of liquids through the stomach, while not allowing solids to be emptied.   Unintentional damage to the vagus nerve can be occur for a number of other reasons, including surgery or persistent high blood sugar, as in some diabetics.

The tone of the stomach and how much food can fit is controlled by enteric nerve cells that release nitric oxide (NO.)  NO keeps the stomach relaxed.  Interfering with cholinergic signaling can also keep the stomach relaxed, to fit more food.  Medications like opiates and anticholinergics have this effect.

In GP patients, stomach biopsies show that the enteric neurons are not shaped correctly. There are far fewer interstitial cells of Cajal than normal, and those that remain look damaged.  There are less nerve fibers than normal.  83% of GP patients have abnormalities in their stomach biopsies.

References:

Sarosiek, Irene, et al. Surgical approaches to treatment of gastroparesis: Gastric electrical stimulation, pyloroplasty, total gastrectomy and enteral feeding tubes.  Gastroenterol Clin N Am 44 (2015) 151-167.

Pasricha, Pankaj Jay, Parkman, Henry P. Gastroparesis: Definitions and Diagnosis. Gastroenterol Clin N Am 44 (2015) 1-7.

Parkman, H. P. Idiopathic Gastroparesis. Gastroenterol Clin N Am 44 (2015) 59-68.

Nguyen, Linda Anh, Snape Jr., William J. Clinical presentation and pathophysiology of gastroparesis.  Gastroenterol Clin N Am 44 (2015) 21-30.

Bharucha, Adil E. Epidemiology and natural history of gastroparesis. Gastroenterol Clin N Am 44 (2015) 9-19.

Camilleri, Michael, et al. Clinical guideline: Management of gastroparesis. Am J Gastroenterol 2013; 108: 18-37.

Gastroparesis: Less common causes (Part Five)

A number of other conditions can cause GP less frequently.  Parkinson disease is well known to cause GI motility issues, including GP.  In this group, the GI dysfunction is due to poor control of the smooth muscle in the GI tract.  Multiple sclerosis, muscular dystrophy, myopathy and having a stroke can negative impact gastric emptying.  50-75% of scleroderma patients with GI symptoms have delayed emptying.  29% of Sjogrens patients have GP.  GP is also sometimes present in polymyositis cases.

10.8% of GP cases are associated with some type of connective tissue disorder.  A clear connection to hypermobility type EDS is being elucidated.  Pseudoobstruction syndromes are sometimes comorbid with GP.  A significant number of patients affected by conditions that feature autonomic neuropathy have GP.

Some viral infections can cause acute GP, which generally resolves within a year.  Spinal cord injury, hypothyroidism, hyperparathyroidism, Addison’s disease, and regular use of opiates and/or anticholinergic medications can also contribute.

While the reason for this link is unknown, gastroparesis occurs disproportionately in patients who have had their gallbladders removed.  In many patients, the gastroparesis does not immediately follow gallbladder removal surgery – it can sometimes take years to present.  Prior gallbladder removal can worsen diabetic or idiopathic GP.  Gallbladder removal (cholecystectomy) is associated with several conditions that can be comorbid with gastroparesis, including chronic fatigue syndrome (CFS), fibromyalgia, depression and anxiety.  Severe upper abdominal pain and retching are cardinal GP symptoms in this population, with nausea and constipation less severe.

GP patients who previously had their gallbladders removed are frequently older women who are overweight despite not consuming enough calories.  Overweight people with GP are more likely to have severe bloating.  Significant bloating indicates poor response to management.  Medications that increase reuptake of norepinephrine, such as tricyclic antidepressants, can help manage bloating in some patients.

References:

Sarosiek, Irene, et al. Surgical approaches to treatment of gastroparesis: Gastric electrical stimulation, pyloroplasty, total gastrectomy and enteral feeding tubes.  Gastroenterol Clin N Am 44 (2015) 151-167.

Pasricha, Pankaj Jay, Parkman, Henry P. Gastroparesis: Definitions and Diagnosis. Gastroenterol Clin N Am 44 (2015) 1-7.

