Systemic disorders that affect gastrointestinal motility

Chapter 43

Systemic disorders that affect gastrointestinal motility Yeong Yeh Leea, Mohammad Majharul Haqueb, Rona Marie Lawenkoc, Amol Sharmad a

Universiti Sains Malaysia, Gelugor, Penang, Malaysia, bNarayanganj General Hospital, Dhaka, Bangladesh, cSection of Gastroenterology, De La Salle Health Sciences Institute, Dasmarinas, Philippines, dDivision of Gastroenterology/Hepatology, Medical College of Georgia, Augusta University, Augusta, GA, United States

Key Points ●

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Metabolic disorders, such as diabetes mellitus and thyroid dysfunction, connective tissue disorders such as systemic sclerosis and Ehlers Danlos syndrome, miscellaneous disorders such as amyloidosis and sarcoidosis and collagen vascular disorders can all affect gastrointestinal nerve and muscle disorders causing significant GI symptoms. Prevalence and severity of systemic disorders that affect GI motility can be variable, depending on etiology, disease activity and stage or progression of disease. Mechanisms of GI motility disturbance in systemic disorders are not entirely clear, and thus management is usually symptombased and involves control of disease activity.

Introduction A systemic disease is defined as a disorder that can affect a few organs and tissues or even the whole body. Systemic disorders that influence gastrointestinal (GI) motility are listed in Table 1. In specific disorders, such as diabetes mellitus, abnormal GI motility or dysmotility can arise from the disease itself or a result of complications of diabetes. GI symptoms are non-specific and symptoms alone cannot differentiate between potential inflammatory, or malignant pathologies. Drugs and infectious conditions which may present with systemic manifestations and dysmotility are often excluded. Presence of “red flags”, such as weight loss, GI bleeding, anemia, or significant family history, would warrant endoscopy or imaging studies to exclude mucosal and obstructive causes prior to considering motility testing. The current chapter provides an overview of relevant systemic diseases with disturbed motility, and the general approach and management of these specific conditions.

Systemic disorders associated with disturbed motility Diabetes mellitus Background Diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia due to impaired insulin secretion or peripheral resistance to the action of insulin. Type 2 diabetes is the predominant form, and commonly associated with obesity, due to increase in visceral fats. Diagnosis is rarely made based on symptoms (e.g., thirst, polyuria) but rather on abnormal fasting plasma glucose, oral glucose tolerance test or hemoglobin A1C levels. Significant morbidity is associated with diabetes and include both macrovascular (atherosclerosis) and microvascular (retinopathy, nephropathy and neuropathy) complications. GI symptoms, such as early satiety or epigastric fullness, occur more frequently among diabetic and obese individuals than in the general population. Women are more affected than men, and likewise, have greater psychological disturbances. The natural history of GI symptoms in diabetes is unknown. Though, a community study in Australia showed a tendency Clinical and Basic Neurogastroenterology and Motility. https://doi.org/10.1016/B978-0-12-813037-7.00043-1 © 2020 Elsevier Inc. All rights reserved.

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TABLE 1  Systemic disorders that affect GI motility Metabolic and endocrine disorders Diabetes mellitus (including obesity) Thyroid disorders Connective tissue disorders Systemic sclerosis Systemic lupus eythematosus Mixed connective tissue disorder Dermatomyositis/polymyositis Rheumatoid arthritis Ehlers Danlos syndrome Benign joint hypermobility syndrome Infiltrative disorders Amyloidosis Sarcoidosis Neurological disorders Parkinson disease

for new symptoms to appear and old ones to disappear and that symptom “turnover” is not associated with glycemic control or autonomic neuropathy [1]. The pathogenesis of these symptoms is likely a result of a dysfunction in the gut–brain axis which include the following: autonomic (vagal and myenteric) and peripheral neuropathy, diabetic encephalopathy, acute or chronic hyperglycemia and psychological dysfunction [1]. Adverse effects of anti-diabetic drugs must be excluded before symptoms are attributed to diabetes-associated dysmotility. An example of which is diarrhea which may be a result of intake of metformin, α-glucosidase inhibitor (acarbose), lipase inhibitor (orlistat) or the newer, glucagon-like peptide-1 (GLP1) receptor agonist (exenatide, liraglutide).

Diabetic gastroparesis Diabetes is the most common cause of gastroparesis, implicated in about 1/3 of patients. However, the association between symptoms and delay in gastric emptying is not always linear. Based on a recent population study in Minnesota which spanned over 10-years, gastroparesis was more common in patients with type 1 vs. type 2 diabetes (5% vs. 1%) [2]. A longer duration of diabetes, female sex, more frequent hypoglycemia despite higher HbA1C levels have been shown to be predictive factors for gastroparesis. Pathophysiology involves two intrinsic defects, namely, autonomic neuropathy and damage of the interstitial cells of Cajal (ICC) with immune infiltration (Fig. 1). The irreversible autonomic neuropathy of the vagus nerve occur as a result of advanced glycosylation end (AGE) products, oxidative stress, inflammation and ischemia. In both idiopathic (IG) and diabetic gastroparesis (DG), recent studies using full-thickness gastric biopsies, indicate prominent histologic changes such as loss or damage of the ICC and enteric nerves, as well as, immune infiltration of myenteric plexus. Thickened basal lamina around smooth muscle cells and nerves was also characteristic of DG, while fibrosis around nerves was more typical of IG [3]. As for symptomatology, early satiety, fullness, vomiting and retching are more prominent in DG, while epigastric pain is more marked in IG. Gastric scintigraphy is the gold-standard test for diagnosing gastroparesis. Others, such as stable isotope breath test and wireless motility capsule (WMC), are also used to measure delays in gastric emptying. Before any motility testing are done, it is important that blood glucose levels are first optimized and any medication that can affect gastric emptying are withheld. Therapy is not solely focused on accelerating gastric emptying and should be individualized. Clinical response may be less than satisfactory, but ongoing clinical trials with novel agents, including ghrelin agonists have been promising [4]. Optimizing glycemic control is of primary importance, as ongoing hyperglycemia may further impair gastric motility, worsen symptoms and inhibit the effects of prokinetics. Despite the link of obesity to diabetes, patients with DG are often malnourished. Nutritional support either orally or via enteral tube feeding must be provided. Avoidance of large, high fat and high fiber meals, smoking and alcohol are advised to patients. Pharmacologic therapy with prokinetics is the main treatment to improve symptoms. Common classes include: ­dopamine D2 receptor antagonists (e.g., metoclopramide), motilin receptor agonists (e.g., erythromycin), 5HT4 receptor



