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Git J Club Dm Git

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Git J Club Dm Git

  1. 1. Case history: <ul><li>50 years old woman, married with 5 children. </li></ul><ul><li>Presented with early satiety, nausea & vomiting. </li></ul><ul><li>Her father was diabetic & died from diabetic nephropathy with retinopathy. </li></ul><ul><li>Upper GI endoscopy revealed gastric stasis inspite of prolonged fasting with antral changes due to food stasis. </li></ul><ul><li>RBS, FBS & GTT; proved to be diabetic. </li></ul>
  2. 2. Case history: <ul><li>52 years old woman, gravida 5 para 5. </li></ul><ul><li>Presented with early satiety, nausea & vomiting for the last 2 years. </li></ul><ul><li>Known case of T2DM for the last 15 years, complicated by IHD, but no evidence of autonomic/peripheral neuropathy or nephropathy/retinopathy. </li></ul><ul><li>Upper GI endoscopyu revealed gastric stasis in spite of prolonged fasting with antral changes due to food stasis + prepyloric polyp for which biopsies were done & sent for histopatholohy. </li></ul><ul><li>Scheduled for snare polyp removal after knowing the biopsy results. </li></ul><ul><li>FBS 300, BU/S.Cr normal, s.cholestero 254, s.triglyceride normal. </li></ul>
  3. 4. GIT complications of DM : Pathophysiology / management: Prepared by: Dr. Mohammad Shaikhani. Assistant professor Sulaimani University College of Medicine. From nature clinical GEH 2008.
  4. 5. Introduction: <ul><li>Diabetics have GIT complications more frequently than non-diabetics. </li></ul><ul><li>UGI symptoms: nausea, vomiting, heartburn, are the most frequent. </li></ul><ul><li>Diabetic diarrhea is as an important problem, but constipation is more frequently found. </li></ul><ul><li>Diabetic women are more at risk of developing GIT symptoms than men. </li></ul>
  5. 6. DM/GIT Pathophysiology: glycemic control <ul><li>DM can potentially affect any part of GIT. </li></ul><ul><li>No single RFs identified& mostly multifactorial, involving reversible/irreversible processes. </li></ul><ul><li>Both hypoglycemia/hyperglycemia, can have a reversible effect on the metabolic&signaling pathways of enteric neurons & alter intestinal function. </li></ul><ul><li>Hyperglycemia,inhibits vagal nerve activity. </li></ul><ul><li>GIT symptoms / complications do not always correlate with the DM duration or glycemic control. </li></ul>
  6. 7. <ul><li>Many GI symptoms, can precede or not correlate with the presence of autonomic neuropathy, often assumed to be the major cause of many GIT symptoms. </li></ul><ul><li>Other pathophysiologic processes; enteric myopathy&neuropathy from autoimmune damage& metabolic insults altering critical cellular pathways & essential trophic factor signaling, resulting in smooth muscle atrophy& neural apoptosis, or trans differentiation , loss of ICC& an imbalance in the number of excitatory / inhibitory enteric nerves </li></ul><ul><li>ICC serve as pacemaker cells responsible for initiating & organizing phasic contractions& propagation of electrical activity in smooth muscles, analogous to cardiac Purkinje fibers. </li></ul>DM/GIT Pathophysiology: Autonomic neuropathy
  7. 8. <ul><li>Hypoxia from microvascular disease, mitochondrial dysfunction, formation of irreversible advanced glycation end products, peroxynitrite-mediated endothelial/ enteric neuron damage. </li></ul><ul><li>H yperglycemia can induce apoptosis of enteric neurons &impair activity of the phosphatidylinositol 3-kinase (PI3K) pathway; apoptosis can be prevented by glial-cell-derived neurotrophic factor </li></ul>DM/GIT Pathophysiology: Others
  8. 9. <ul><li>Imbalances in the number of excitatory / inhibitory enteric neurons alter complex motor functions as peristalsis, reflexive relaxation, sphincter tone, vascular flow / intestinal segmentation. </li></ul><ul><li>Defective trophic signaling / enteric innervation cause abns in epithelial function &development, resulting in enhanced nutrient transport potentially complicate glycemic control & abnormalities in salt / water transport,contribute to diabetic diarrhea. </li></ul><ul><li>Compromised intestinal vascular flow can also cause abdominal pain, bleeding, mucosal dysfunction. </li></ul><ul><li>These motor function alterations causes dysphagia /reflux esophagitis in the esophagus, gastroparesis / dyspepsia in the stomach, pseudo-obstruction in SI, constipation, diarrhea/ incontinence in the colon. </li></ul>DM/GIT Pathophysiology: Others