Parkman, H. P. Idiopathic Gastroparesis. Gastroenterol Clin N Am 44 (2015) 59-68.

Nguyen, Linda Anh, Snape Jr., William J. Clinical presentation and pathophysiology of gastroparesis.  Gastroenterol Clin N Am 44 (2015) 21-30.

Bharucha, Adil E. Epidemiology and natural history of gastroparesis. Gastroenterol Clin N Am 44 (2015) 9-19.

Camilleri, Michael, et al. Clinical guideline: Management of gastroparesis. Am J Gastroenterol 2013; 108: 18-37.

Gastroparesis: Post-surgical gastroparesis (Part Four)

Surgery is also a common trigger for gastroparesis.  GI surgery is often complicated by post-operative ileus, in which the GI tract is temporarily paralyzed, at least partially due to mast cell degranulation.  Gastroparesis is often viewed as analogous to post-op ileus, localized to the stomach.  In patients with post-op infections or organ failure, GP is also seen sometimes.  The gastric inflammation associated with surgery inhibits motility acutely.

A number of surgeries have been associated with GP, especially those that manipulate the stomach.  Partial or complete removal of the stomach (gastrectomy) can cause GP.  Removal of all or part of the pancreas also induces gastroparesis in about 20% of patients.  It is most often seen alongside other post-op complications.

(Author’s note: the previous paragraph originally had a sentence that said the following: “6.9% of patients who undergo radical gastrectomy develop GP.”  This is not correct and nonsensical, I made a mistake when typing this up.  I deleted the sentence from the above paragraph, and added a new sentence a few paragraphs down that says: “In a study with over 500 patients who underwent radical gastrectomy for gastric cancer, 6.9% of patients had gastroparesis.”  Sorry for any confusion I may have caused with this error.)

7.2% of all reported gastroparesis cases occurred following gastrectomy or fundoplication, operations that manipulate the stomach.  Fundoplication, which “wraps” the stomach around the esophagus to decrease reflux, can damage nerves and interfere with stomach relaxation.  If vagus nerve function is damaged, GP can result, often with a dominant bloating presentation.  Overall, Nissen fundoplication is the most common cause of post-surgical gastroparesis.  A follow up surgery to revert to a partial fundoplication with pyloroplasty (“loosening the wrap”) can sometimes reverse the gastroparesis.

Bariatric (weight loss) surgery carries the risk of upper GI dysfunction.  While this most often affects the esophagus, GP is sometimes seen, and it is usually very severe and persistent.  Botox injections and gastric electrical stimulation are sometimes fruitful in this population.

Gastroparesis can also result from a number of surgeries that do not directly manipulate the stomach.  Most of these surgeries could result in vagus nerve damage and therefore impact upper GI motility.  Removal of part of the esophagus, botox injections for achalasia, lung transplantation and liver surgeries can all cause gastroparesis.  Conditions that require gastric surgery can directly cause gastroparesis prior to surgical intervention.  In a study with over 500 patients who underwent radical gastrectomy for gastric cancer, 6.9% of patients had gastroparesis.

Conversely, stomach surgery can sometimes alleviate gastroparesis symptoms.  Subtotal or complete gastrectomy improves symptom profiles in 67% of patients.  In one small patient cohort, 6/7 patients having subtotal gastrectomy had immediate resolution of vomiting, with significant improvement in quality of life for up to six years.  Patients who have nausea as a cardinal symptom, who have previously needed TPN, or who have had retained food in the stomach during endoscopy, are less likely to have resolution due to these surgeries.  Post-op ileus, wound infection, intestinal obstruction and anastomotic leakage are common complications of these surgeries to mitigate gastroparesis.

References:

Sarosiek, Irene, et al. Surgical approaches to treatment of gastroparesis: Gastric electrical stimulation, pyloroplasty, total gastrectomy and enteral feeding tubes.  Gastroenterol Clin N Am 44 (2015) 151-167.

Pasricha, Pankaj Jay, Parkman, Henry P. Gastroparesis: Definitions and Diagnosis. Gastroenterol Clin N Am 44 (2015) 1-7.