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FIG. 1  The chart depicts the pathogenesis of diabetic gastroparesis (A) that involves two intrinsic defects, i.e., autonomic neuropathy and interstitial cells of Cajal (ICC) damage from immune infiltration. (B) and (C) illustrate normal state and diabetic gastroparesis state respectively. (Adapted from Koch KL. Gastric neuromuscular function and neuromuscular disorders. In: Feldman M, Friedman LS, Brandt LJ, editors. Sleisenger and Fordtran's gastrointestinal and liver disease: pathophysiology/diagnosis/management. Philadelphia: Elsevier; 2010. P. 789–815.)

agonists (e.g., prucalopride), and the newer neurokinin receptor antagonists (e.g., aprepitant), and ghrelin receptor agonists (e.g., relamorelin) (Table 2). Non-pharmacologic therapies include endoscopic and surgical approaches [5]. Endoscopic therapies include botulinum toxin injection of pylorus, transpyloric stenting, and more recently gastric per-oral endoscopic myotomy (G-POEM). Surgical options include gastric electrical stimulation implant, pyloroplasty, gastrectomy and possibly, pancreatic transplantation.

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TABLE 2  A summary of current and new drugs used for the management of GI motility disorders associated with or caused by various systemic disorders Mechanism of action

Dose

Side effects

Remarks

Domperidone

Peripheral D2 receptor antagonist and promotes release of Ach.

Initially 10 mg 3 times daily; can be increased up to 20 mg 3 times daily.

May cause diarrhea, galactorrhea, prolonged QT interval. May develop tolerance after 5 weeks of administration.

Should have baseline ECG & concomitant use of drugs that prolong QT interval should be avoided. Primarily effective in foregut

Metoclopramide

Central D1 and D2 receptor antagonist and 5-HT4 receptor agonist

Initially 5 mg before meals and at bed time; then can be increased up to 10 mg, 3 times daily.

Galactorrhea, extrapyramidal symptoms, even irreversible tardive dyskinesia

Concomitant use of neuroleptic drugs (like haloperidol, chlorpromazine, risperidone) increase the risk of extrapyramidal symptoms. Actions limited to proximal gut

Levosulpiride

D2 receptor antagonist & 5-HT4 receptor agonist has greater central antidopaminergic, antiemetic and antidyspeptic activity

25 mg 3 times daily (accelerate gastric emptying)

Similar with other D2 receptor antagonist

Accelerate gastric emptying in diabetics and improve glycemic control over 6 months period

Itopride

D2 receptor antagonist with anti-acetylcholine esterase activity

100 mg 3 times daily (functional dyspepsia)

No significant side effects

Devoid of CNS/ CVS side effects but causes minimal elevation of prolactin level

Neostigmine

Stimulate muscarinic M2 type receptor on smooth muscle cell

Neostigmine—2 mg IV slowly

Cholinergic side effects including increased salivation, abdominal pain, nausea, vomiting, diarrhea, decreased pupil size

Neostigmine is used in Ogilvie's syndrome. Pyridostigmine is used in intestinal pseudo obstruction

Facilitates Ach release from cholinergic nerve terminals by blocking presynaptic muscarinic MI and M2 auto receptors and inhibit acetylcholinesterase

100 mg 3 times daily (functional dyspepsia)

Headache, diarrhea

Acotiamide significantly improves gastric emptying and gastric accommodation. A promising agent for functional dyspepsia

Group

Drugs

Dopamine receptor antagonist

Cholinergic agent (cholinesterase inhibitor)

Pyridostigmine

Newer agent Acotiamide

Pyridostigmine— 60 mg 3 times daily

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TABLE 2  A summary of current and new drugs used for the management of GI motility disorders associated with or caused by various systemic disorders—cont’d Group

Drugs

Serotonergic agonist

Cisapride, tegaserod

Mosapride

Mechanism of action

Dose

Side effects

Remarks

5 HT4 receptor agonist and a weak 5-HT3 antagonist

Not used nowadays

Has high affinity for the heart voltagegated K+ channel and so may cause druginduced ventricular arrhythmia

Previously, they were used for gastroparesis and constipation predominant IBS

Selectively acts on 5HT4 receptor

10–15 mg per day.

Full 5HT4 agonist and partial 5-HT3 antagonist

2–4 mg daily (under clinical evaluation)

Headache, nausea, abdominal pain, diarrhea

No significant effect on K+ channel and so is safe without significant cardiovascular effect

(New generation) Prucalopride, naronapride, velusetrag, YKP10811

Highly selective 5-HT4 agonist and have very lowaffinity for other serotonin receptor & heart voltagegated K+ channel

Prucalopride- 2 mg once daily. For elderly- 1 mg per day

Headache, nausea, abdominal pain, diarrhea

Accelerates gastric emptying intestinal and colonic transit. No significant risk of arrhythmia

Tandospirone

5-HT1A agonist

Under clinical evaluation

Under clinical evaluation

Enhances gastric accommodation

Neurokinin-1 receptor (NK1R) antagonist

Aprepitant

Antagonism of NK1R in vagal nuclei of brainstem.

125 mg daily

Mild adverse effects

Useful for nausea associated with gastroparesis and related disorders

Motilin receptor agonist

Macrolideerythromycin, azithromycin

Motilin receptor agonist

IV erythromycin (3 mg/kg) every 8 h; followed by 125 mg thrice daily orally

Abdominal pain and may cause QT prolongation. Can't be used for long term (>4 weeks)

Most useful in acute gastroparesis

Camicinal, mitemcinal, atilmotin

Selective Motilin receptor agonist

Under clinical evaluation

Under clinical evaluation

Activates the antrum preferentially relative to the fundus, small intestine or colon

Relamorelin, unimorelin

Ghrelin receptor agonist

Under clinical evaluation

Hyperhydrosis, dizziness, fatigue, decreased blood pressure

Ulimorelin accelerates gastric emptying and improves upper GI symptoms in diabetic gastroparesis

Renzapride

Ghrelin agonist

ECG, electrocardiogram; CNS, central nervous system; CVS, cardiovascular system; Ach, acetylcholine; GI, gastrointestinal.