  9. 10. Clinical effects: <ul><li>Eso: dysphagia /reflux esophagitis </li></ul><ul><li>Stomach: Gastroparesis / dyspepsia </li></ul><ul><li>SI: Pseudo-obstruction </li></ul><ul><li>Colon: Constipation, diarrhea/ incontinence. </li></ul>
  10. 11. ESOPHAGEAL COMPLICATIONS: <ul><li>Up to 50% have eso abns: motility disturbance /or GERD </li></ul><ul><li>Eso dysfunction correlates best with the presence of diabetic motor neuropathy & not with autonomic neuropathy </li></ul><ul><li>In patients with diabetic motor neuropathy, abnormalities as increased acid reflux, reduced amplitude of peristaltic waves, reduced rate of smooth muscle contraction, decreased peristaltic efficacy, impaired lower esophageal sphincter tone / function particularly prevalent. </li></ul><ul><li>Esophageal symptoms are slightly more common& proportionately less common than motility manometric changes. </li></ul><ul><li>25% had reflux symptoms vs 9.5% of control. </li></ul>
  11. 12. ESOPHAGEAL COMPLICATIONS: <ul><li>Candida esophagitis is also prevalent, particularly with poor glycemic control. </li></ul><ul><li>Factors that predispose to oral/esophageal candidiasis include defective esophageal clearance secondary to dysmotility, high glucose content of secretions& decreased candicidal activity of polymorphonuclear cells. </li></ul><ul><li>In many cases the eso complications successfully treated. </li></ul><ul><li>GERD, can be managed effectively with conventional anti GERD trts. </li></ul><ul><li>Antireflux operations, should be reserved only for those patients with disease that is refractory to medical treatment. </li></ul>
  12. 13. ESOPHAGEAL COMPLICATIONS:trt <ul><li>Oral/eso candidiasis are best treated by improving glycemic control & the use of oral antifungal agents as fluconazole. </li></ul><ul><li>Symptomatic dysphagia is more difficult to manage, particularly if it exists in the presence of advanced diabetic motor neuropathy. </li></ul><ul><li>Early diagnosis of dysphagia is important so that better glycemic control can be initiated when this condition is still reversible. </li></ul>
  13. 14. GASTRIC COMPLICATIONS: Diabetic gastroparesis <ul><li>Common, sometimes &very troubling. </li></ul><ul><li>Symptoms: epigastric fullness, bloating, nausea,vomiting suggest paresis, but relatively nonspecific, usually, not always, caused by delayed gastric emptying. </li></ul><ul><li>Although pain can occur, it is not an integral component&if present,suggests alternative diagnosis or additional complicating factors. </li></ul><ul><li>Symptoms clearly wax / wane, suggests some temporal variability. </li></ul><ul><li>Usually occurs in the setting of chronic diabetes in which there is evidence of generalized end-organ damage, as retinopathy, neuropathy & nephropathy. </li></ul><ul><li>In PC, occur in 5–12% &in referral centers,much higher, 50%. </li></ul>
  14. 15. GASTRIC COMPLICATIONS: Diabetic gastroparesis <ul><li>It can has a major effect on the management of diabetes as it: </li></ul><ul><li>Complicates glycemic control & effectiveness of OHD. </li></ul><ul><li>Recurrent symptoms can prompt multiple hospitalizations </li></ul><ul><li>Have a deleterious impact on nutrition. </li></ul><ul><li>Can cause recurrent episodes of hypoglycemia. </li></ul><ul><li>It does not seem to increase mortality </li></ul><ul><li>It is not certain whether therapeutic interventions alter its long-term course. </li></ul>
  15. 16. Diabetic gastroparesis:pathogenesis <ul><li>Not clear. </li></ul><ul><li>Chronic hyperglycemia leads to neuropathic changes/ dysfunctional innervation of the stomach& delayed gastric emptying. </li></ul><ul><li>Modest increases in blood sugar can delay gastric emptying, alter antroduodenal motility, induce a sense of fullness&limit efficacy of some prokinetics. </li></ul><ul><li>Hormonal changes:diabetic& idiopathic gastroparesis, occurs primarily in females. </li></ul><ul><li>Concomitant psychiatric disorders. </li></ul><ul><li>Medications:synthetic analogs of amylin (e.g.pramlinitide)& functional analogs of GLP1(e.g. exanatide). </li></ul><ul><li>Psychiatric factors may correlate better with symptoms than the results of emptying studies. </li></ul>