Parkman, H. P. Idiopathic Gastroparesis. Gastroenterol Clin N Am 44 (2015) 59-68.

Nguyen, Linda Anh, Snape Jr., William J. Clinical presentation and pathophysiology of gastroparesis.  Gastroenterol Clin N Am 44 (2015) 21-30.

Bharucha, Adil E. Epidemiology and natural history of gastroparesis. Gastroenterol Clin N Am 44 (2015) 9-19.

Camilleri, Michael, et al. Clinical guideline: Management of gastroparesis. Am J Gastroenterol 2013; 108: 18-37.

Gastroparesis: Diabetes and gastroparesis (Part 3)

Diabetes is one of the most common causes of gastroparesis. 40% of patients with long term diabetes mellitus type I and 20% with diabetes mellitus type II have delayed gastric emptying.   In 1995, 21% patient of gastroparesis patients had DM; in 2004, 26.7%.

Diabetes patients are more likely to have nausea and vomiting as the cardinal GP symptoms, rather than epigastric pain seen more frequently in idiopathic GP.  `Diabetic GP is known to cause more severe gastric retention than idiopathic GP.

Diabetic patients with gastroparesis are at risk for developing difficulty in managing sugar levels.  Poor control of blood sugar can contribute to delayed gastric emptying.  Hyperglycemia is associated with decreased movement of the stomach, an effect more pronounced above 250 mg/dL.  Additionally, some medications used for diabetes, like exenatide for type II diabetes, can delay gastric emptying.  Persistent hyperglycemia is often cited as contributing to vagus nerve damage, which can also result in GP.

In one series, 58% of DM patients had increased tone in the pyloric sphincter, through which food passes from the stomach into the small intestine.  Pyloric tone is often elevated in GP patients.  Botox injections into the pyloric sphincter has been associated with increased gastric emptying and relief of symptoms in diabetic GP patients.

Gastric electric stimulation is more likely to be successful in diabetic patients versus those whose GP is not associated with diabetes, showing 50% reduction in symptoms over those with idiopathic GP.  Patients also experience better glycemic control when GP is more controlled, as reflected by reduction in hemoglobin A1C.

Gastroparesis in diabetes patients is well studied.  Curiously, improving glycemic control is not associated with symptom improvement (or change at all) in patients with type II diabetes.  In type I diabetics, symptom change has only correlated well with depression.

References:

Sarosiek, Irene, et al. Surgical approaches to treatment of gastroparesis: Gastric electrical stimulation, pyloroplasty, total gastrectomy and enteral feeding tubes.  Gastroenterol Clin N Am 44 (2015) 151-167.

Pasricha, Pankaj Jay, Parkman, Henry P. Gastroparesis: Definitions and Diagnosis. Gastroenterol Clin N Am 44 (2015) 1-7.

Parkman, H. P. Idiopathic Gastroparesis. Gastroenterol Clin N Am 44 (2015) 59-68.

Nguyen, Linda Anh, Snape Jr., William J. Clinical presentation and pathophysiology of gastroparesis.  Gastroenterol Clin N Am 44 (2015) 21-30.

Bharucha, Adil E. Epidemiology and natural history of gastroparesis. Gastroenterol Clin N Am 44 (2015) 9-19.

Camilleri, Michael, et al. Clinical guideline: Management of gastroparesis. Am J Gastroenterol 2013; 108: 18-37.

Gastroparesis: Treatment (part 2)

Initial management of gastroparesis often focuses on treating dehydration and electrolyte and nutritional deficits.  One study found that 64% of gastroparesis patients were not consuming enough daily calories to support the needs of their bodies, which can worsen symptoms.  Vitamins A, B6, C, and K, as well as iron, potassium and zinc are frequently deficient in this population.  Small meals low in fat and fiber are recommended for gastroparesis patients.  Liquids or blended solids often empty normally from the stomach.

For cases in which oral diet is unable to provide sufficient calories and nutrition, placement of a feeding tube may be necessary.  Jejunal feeding tubes are often used successfully.  Prior to surgical placement of a feeding tube, a nasojejunal tube should be used successfully.  PEG-J or Jet-PEG tubes allow venting of gastric secretions to reduce vomiting and nausea while providing a feeding route.