Tachyphylaxis is a major problem (due to motilin receptor down regulation)

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Other motility disorders Upper GI symptoms, such as dysphagia (25% tertiary and 5% community) and reflux symptoms (40% tertiary and 15% community) are common, and often associated with esophageal motor and sensory dysfunction associated with diabetes [6]. With acute hyperglycemia [7], esophageal motor abnormalities include reduced peristaltic amplitude, velocity, and reduced lower esophageal sphincter (LES) pressures. Esophageal hypersensitivity is also associated with acute hyperglycemia. On the other hand, chronic hyperglycemia may cause irreversible changes to the myenteric plexus, with increased stiffness of the esophageal wall and reduced longitudinal muscle shortening. In addition, presence of esophageal hyposensitivity lead to ineffective motility causing the above symptoms [6]. Investigation and treatment of dysphagia and reflux in diabetes are the same as in the general population. Obesity, with its associated increase in abdominal visceral fat, and eventual increased intra-abdominal pressure contribute to the dysfunction of the gastroesophageal (GE) junction through formation of partial hiatus hernia [8]. Distorted GE junction plus an expansion of the acid pocket result in greater short segment reflux and potentially lead to Barrett's metaplasia and cancer [9]. In the small bowel, transit is often abnormal, a characteristic of which is early return of phase III of the migrating motor complex after a meal. With slow-transit, there is increased risk for small intestinal bacterial overgrowth (SIBO). Furthermore, loss of adrenergic innervation of the small bowel may cause diarrhea. As with other parts of the GI tract, diabetes affect the colon and cause a delay in colonic transit and present as constipation. Analysis of colectomy tissues have reported loss of myenteric neurons especially of inhibitory nitrergic neurons. Disturbed external anal sphincter function and rectal hyposensitivity are also underlying etiologies for constipation in diabetic individuals. A diagnosis of impaired motility in the small and large bowel can be done utilizing a WMC. Abnormalities in anorectal function can be assessed using anorectal manometry. Treatment is targeted to the specific etiology. Certain agents may be used in refractory diarrhea, for example, subcutaneous octreotide or oral alpha-2 agonist (clonidine). Drugs for constipation include cholinesterase inhibitor (pyridostigmine) and 5HT-4 agonist (mosapride).

Thyroid disorders Background Thyroid hormones, in the active form of triiodothyronine (T3), are critical for brain and somatic development of infants and of metabolic activity in adults. Thyroid hormones have functional roles on almost all organs including the GI tract through controls in rates of secretion of digestive juices and bowel motility. Excess (hyperthyroidism) and deficiency (hypothyroidism) of thyroid hormones are two thyroid conditions which may affect the GI function (Fig. 2). Essentially, hyperthyroidism results from either de novo increase in hormonal synthesis, inflammation, or destruction of the thyroid tissue. Causes of hyperthyroidism include: Graves' disease (the most common cause), toxic adenoma, toxic multi-nodular goiter, thyroiditis or exogenous thyroid hormone administration. On the other hand, hypothyroidism results from inadequate production of thyroid hormone or suboptimal action of thyroid hormone on the target tissues. Hypothyroidism is mostly due to Hashimoto's thyroiditis, thyroid ablation, or thyroidectomy for hyperthyroidism. Both thyroid disorders tend to affect older persons and women more than men.

Effects of hyperthyroidism on GI motility Weight loss is probably the most common GI manifestation associated with hyperthyroidism, and may be due to increase in metabolic rate or increase in gut motility with consequent malabsorption. Hyperthyroidism may result in a variety of GI symptoms. Firstly, hyperthyroidism is known to cause dysphagia, due to compression from an enlarged goiter. Neuromuscular dysfunction associated with thyrotoxic hypokalemic periodic paralysis and myasthenia gravis may also present with dysphagia. Thyrotoxic myopathy of striated muscles of the pharynx and upper esophageal sphincter may manifest more commonly as oropharnygeal dysphagia than esophageal dysmotility. In general, dysphagia associated with thyrotoxicosis tends to resolve after resolution of hyperthyroidism. Apart from dysphagia, patients with hyperthyroidism may also complain of epigastric pain, fullness, eructation, nausea, and vomiting [10]. Dyspeptic symptoms often correlate with activity of the thyroid disease. Gastric emptying may be normal, rapid or delayed. Altered or impaired gastric myoelectrical activities have been documented in hyperthyroid individuals. However, findings from myoelectrical activities do not always correlate with gastric scintigraphic studies. Other mechanisms may explain the variations observed in gastric emptying studies in hyperthyroidism, such as the role of local GI hormones, ghrelin and gastrin, on the gut–brain axis. Ghrelin has been shown to accelerate gastric emptying through

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Regulation of thyroid hormone

Hypothalamus TRH

–

+ –

Pituitary gland TSH

+ T4 & T3

Thyroid gland T4

T3

T4 & T3

Peripheral tissues T3 T4

Hyperthyroidism

Hypothyroidism

- Increase de novo synthesis - Inflammation or destruction

- In adequate production - Target tissue resistance

Esophagus

Oro-pharyngeal dysphagia & esophageal dysmotility.

Dysphagia, heartburn (due to low LES pressure and reduced amplitude of contractions).

Stomach

Epigastric pain, fullness, eructation, nausea, vomiting.

Dyspepsia, nausea, or vomiting (from delayed gastric emptying)

Small intestine

Large intestine

Normal, rapid or delayed gastric emptying Diarrhea, steatorrhea.

Chronic intestinal pseudo obstruction.

There may be associated ulcerative colitis or celiac sprue.

SIBO - causing flatulence, bloating discomfort or even diarrhea.

Low mean resting and squeeze pressure of anal sphincter.

Constipation (from diminished colonic motility) and may lead to ileus, mega colon, or pseudoobstruction.

Low threshold for rectal sensation.

Increased threshold for rectal sensation. Reduced maximum tolerated volume.