  16. 17. Diabetic gastroparesis:diagnosis <ul><li>Suggested by history. </li></ul><ul><li>PE does not usually useful, but rarely a succussion splash can provide an evidence. </li></ul><ul><li>Concomitant GI pathology must be ruled out, usually by OGD. </li></ul><ul><li>The gold standard is nuclear scintigraphy: Delayed emptying of a labeled solid meal in the absence of any anatomic abnormalities. </li></ul><ul><li>Involves scans every 15 minutes, usually, 4–6 scans for 4 hours; gastric retention of >10% of the meal at 4 hours is diagnostic. </li></ul><ul><li>Other measures:breath tests, radioopaque markers,EGG, capsule endoscopy& measurement of antroduodenal motility. </li></ul><ul><li>Documented gastric emptying abns are common in T1 or T2 DM, the relationship with specific symptoms is not particularly tight. </li></ul><ul><li>Gastric emptying can be accelerated in some patients with T2DM. </li></ul><ul><li>Nonspecific UGI symptoms are common in the general population&in individuals with functional dyspepsia. </li></ul><ul><li>Some favor the ‘diabetic gastropathy’ </li></ul>
  17. 18. Diabetic gastroparesis:Trt <ul><li>Depend on the severity of symptoms, the ability of the patient to maintain adequate nutrition& their responsiveness to therapy. </li></ul><ul><li>The primary aim is to optimize glycemic control, as hyperglycemia induces environmental changes in the enteric nervous circuitry. </li></ul><ul><li>Beyond glycemic control, the treatment parallels that of gastroparesis in general&include: </li></ul><ul><li>Diet modification. </li></ul><ul><li>Pharmacotherapy. </li></ul><ul><li>More invasive approaches for ‘gastric failure’. </li></ul>
  18. 19. Diabetic gastroparesis Trt: Diet <ul><li>Dietary modifications have some success. </li></ul><ul><li>A ‘grazing diet’ of frequent small meals can minimize postprandial fullness. </li></ul><ul><li>Avoidance of nutrients that delay gastric emptying (fat, fiber) might also be helpful. </li></ul><ul><li>As the rate of emptying of liquids is generally preserved in diabetic gastroparesis, the consumption of foods that have been blended&liquid nutritional supplements might be reasonable approach. </li></ul>
  19. 20. Diabetic gastroparesis Trt: drugs <ul><li>More severe symptoms require pharmacologic intervention. </li></ul><ul><li>Prokinetic /or anti-emetics (metochlopromide/doperidone): enhance coordinated pressure waves moving through the antrum, pylorus&duodenum. </li></ul><ul><li>Cholinergic agonists (e.g. bethanechol) increase the frequency &/ or amplitude of gastric contractions, but not necessarily in a peristaltic sequence. </li></ul><ul><li>Metoclopramide / domperidone are dopamine receptor antagonists. </li></ul><ul><li>Metoclopramide crosses BBB, but domperidone does not ,so limited CNS effects. </li></ul>
  20. 21. Diabetic gastroparesis:Trt <ul><li>Endogenous dopamine inhibits gastric emptying, dopamine-receptor- mediated pathways in the brain stem affect nausea. </li></ul><ul><li>By blocking these sites, metoclopramide/domperidone exert their therapeutic effect. </li></ul><ul><li>Metoclopramide can also act as a 5-HT receptor 4 agonist to stimulate cholinergic neural pathways in the stomach. </li></ul><ul><li>A patients who do not respond to one prokinetic might respond to another. </li></ul>
  21. 22. Diabetic gastroparesis Trt: Metochlopromide <ul><li>Metaclopramide is the most commonly used prokinetic, effective in the short term, improving both symptoms /gastric emptying rates, but its long-term efficacy has not been proven& limited data on benefits of periodic or cyclical use. </li></ul><ul><li>Adverse effects from minor to severe; tardive dyskinesia is an uncommon but serious adverse effect can persist despite withdrawal, dictating a thorough discussion with patients. </li></ul><ul><li>Milder adverse effects including drowsiness,fatigue, restlessness , irritability, are relatively common. </li></ul><ul><li>Acute dystonic reactions can occur in up to 1%. </li></ul><ul><li>Prolonged treatment can produce Parkinsonian-like symptoms. </li></ul><ul><li>In women, increases in prolactin result in lactation, breast engorgement/ irregular periods. </li></ul>
  22. 23. Diabetic gastroparesisTrt: domperidone <ul><li>Domperidone’s mechanism of action / effect on gastric emptying are similar to those of metoclopramide,with development of tachyphylaxis/loss of efficacy over time. </li></ul><ul><li>Can result in symptomatic relief without a corresponding improvement in gastric emptying, which suggests that the anti-emetic effect may be important. </li></ul><ul><li>Does not cross BBB, it is unlikely that it will induce extra-pyramidal side effects. </li></ul>