TPN (total parental nutrition) is given intravenously, but carries risks, including central line infections.  For patients in whom oral feeding is not feasible, a feeding tube is often considered the safer option.

Metoclopramide, a dopamine D2 receptor antagonist, is approved for treatment of gastroparesis.  However, treatment beyond 12 weeks should be considered only if the improvement on this medication is significant enough to outweigh risks.  Metoclopramide can cause dystonia and tardive dyskinesia.  Benzodiazepines and antihistamines are sometimes used to treat these side effects.  Domperidone is also a dopamine D2 receptor antagonist, but has lower incidence of side effects.  It is not approved in the US, but can be obtained via special FDA approval for US patients.

Medications to increase gastric motor activity, like erythromycin, are often used in gastoparesis patients.  When taken orally, erythromycin often becomes less effective after several weeks of relief.  Proton pump inhibitors and H2 antihistamines may provide some relief as gastroparesis is often associated with and irritating to GERD.

Medications for management of nausea and vomiting are mainstays for many gastroparesis patients, with phenothiazines or antihistamines often used for this purpose.  5-HT3 receptor antagonists like ondansetron are also widely used.  The neurokinin receptor-1 antagonist aprepitant is sometimes used after failing other antiemetics.  Scopolamine patches and dronabinol are also options.  Tricyclic antidepressants can be used to manage nausea, vomiting and abdominal pain, with nortriptyline and desipramine often preferred over amitriptyline, which can cause delayed emptying.  Mirtazapine has been reported as successful in a case study.

Abdominal pain associated with gastroparesis can be difficult to manage because opiates can induce gastroparesis.  Gabapentin, tramadol, tapentadol, pregabalin and nortriptyline are non-opiate options for pain management.

For some patients, more invasive treatment is indicated.  Some patients with gastroparesis have increased tone in the pyloric canal, which can contribute to delayed gastric emptying.  Injection of botulinum toxin (Botox) into the pyloric sphincter is sometimes tried.  In double-blind studies, use of Botox increases gastric emptying but does not improve symptom profiles.

There are surgical options to manage gastroparesis, with varying results.  Gastric electrical stimulation is considered for patients with long term symptoms that have not improved despite treatment.  These devices are implanted and provide low grade electrical stimulation to the stomach and increase motility.  In diabetic gastoparesis patients, this method improved quality of life and decreased symptoms.  Patients who acquired gastroparesis following surgery, or whose gastroparesis is idiopathic, were less likely to improve using GES.  Pyloroplasty and gastrectomy (partial or complete) have been trialed in some patients, but there is not a clear trend in the data.

Acupuncture has been shown to benefit gastroparesis patients in a number of studies, including one blinded, randomized study. Symptom severity was improved in those receiving acupuncture and gastric emptying time was decreased.  Autogenic retraining using the program developed by NASA for space motion sickness has shown some benefit.  Autogenic retraining was found to be more successful in patients with intact autonomic function.

References:

Sarosiek, Irene, et al. Surgical approaches to treatment of gastroparesis: Gastric electrical stimulation, pyloroplasty, total gastrectomy and enteral feeding tubes.  Gastroenterol Clin N Am 44 (2015) 151-167.

Pasricha, Pankaj Jay, Parkman, Henry P. Gastroparesis: Definitions and Diagnosis. Gastroenterol Clin N Am 44 (2015) 1-7.

Parkman, H. P. Idiopathic Gastroparesis. Gastroenterol Clin N Am 44 (2015) 59-68.

Nguyen, Linda Anh, Snape Jr., William J. Clinical presentation and pathophysiology of gastroparesis.  Gastroenterol Clin N Am 44 (2015) 21-30.

Bharucha, Adil E. Epidemiology and natural history of gastroparesis. Gastroenterol Clin N Am 44 (2015) 9-19.

Camilleri, Michael, et al. Clinical guideline: Management of gastroparesis. Am J Gastroenterol 2013; 108: 18-37.