FIG. 2  A summary of thyroid hormone regulation and the motility effects on different parts of the GI tract of hyperthyroidism and hypothyroidism. The regulation of circulating thyroid hormones are regulated through a feedback system that involves the hypothalamic-pituitary-thyroid axis. (Adapted from https://emedicine.medscape.com/article/122393-overview; accessed 17 October 2018.)

induction of phase 3 of migrating motor complex, and affect GI motility via specific ghrelin receptors located on myenteric, vagal and central neurons [11]. Orocecal transit time is often accelerated in hyperthyroidism, resulting in diarrhea in up to 25% of cases. Diarrhea may occur in medullary thyroid carcinoma, as part of the multiple endocrine neoplasia (MEN) syndrome, characterized by elevated levels of calcitonin, prostaglandins, or 5-hydroxyindoleacetic acid. Diarrhea can also be due to associated ulcerative colitis or celiac sprue. Hyperphagia and stimulation of the sympathetic adrenergic system seen in hyperthyroidism may also lead to steatorrhea. Lastly, anorectal physiology may be impaired with lower mean anal resting and squeeze pressures observed in those in thyrotoxic state compared to controls. Likewise, abnormal sensory threshold in response to intrarectal balloon distension has been shown [12].

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There are no specific endoscopic, manometric or radiologic features for GI dysmotility associated with hyperthyroidism. In addition to thyroid function tests, serum electrolyte and breath testing can be useful to diagnose periodic paralysis and to measure oro-cecal transit time respectively. Symptoms may resolve following control of thyroid disease through either medical (antithyroid drugs, e.g., carbimazole or radio‑iodine therapy) or surgery when indicated. Beta blockers may help control diarrhea, while prokinetics can reduce upper GI symptoms.

Effect of hypothyroidism on GI motility Although exact mechanisms of dysmotility remain unclear, hypothyroidism is known to cause accumulation of glycosaminoglycans, mostly hyaluronic acid, in interstitial tissues and smooth muscles of the GI tract causing delay in bowel transit [10]. Esophageal dysmotility is characterized by low LES pressure and reduced amplitude of contractions thereby resulting in dysphagia or heartburn. Dyspepsia, nausea, or vomiting tend to occur due to delayed gastric emptying. Constipation is very common in hypothyroidism and results from diminished colonic motility. Ileus, megacolon, or pseudo-obstruction have been reported. Compared to controls, the threshold for rectal sensation was reportedly higher and the maximal tolerable volume was reduced during rectal balloon distension studies [12]. In more than half of hypothyroid patients, SIBO occurs and develop from either small intestinal dysmotility or reduced acid production from co-existing autoimmune gastritis [13]. SIBO presents with abdominal discomfort, flatulence, bloating and even diarrhea. Similar to GI dysmotility from hyperthyroidism, no specific endoscopic, manometric or radiologic features are associated with hypothyroidism. In addition to thyroid function test, abdominal X-ray, hydrogen breath test, gastric scintigraphy, and colonic transit study may be performed as indicated. Treatment would depend on clinical presentation. Thyroid hormone replacement is the primary therapy. Prokinetic agents may be useful for stasis-related symptoms and antibiotics are given for SIBO.

Systemic sclerosis Background Scleroderma comprise a heterogeneous group of conditions characterized by presence of thickened, sclerotic skin lesions. Based on the extent of skin and internal organ involvement, systemic sclerosis (SS) is further classified into limited cutaneous (CREST syndrome, i.e., calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia), diffuse cutaneous, scleroderma sine scleroderma, environmentally induced SS and overlap syndromes. Systemic manifestations are diverse, with almost all patients having GI symptoms. The early occurrence of severe GI dysmotility has been shown to be a poor prognostic marker. Prevalence is variable and range between 4 and 489 cases/million individuals. Most cases occur in women, between the ages of 35 and 65 years old, but 10% of patients report symptom onset as early as 8 years old. Internal organ is less involved in pediatric disease, with pulmonary and GI involvement as the most common. Patients who do not develop organ involvement within 5 years of disease onset have better prognosis, though, overall mortality is still greater than in the general population. SS should be suspected in patients with Raynaud phenomenon, skin thickening, puffy or swollen fingers, digital pitting, painful skin ulcers, calcinosis cutis, mucocutaneous telangiectasia, tendon friction rubs and an abnormal nailfold capillaroscopy. The following serologic tests support the diagnosis of SS when positive: antinuclear antibody (ANA, positive in 95% of SS), anti-topoisomerase I (or anti-Scl-70, associated with diffuse cutaneous SS and marker for severe interstitial lung disease), anticentromere antibody (ACA, marker for limited cutaneous SS) and anti-RNA polymerase III (marker of diffuse cutaneous SS, rapid progressive skin disease, and increased risk for renal crisis and cancer). While these tests are highly specific they are only moderately sensitive (20–50%). Additional autoantibodies (for e.g., rheumatoid factor, antiRNP etc.,) and organ-specific tests may be sometimes warranted. Pathogenesis remain incompletely understood, although three key events are considered important, namely, immune activation, vascular damage and excessive synthesis and deposition of normal extracellular matrix. However, the order of event is unclear but it is hypothesized that microvascular changes occur first, followed by immune activation, development of autoantibodies, and release of cytokines and growth factors. Lastly, multiple cycles of ischemia and inappropriate immune events then lead to collagen synthesis and deposition as illustrated in Fig. 3. Furthermore, there are genetic and epigenetic triggers linked to SS. Individuals with Class I Human Leucocyte Antigen (HLA) allele types A, B, C, and G and Class II HLA alleles DP, DQ and DR were found to be more susceptible to SS. While exogenous triggers, including gadolinium, L-tryptophane, viruses and fungi have also been found to be associated with SS [14].



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FIG. 3  Pathogenesis of systemic sclerosis (SS) and GI involvement of SS remain unknown, but three events are deemed important, i.e., vasculopathy, immunopathy and fibropathy, not necessarily in that order. (Adapted from reference McFarlane IM, Bhamra MS, Kreps A, Iqbal S, Al-Ani F, SaladiniAponte C, et al. Gastrointestinal manifestations of systemic sclerosis. Rheumatology (Sunnyvale) 2018;8. https://doi.org:10.4172/2161-1149.1000235.)

Similar events occur in the GI tract as part of SS. Vascular involvement is evidenced by presence of angiodysplasia and telangiectasia throughout the entire GI tract. Both cellular and humoral immune dysfunctions occur in SS, with Th2 CD4+ T cells involved in cell-mediated immunopathy, and release of cytokines which upregulate humoral immunity (autoantibodies) and activate fibroblasts. Anti-myenteric autoantibodies have been shown to cause neuropathic and myopathic effects, and in vitro studies showed that these effects are potentially reversible when IVIG therapy is given early before fibrosis sets in [15]. Fibroblast activation leads to increase in TGF-β production which converts fibroblast into myofibroblast and later produce excess type I and III collagen. The pathogenesis of GI involvement is also illustrated in Fig. 3.