  23. 24. Diabetic gastroparesis Trt: Erythromycin <ul><li>A molecular mimic of motilin, an endogenous peptide that initiates the migrating motor complex in the upper gut. </li></ul><ul><li>Itbinds to the motilin receptor/initiates similar biologic effects,explains the frequent GIT intolerance experienced. </li></ul><ul><li>IV erythromycin a more potent prokinetic than the oral preps. </li></ul><ul><li>Liquid suspension may have rapid absorption/ convenient dosage modification. </li></ul><ul><li>Long-term efficacy is limited. </li></ul><ul><li>The potential benefit of developing a motilin analog still not successful. </li></ul>
  24. 25. Diabetic gastroparesis Trt: cisapride <ul><li>Cisapride /tegasorod are 5-HT receptor 4 agonists induce the release of acetylcholine from myenteric cholinergic neurons. </li></ul><ul><li>Cisapride was originally targeted for GERD& tegasorod for constipation-predominant IBS. </li></ul><ul><li>Both stimulate gastric emptying, with cisapride a more potent prokinetic than tegasorod. </li></ul><ul><li>Both have been withdrawn because of cardiac complications. </li></ul>
  25. 26. Diabetic gastroparesis Trt: others <ul><li>GIT hormon ghrelin, sildenafil,clonidine, opioid receptor agonists, antidepressants, yet to be proven clinically effective. </li></ul>
  26. 27. Diabetic gastroparesis Trt: new <ul><li>Considered for individuals who do not respond to dietary/pharmacologic therapy. </li></ul><ul><li>Two innovative approaches, but their place remains to be determined. </li></ul><ul><li>Intrapyloric inj of botulinum toxin may decrease pylorospasm& improve symptoms with 50% improvement in gastric emptying or symptoms. </li></ul>
  27. 28. Diabetic gastroparesis trts:OTHERS <ul><li>Gastric electrical stimulation (‘pacing’) (Enterra, Medtronic Inc.) </li></ul><ul><li>A significant symptom relief (decreased nausea/ vomiting) </li></ul><ul><li>Diabetics particularly benefited compared with those who had idiopathic gastroparesis. </li></ul><ul><li>Involves surgical intervention, sometimes has to be removed because of complications. </li></ul>
  28. 29. <ul><li>Venting gastrostomies or jejunal feeding tubes </li></ul><ul><li>Venting gastrostomy will relieve distention, nausea/vomiting. </li></ul><ul><li>In individuals who are undernourished, enteral feeding can be an option. </li></ul><ul><li>As the dysfunctional stomach needs to be bypassed, access to the small bowel is necessary either via PEG or PEJ, or a surgical jejunostomy. </li></ul>Diabetic gastroparesis trts: OTHERS
  29. 30. <ul><li>Surgery: drainage procedures (e.g. pyloroplasty) or subtotal (or near-total) gastrectomy with Rouxen-Y anastamosis </li></ul><ul><li>Although reports of symptom relief after surgical intervention, there are considerable postoperative complications,so extremely limited. </li></ul>Diabetic gastroparesis trts:Surgery
  30. 31. Diabetic gastroparesis:Trt
  31. 32. UGIB: <ul><li>Patients who have hyperglycemia/or DKA frequently present with hematemesis </li></ul><ul><li>The Mallory–Weiss tear is often considered bz of nausea/ vomiting accompanying DKA </li></ul><ul><li>The most common finding in patients with hematemesis is esophagitis, secondary to vomiting. </li></ul><ul><li>Negative endoscopy findings are not uncommon. </li></ul><ul><li>Hematemesis resolves quickly when the underlying metabolic abnormalities are treated. </li></ul>
  32. 33. SI:Diarrhea <ul><li>Diabetic duarrhea. </li></ul><ul><li>Concomitant celiac disease </li></ul><ul><li>Medications </li></ul><ul><li>Fecal incontinence. </li></ul>
  33. 34. SI:Diarrhea <ul><li>Constipation is a more common but diarrhea is more clinically relevant / troubling. </li></ul><ul><li>At least 2 mechanisms plus others: </li></ul><ul><li>1. Impaired adrenergic regulation of fluid / electrolyte transport secondary to decreased α2-adrenergic input. </li></ul><ul><li>2. Slow intestinal transit/subsequent bacterial overgrowth. </li></ul>