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Esophageal disorders Esophageal dysfunction was the earliest described visceral involvement and the most common GI disorder in SS. Almost 70% have involvement of the smooth muscles in the distal two-thirds of the esophagus, with sparing of the skeletal muscles in the upper third. From a large 15 million population study with matched samples of 13, 633 systemic sclerosis patients vs. 54,232 healthy controls, the percentage prevalence of dysphagia, reflux and Barrett's esophagus was observed at 4.3 vs. 1.9, 34.8 vs. 15.4, and 1.7 vs. 0.3, respectively [16]. Gastroesophageal reflux disease (GERD) in SS occur as a result of esophageal hypomotility, incompetent LES, presence of hiatus hernia, lack of saliva buffer due to concomitant Sjogren syndrome and/or impairment in gastric emptying. Heartburn is usually worse at night and after meals. Esophageal motility may be of low amplitude initially, but as disease progresses, peristalsis become ineffective and later completely absent (Fig. 4). As the esophagus becomes more rigid, dilation follows. An impaired peristaltic reserve, assessed by multiple rapid swallows (MRS) during manometry, was reported as the most common finding in SS, which suggests that myopathy is the main cause of dysfunction [17]. The LES pressure is often decreased early in the disease, even before a clinical diagnosis of scleroderma is made. Strictures can occur as a complication of GERD, and present as dysphagia. GERD may also contribute to interstitial lung disease seen in SS patients. Candidal, viral esophagitis and pill-induced esophagitis also commonly arise because of acid suppression and immunosuppressive therapy given to SS. Diagnosis of dysmotility and GERD can be made with high resolution manometry and 24-h pH-impedance test or with Bravo capsule. MRS can be performed during manometry to assess peristaltic integrity and reserve. Therapy includes giving proton pump inhibitors (PPI), and/or prokinetics which are helpful initially but often fail in advanced disease. Fundoplication is reserved for severe disease, but outcomes remain suboptimal. Presence of symptomatic strictures require esophageal dilation.

Small bowel disorders The second most common GI involvement in SS is the small bowel, seen in about 40 to 88%, with the duodenum as the most frequent region affected [14]. Progression of small bowel disease is often rapid with significant morbidity and mortality. Though more than half of patients are asymptomatic, symptoms can be severe and difficult to manage. Conditions such as SIBO, pneumatosis cystoides intestinalis (PCI), jejunal diverticula and chronic intestinal pseudo-obstruction (CIPO) may be seen. SIBO seen in about half of patients, lead to significant malabsorption, with resultant vitamin (low vitamin B12 from microbial consumption and high folate from bacterial production) and nutritional deficiencies (albumin, iron, carotene, and selenium). Malabsorption may also be due to associated celiac disease. Workup for SIBO may include hydrogen breath testing or jejunal aspirate and cultures. Blood testing is done to document anemia or suspected malabsorption. Cyclical antibiotics may be given in persistent diarrhea or recurrent SIBO. CIPO is a condition with clinical presentations similar with acute or chronic bowel obstruction, in the absence of any mechanical occlusion even though there is radiologic bowel dilatation (Fig. 5). This is the most difficult problem to manage in SS [18]. Patients may experience periods of acute exacerbations with intractable vomiting and pain and even develop perforation when serosal fibrosis sets in. Loss of wall compliance in the muscularis layer in small bowel involvement may lead to formation of jejunal diverticula which sometimes perforate or bleed.

FIG. 4  Features of esophageal high-resolution manometry. (A) Normal study in a 20-years-old female with recurrent belching (B) features of esophageal involvement of systemic sclerosis in a 48-years-old female with dysphagia (C) “achalasia-like” features in a 51-years-old male with amyloidosis.



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FIG. 5  Plain abdominal x-ray features of (A) chronic intestinal pseudo-obstruction (CIPO) showing dilatation of small and large bowel without evidence of an abrupt transition point or mechanically obstructing lesion and (B) pneumatosis cystoides intestinalis (PCI) showing abnormal air shadows indicative of air-filled cysts without evidence of pneumoperitoneum. (Modified from references Shah J, Shahidullah A. Chronic intestinal pseudo-obstruction in systemic sclerosis: an uncommon presentation. Case Rep Gastroenterol 2018;12:373–8. https://doi.org/10.1159/000490526; Wang YJ, Wang YM, Zheng YM, Jiang HQ, Zhang J. Pneumatosis cystoides intestinalis: six case reports and a review of the literature. BMC Gastroenterol 2018;18:1–8. https://doi. org/10.1186/s12876-018-0794-y.)

Abnormalities can be measured by small bowel manometry where mean contractile amplitudes during fasting and postprandial periods, spontaneous phase III periods, and octreotide-induced activity complexes were found to be r­ educed [19]. Other tests include WMC to measure small bowel transit and imaging studies, such as CT or MR enterography. Prokinetics only work in the early stage. Octreotide and erythromycin in combination seem to provide sustained relief in CIPO [20] but prolonged use of octreotide may be associated with cholelithiasis and bowel perforation. PCI which is a benign, rare condition wherein multiple air-filled cysts occur within the intestinal wall (Fig. 5), commonly in the jejunum, and result to pneumoperitoneum when they rupture is treated conservatively with oxygen, antibiotics and bowel rest [21].

Dysmotility in other parts of the GI tract Gastroparesis can occur in approximately half of SS cases, and symptoms are similar with those of IG, including early satiety, nausea, vomiting, pain and bloating. Presence of gastroparesis can exacerbate GERD and worsen malnutrition. Non-invasive techniques including 13C-octanoic acid breath test and ultrasound have been used successfully to evaluate gastric emptying in SS [22, 23]. Prokinetics are useful in the early stages but in later stage or refractory cases, percutaneous gastrostomy become a viable option. Colonic involvement occurs in approximately 20–50% of SS and tend to be pan-colonic. Hypomotility leads to delayed colonic transit, constipation and diverticulosis. Prolonged constipation can lead to SIBO (causing diarrhea), stercoral ulcers (due to pressure effects of inspissated stools), rectal prolapse, volvulus, PCI and rarely infarction. CIPO can also occur in colon. Treatment-wise, stimulant laxatives (e.g., bisacodyl) and prokinetics (e.g., metoclopramide, domperidone and prucalopride) can be used in constipation. Colonic resection is considered for severe pseudo-obstruction and perforation, but postoperative ileus may be significant. Anorectal dysfunction is also common in SS, and is closely linked with esophageal involvement even in the early course of disease [24]. Fecal incontinence arises when there is internal anal sphincter (IAS) atrophy and fibrosis seen in endoanal ultrasound or MRI. Anorectal manometry may show reduced resting pressure and abnormal squeeze pressure compatible with IAS defect. Absence of the rectoanal inhibitory reflex (RAIR) is also common, wherein incontinence occur as the local

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reflex fails to relax in response to distension. Absent RAIR suggests a neuropathic pathogenesis [25]. Biofeedback has been shown to be effective in SS in the same extent as its use in functional fecal incontinence [26].

Systemic lupus erythematosus (SLE) SLE is a chronic inflammatory disease of unknown cause affecting the skin, joints, kidneys, lungs, nervous system, serous membranes and the GI tract. GI involvement occurs in about 40% of patients in their lifetime. Dysphagia is the most frequent GI complaint, with esophageal dysmotility seen in approximately 20–70% of cases. Degree of esophageal dysmotility do not correlate with disease activity or duration, although there have been reports of its association with Raynaud phenomenon and anti-RNPs [27]. The pathogenesis of esophageal dysmotility is not clear but an inflammatory reaction in the muscles or vasculitis of the Auerbach's plexus may be implicated. However, the LES is spared in SLE unlike in SS [28]. CIPO is a rare complication of SLE, usually occurring with active disease but can be the initial presentation. Fewer than 30 cases have been reported in SLE so far, and patients respond well to a combination of high-dose intravenous corticosteroids, immunosuppressants, prokinetics and supportive care, avoiding unnecessary surgery in most cases [29]. Severe diarrhea can occur because of a rare protein-losing enteropathy (PLE), typically observed in young females with severe SLE. These patients often respond to dietary (low-fat, high-protein and high medium-chain triglyceride) and immunosuppressive therapies.

Other collagen vascular disorders Mixed connective tissue disorder (MCTD) is a generalized form of collagen vascular disorder characterized by presence of anti-U1 RNP with clinical features of SLE, SS and polymyositis, occurring sequentially. GI involvement is the most common overlap feature, occurring in about 60–80% of patients. Esophageal dysmotility is the most common involving both smooth and skeletal muscles, but is less severe compared to SS [30]. Like SS, interstitial lung disease may be linked with dysmotility and reflux, but a causal relationship is not confirmed. Hypomotility may also occur in other parts including the stomach, presenting as gastroparesis (6%) and small bowel with development of SIBO. Dysphagia due to esophageal dysmotility has been reported in 35% of patients with dermatomyositis/polymyositis, common in older patients, and may explain the high prevalence of bacterial pneumonia probably due to stasis seen in these patients. In rheumatoid arthritis (RA), small studies report the presence of dysphagia and reflux due to esophageal dysmotility but did not control for medications and co-morbidities including amyloidosis and Sjogren syndrome [31]. Oropharyngeal dysphagia has been reported in association with temporomandibular joint involvement and cervical deformities. Although there may be autonomic neuropathy in RA, GI involvement including gastroparesis and bowel dysmotility has not been described.

Amyloidosis Background Amyloidosis refers to extracellular tissue deposition of insoluble fibrils that are composed of low molecular weight subunits of a variety of serum proteins. These fibrils (non-branching, anti-parallel twisted and β-pleated) can be identified on biopsy specimens both by their characteristic appearances on electron microscopy and by their ability to bind Congo red (leading to green birefringence under polarized light). Fibril depositions result in a wide range of clinical manifestations depending upon their type, location, and the amount of amyloid. Amyloidosis may be acquired or hereditary, and either be systemic or localized. The common forms of systemic amyloidosis are: primary (AL), secondary (AA), dialysis-related, senile and familial amyloidotic polyneuropathy. Primary (AL) or light chain (L)-associated amyloidosis is the most common form, with generalized deposition of excess light chains. It is associated with plasma cell dyscrasia. Secondary (AA) amyloidosis or acute-phase reactant-serum amyloid A protein (A) is associated with infectious, inflammatory, or, less commonly, neoplastic disorders. The epidemiology of amyloidosis is not exactly known because of its rare prevalence, and the wide spectrum of etiologies and manifestations associated with the disorder. Acquired amyloidosis manifests between 45 and 64 years of age. Although significant morbidity may result from GI amyloidosis, death is most often due to renal failure, restrictive cardiomyopathy, or ischemic heart disease. Each type of amyloidosis show varying predilections in its deposits in target organs, with AA amyloidosis reporting the highest rates of GI manifestations (10–70%) [32]. AL amyloidosis, for unclear reasons, has been reported to cause fewer extrahepatic GI manifestations. Senile amyloidosis is found in 10–36% of patients over 80 years old and mainly involves the heart but can also be seen throughout the GI tract.



Systemic disorders that affect gastrointestinal motility Chapter | 43  613

GI dysmotility associated with amyloidosis GI disease in amyloidosis results from either mucosal or neuromuscular infiltration. Extrinsic autonomic neuropathy may also occur and affect the gut function. The most common GI sites of amyloid infiltration include the second part of the duodenum (100%), the stomach and colorectum (>90%), and the esophagus (approximately 70%) [32]. Neuromuscular infiltration in tissue wall results in a myopathic process characterized by low amplitude contractions, typically associated with prolonged intestinal transit. Esophageal involvement may cause dysphagia, chest pain, and heart burn. Most common radiographic features include a dilated, atonic esophagus with decreased peristalsis, sometimes with distal narrowing and proximal dilatation mimicking achalasia (Fig. 4). But unlike achalasia, patient experiences a rapid onset of symptoms and significant weight loss. Gastric involvement may result in gastroparesis or even gastric outlet obstruction. Involvement of the small bowel or colon may result in pseudo-obstruction or mechanical obstruction. Intestinal dysmotility can also result in rapid intestinal transit and cause diarrhea. While patients with AA amyloidosis usually present with diarrhea and malabsorption, patients with AL amyloidosis present with constipation, mechanical obstruction, or CIPO [33]. GI amyloidosis should be suspected in patients with unexplained diarrhea, weight loss, autonomic dysfunction or GI bleeding in the presence of disorders known to be associated with amyloidosis (including plasma cell dyscrasia, chronic inflammatory disease, and chronic renal failure on maintenance dialysis). A diagnosis of GI amyloidosis requires a tissue biopsy (rectal or duodenal mucosal biopsies) since endoscopic, manometric or radiologic findings of GI amyloidosis are nonspecific. Treatment of GI amyloidosis depends on clinical presentation and underlying cause. Dysphagia, secondary to esophageal infiltration, can be managed with balloon dilatation. For nausea, vomiting and gastroparesis, dietary modification (small meals consisting of liquid or homogenized foods) and prokinetics (e.g., promethazine, domperidone and metoclopramide) may help. In cases of severe dysmotility when enteral feeding fails, parenteral nutrition may be necessary. Neostigmine may help in CIPO. In patients with diarrhea, bloating or SIBO, empiric treatment with antibiotic may be given. If there is no response, glucocorticoids and octreotide can be tried. If the cause of GI amyloidosis is known, treatment of underlying cause that includes high-dose chemotherapy followed by autologous stem-cell transplantation may be the best approach in managing GI complications [32].