  34. 35. SI,Diarrhea: diagnosis <ul><li>A combination of hydrogen breath testing&nuclear scintigraphy provide a more accurate assessment of the relationships among small bowel transit, nutrient absorption& small bowel bacterial overgrowth. </li></ul><ul><li>Individuals with diarrhea&associated autonomic neuropathy, primarily diabetes, can have an extremely rapid orocecal transit time (<20 minutes) associated with a positive glucose or lactulose hydrogen breath test. </li></ul><ul><li>Differentiation of rapid-transit from slow-transit diarrhea in patients with diabetes is important. </li></ul><ul><li>Obviously, antibiotic treatment is appropriate for slow-transit diarrhea with bacterial overgrowth, whereas rapid-transit diarrhea might be more effectively treated with more conventional antimotility drugs as loperamide. </li></ul>
  35. 36. SI:Diarrhea <ul><li>Celiac disease occurs in 5% of patients with type 1 diabetes. </li></ul><ul><li>Serologic testing followed by small bowel biopsy is appropriate for the majority. </li></ul><ul><li>Metformin is the medication most commonly associated with diarrhea in this population, but newer medications as acarbose/ miglitol,artificial sweeteners </li></ul>
  36. 37. SI:Diarrhea <ul><li>Fecal incontinence particularly affects elderly patients, can be described as diarrhea. </li></ul><ul><li>?Pancreatic insufficiency / islet cell tumors </li></ul>
  37. 38. Diarrhea: trt <ul><li>Specifically tailored to the underlying pathophysiology (e.g. diet modification for patients with celiac disease or rotating antibiotics for those with small bowel bacterial overgrowth). </li></ul><ul><li>If no specific cause of the diarrhea is identified, empiric therapy with simple antidiarrheal agents (e.g. loperamide) is a reasonable. </li></ul><ul><li>A trial of clonidine is an option for patients in whom it is well tolerated. </li></ul><ul><li>Octreotide effective in diabetic diarrhea,but not often required. </li></ul>
  38. 39. Colonic comps:constipation <ul><li>Constipation requiring laxative is the most common GIT symptom higher in women than men, more in those who take medications that promote constipation (e.g. CCBs). </li></ul><ul><li>Most likely results from slow transit caused by loss of ICC function & smooth muscle myopathy, although autonomic neuropathy/neuroendocrine imbalances might also contribute. </li></ul><ul><li>There are no specific trts for diabetes-associated constipation, although better glycemic control may be of some benefit. </li></ul><ul><li>In most cases, treated the same as idiopathic chronic constipation </li></ul><ul><li>Anorectal dysfunction, from anorectal sensory or motor abns, can benefit from biofeedback training. </li></ul><ul><li>In the absence of defecatory dysfunction, bulking agents, osmotic laxatives (e.g. polyethylene glycol), stimulant laxatives tried. </li></ul>
  39. 40. Colonic comps:constipation <ul><li>The new Cl–-channel agonist, lubiprostone, might also be effective in chronic constipation. </li></ul><ul><li>The prevalence of fecal incontinence secondary to anorectal dysfunction increased in DM. </li></ul><ul><li>Fecal incontinence in DM not well understood& involve many factors, including: </li></ul><ul><li>Aberrant autonomic/enteric regulation of the internal anal sphincter, rectal contraction,acute hyperglycemia, as it inhibits external anal sphincter function /decreases rectal compliance& tighter glycemic control can improve symptoms. </li></ul>
  40. 41. Summary:
  41. 42. Summary: <ul><li>Patients with DM often have GIT symptoms, but the extent/ severity & the specificity of the symptoms are not nearly as well defined as frequently assumed. </li></ul><ul><li>Any part of GIT affected& the presenting symptoms depend on the composite of dysfunctional elements. </li></ul><ul><li>GERD, Candida esophagitis,gastroparesis, diarrhea and constipation are among the many common GIT complications of DM. </li></ul><ul><li>No specific RF has been identified & their etiology is most likely to be multifactorial, involving both reversible /irreversible processes. </li></ul>
  42. 43. Summary: <ul><li>Trt directed at tighter glycemic /symptom control in most. </li></ul><ul><li>For others, effective management is problematic because no therapies are available to prevent or correct the underlying disease mechanisms. </li></ul><ul><li>Reduced key trophic factors cause trans differentiation of pacemaker interstitial cells of Cajal into a smooth-muscle-like phenotype. </li></ul><ul><li>Therapies directed at restoring the normal milieu of trophic signals could correct the dysfunction of the interstitial cells of Cajal& resolve many GI complications. </li></ul><ul><li>Advances in stem cell technology hold promise. </li></ul>

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