Sarcoidosis Background Sarcoidosis is a systemic granulomatous disease of unclear etiology, and is characterized by formation of non-necrotizing granulomas. It is a global disease with variable incidence, presentation, and prognosis with the highest incidence reported in the United States and Sweden. It tends to occur more frequently in women and can affect any age groups, but more prominent in individuals aged 40 years or younger. The disease mainly affects the lungs and chest lymph nodes, with extremely rare GI involvement.

GI dysmotility associated with sarcoidosis Among the many organs associated with GI sarcoidosis, the stomach is the most frequent site affected. Patients may present with postprandial epigastric pain, hematemesis, melena, nausea, vomiting, and early satiety. Oropharyngeal and esophageal motility may occur if the bulbar and myenteric nerves are involved through granulomatous infiltration or from compression of adjacent lymph nodes. When myenteric neurons are affected, an achalasia-like presentation may develop. Likewise, dysphagia may also develop from direct mucosal or muscular infiltration of the esophagus. Endoscopic findings are nonspecific and esophageal manometry may reveal achalasia-like features (i.e., absence of peristalsis with raised integrated relaxation pressure). Very few cases of small bowel sarcoidosis have been reported with duodenal involvement occurring in a higher frequency than any other area. Clinical manifestations of small bowel sarcoidosis are non-specific and can mimic Crohn's disease. Non-bloody diarrhea is the most common symptom, with colicky, epigastric and/or periumbilical abdominal pain occurring in approximately half of cases. Concomitant weight loss, anorexia, low-grade fever, and weakness may be present. Involvement of the colon and rectum is rare. Diagnosis of sarcoidosis of the GI tract is based on the presence of non-necrotizing granulomas on biopsy from affected portions with exclusion of other granulomatous diseases. Treatment of GI sarcoidosis depend on the activity and extent of the disease involvement [34]. Asymptomatic patients generally do not require treatment. For patients who are symptomatic and have a substantial amount of granulomatous inflammation on tissue biopsy, glucocorticoids are the treatment of choice.

614  SECTION | C  Biopsychosocial and systemic neurogastroenterology

Prokinetics may help to some extent to address nausea, vomiting and early satiety. Botulinum toxin has been used successfully to treat the achalasia-like condition associated with sarcoidosis.

Hypermobile Ehlers-Danlos syndrome and benign joint hypermobility syndrome Background Over the last decade, gastroenterologists are more frequently recognizing the presence of underlying connective tissue disorders with increased skin and joint flexibility and easy bruising in patients with unexplained GI symptoms. The two most common such syndromes include hypermobile Ehlers-Danlos syndrome (hEDS) and benign joint hypermobility syndrome (BJHS) [35]. These two conditions share the same clinical presentations and similar diagnostic criteria. They are separated chronologically with the diagnosis of hEDS predominantly occurring in pediatric and adolescent patients, whereas BJHS is primarily diagnosed in adult patients. Both hEDS and BJHS use the Beighton score [36], a validated 5-item assessment, shown in Fig. 6, with minor differences in additional major and minor criteria for diagnosis. The latest classification by the International EDS Consortium defines 13 EDS subtypes [37]. Despite an established autosomal dominant inheritance, hEDS is the only EDS subtype without an associated genetic mutation of a collagen or collagenase gene, requiring a purely clinical diagnosis.

GI manifestations Since hEDS and BJHS likely affect the entire GI tract, both upper and lower GI symptoms are present in these patients. In a large series of over 550 patients, one third of BJHS patients reported heartburn and water brash compared to less than a quarter of non-BJHS patients [38]. In the same study, more than 44% of BJHS patients reported postprandial fullness compared to only 27.1% of patients with this condition. Similarly in a cohort of 466, hEDS patients 55% prospectively reported symptoms of GERD [39]. Furthermore, patients with hEDS and BJHS were found to have an eightfold increased risk of having eosinophilic esophagitis [40]. In a retrospective series of 687 EDS, mainly hEDS, patients, IBS and constipation were common and seen in more than a quarter of patients with the hEDS subtype [41]. An Italian study extrapolates that celiac disease may be up to an estimated 10–20 times more prevalent in individuals with BJHS and hEDS [42]. In addition to rectal prolapse, EDS patients are also noted to have frequent findings of hiatal hernias, anterior rectoceles, and diverticulosis. The pathophysiology of GI symptoms in BJHS and hEDS remains unclear. It is hypothesized that connective tissue abnormalities within and around the layers of gut leads to increased compliance, altered visceral hypersensitivity, and visceroptosis, or the downward displacement of the abdominal organs [36]. There may be a link between severe GI symptoms in these patients and postural orthostatic hypotension (POTS) [43]. Further comprehensive investigations including neurophysiological and GI motility studies are needed to evaluate patients with these hypermobility syndromes to uncover their underlying pathophysiology.

Parkinson disease Background Bradykinesias, limb rigidity, and pill-rolling resting tremor are well recognized motor disturbances in Parkinson’s disease (PD). Nonmotor gastrointestinal disturbances are less appreciated but frequently present and bothersome. Chronic constipation, the most common GI symptom in PD, occurs in between 30% and 70% of patients and may present up to 15 years prior to the onset of classic motor symptoms and initiation of constipating dopaminergic medications [44–48]. Some PD patients will be unaware of underlying constipation. Severe constipation is associated with a strong hazard ratio of 3.3–4.2 of developing PD [49].

Gut-brain link The gut may serve as more than a source of misery to those with PD. The Braak pustule proposes that pathologic alphasynuclein propagates in a retrograde, prion-like fashion from the gastric enteric nervous system to the central nervous system via the unmyelinated fibers of the vagus nerve [50]. However, large-scale epidemiological studies have failed to find a consistent correlation between vagotomized patients and protective effects on the development of PD [51, 52]. Another proposed mechanism of pathologic spread may exist from the anorectum to the CNS via the unmyelinated fibers of Onuf’s nucleus with projections to the sacral plexus [44].

Systemic disorders that affect gastrointestinal motility Chapter | 43  615



GI manifestations In series of 66 PD subjects undergoing anorectal manometry and wireless motility capsule, both motility tests commonly employed for the evaluation of constipation, Su et al. found dyssynergic defecation in 89% and slow colonic transit in 62%. Fifty-seven percent of PD subjects demonstrated overlap with both dyssynergia and slow colonic transit [53]. Preliminary results from our lab demonstrate PD subjects have significant rectal hyposensitivity to electrical stimulation and spinoanorectal neuropathy on translumbosacral anorectal magnetic stimulation (TAMS) testing, a novel testing for pelvic neuropathy [54]. Treatment of constipation in PD lacks large randomized controlled trials, however, some small studies suggest benefit of fiber, osmotic laxatives, lubiprostone, and serotonergic agents such as tegaserod and cisapride [55–59]. Small open-label studies have also demonstrated benefit of injection of puboretalis with levodopa, apomorphine, or botulinum toxin [60–62]. No studies to date have evaluated the efficacy of biofeedback therapy in PD patients with dyssynergic defecation. Ongoing studies show early promise in understanding the constipation and the underlying neuropathology of PD, a true gut-brain disorder.

Conclusions Systemic disorders that affect GI motility include metabolic or endocrine disorders, connective tissue disease and infiltrative disorders. Any part of the GI tract can be affected but prevalence and severity may vary, depending on etiology, disease activity and progression of the underlying systemic disease. Pathophysiology of dysmotility in these disorders is often unclear but may involve altered neurohormonal and neuroimmune regulation of the gut–brain axis. There are no specific endoscopic, imaging or manometric features that can reliably distinguish the various disorders, and diagnosis may depend on histology findings such as that seen in systemic sclerosis, amyloidosis and sarcoidosis. Treatment is often symptom-based but control of active disease, for example acute hyperglycemia and thyrotoxicosis may alleviate or improve GI dysmotility. Table 3 provides a summary of findings and management of various dysmotility disorders associated with systemic disorders discussed in the chapter. Future therapies will depend on a greater understanding of underlying pathophysiology and may be targeted on gut–brain interactions.

TABLE 3  A summary of major GI motility disturbance and its management in various systemic disorders Systemic disorder Diabetes mellitus

Esophagus or stomach

Small bowel

Large bowel or pelvic floor

Features

Management

Features

Management

Features

Management

Gastroparesis

Dietary modification

Diarrhea

Antibiotic

Refractory diarrhea

Octreotide

Constipation

Pyridostigmine

SIBO

Prokinetics Botox injection

Clonidine

5HT4 agonist

G-POEM Surgery Hyperthyroidism

Dysphagia

Prokinetic

Diarrhea

Anti-thyroid therapy

Diarrhea/ steatorrhea

Beta blocker Hypothyroidism

Dyspepsia Nausea

Prokinetic

SIBO

Antibiotic

Anti-thyroid therapy Beta blocker

Constipation

Dietary modification Prokinetic

Vomiting Continued

616  SECTION | C  Biopsychosocial and systemic neurogastroenterology

TABLE 3  A summary of major GI motility disturbance and its management in various systemic disorders—cont’d Systemic disorder Systemic sclerosis

Esophagus or stomach

Small bowel

Large bowel or pelvic floor

Features

Management

Features

Management

Features

Management

GERD

PPI

SIBO

Antibiotic

Constipation Diverticulosis

Prokinetic

PCI

Correct vitamin and mineral deficiencies

Prokinetic, e.g., prucalopride

Fundoplication

CIPO

Dysphagia Gastroparesis

Volvulus CIPO

Prokinetic

Bowel rest

PEG

Antibiotic

Fecal incontinence

Laxative, e.g., bisacodyl Colonic resection (severe) Bio-feedback

Octreotide + erythromycin, bowel resection (severe) Amyloidosis

Gastroparesis

Heartburn

Prokinetic

SIBO

Antibiotic

TPN (if severe)

Diarrhea (AA form)

Glucocorticoid

Constipation (AL form)

Neostigmine Bowel resection

Octreotide

PPI

Prokinetic

Prokinetic Sarcoidosis

Dysphagia (achalasia-like)

Prokinetic

Abdominal pain

Botox injection

Anti-spasmodic Antibiotic

Diarrhea

Prednisolone

Rare involvement

–

Ehlers Danlos syndrome and benign joint hypermobility syndrome

Heartburn, hiatus hernia, 8× risk of EoE Postprandial fullness

PPI

Celiac disease

Gluten-free diet

IBS Constipation Diverticulosis Rectal prolapse Anterior rectocele

Low FODMAPs Surgery in severe cases

Parkinson disease

–

–

–

–

Constipation (dyssynergia and slow transit)

Lack of RCTs

G-POEM, gastric per-oral endoscopic myotomy; SIBO, small intestinal bacterial overgrowth; GERD, gastroesophageal reflux disease; PPI, proton-pump inhibitor; PEG, percutaneous endoscopic gastrostomy; PCI, pneumatosis cystoides intestinalis; CIPO, chronic intestinal pseudo-obstruction; TPN, total parenteral nutrition; AA form, secondary amyloidosis; AL form, primary amyloidosis; EoE, eosinophilic esophagitis; RCTs, randomized clinical trials

Acknowledgment The following grants have supported author, Yeong Yeh Lee in his research on GI motility: Fundamental Research Grant Scheme (FRGS) of Ministry of Higher Education of Malaysia (Reference: 203.PPSP.6171192) and Research University Individual (RUI) grant of Universiti Sains Malaysia (Reference: 1001/PPSP/812151).

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