GI involvement in systemic diseases

1. GI involvement in systemic diseases Dr. Eran Israeli

2. General principles • Common!! • The GI manifestation is due to the same mechanism (e.g. neuropathy, infiltration of mucosa)

3. General principles -2 • The GI tract can be the first manifestation of many systemic disorders - Dysphagia in CREST syndrome - Constipation in hyperparathyroidism • The GI manifestations are a complication of the disease - amyloidosis in FMF

4. General principles -3 • GI manifestation is an adverse effect of the treatment of the disease - Chemotherapy - Metformin/ Colchicine / antibiotic-associated diarrhea - NSAIDS • It is better to consider first an uncommon manifestation of a common disease rather than a common manifestation of a rare disease - 70 yrs old male with new onset dyspepsia- gastric adenocarcinoma vs. gastrinoma (Z-E syndrome)

5. General principles -4 • Different mechanisms of disease may only cause a limited “repertoire” of symptoms: Dysphagia: Upper vs. lower / Dysmotility vs. obstructive: - Diabetic autonomic neuropathy - Achalasia- nonprogressive pressure waves, increased LES pressure - Pseudoachalasia- infiltration of a tumor, but also may be a paraneoplastic (autoimmune) phenomenon

6. GI Involvement in Diabetes Mellitus • Globally, as of 2010, an estimated 285 million people had diabetes, with type 2 making up about 90% of the cases. Its incidence is increasing rapidly, and by 2030, this number is estimated to almost double. • Recent work has shown that the gut microbiome may play an important role in obesity and evolution of DM: - modulation of energy harvesting capacity by the host - low-grade inflammation and the corresponding immune response on adipose tissue plasticity, hepatic steatosis, insulin resistance

7. GI Manifestations in DM • A population based survey of 8567 subjects from Sydney, Australia (423 with diabetes), showed that upper GI as well as lower GI symptoms were significantly more prevalent among diabetics than among controls: adjusted odd ratio: 1.4 - 2.1 for the different GI symptoms Bytzer, Arch Intern Med 2001;161:1989

8. Diabetes Mellitus • 75% of pts. have GI manifestations: Constipation Diarrhea Dysphagia Nausea Vomiting

9. Pathogenesis Dysbalance of the autonomic nervous system: Disordered motor function of the GI tract. • Autonomic Neuropathy • Hyperglycemia

10. In IDDM autonomic neuropathy : 20-40% • Most commonly affects sympathetic nervous system • Cholinergic denervation causes relaxation • No response to a2+ (usually increases absorption): malabsorption

11. Pathogenesis-other factors • Enteric myopathy (d/t autoimmune and metabolic insults) • Loss of Interstital cells of Cajal (ICC)- serve as pacemaker cells that are responsible for initiating and organizing phasic contractions, and also for propagation of electrical activity in smooth muscles- decrease of trophic factors for ICC’s in DM • Ischemia and hypoxia from microvascular disease of the GIT • Mitochondrial dysfunction • Formation of irreversible advanced glycation end products

12. Diabetes Mellitus-2 • Esophagus: • low LES pressure • Decreased peristalsis • Esophagitis, candidiasis, dysphagia • Stomach: • Low peristalsis, gastroparesis, pylorospasm, nausea, vomiting, bezoars

13. Diabetes Mellitus -3 • Small bowel: Sympathetic denervation: malabsorption, diarrhea, bacterial overgrowth • Colon: Constipation or diarrhea • Rectum: Low pressure of internal sphincter, incontinence

14. Diabetes Mellitus-4 • Radiculopathy– upper abdominal pain • Stomach - gastric atrophy, macrocytic anemia (IF deficiency), hypochlorydria • Gallbladder - Cholelithiasis • Liver- steatosis, hepatomegaly, steatonecrosis

15. Mechanisms of treatment of hypomotility disorders – GI tract • Diabetes mellitus: control of hyperglycemia • Metoclopramide (Pramin): - antidopaminergic, increases acetyl-choline in myenteric plexus - central effect on vomiting center - vagus excitation - increases gastric contractions - pyloric relaxation • Side effects: CNS, increased prolactin

16. Mechanisms of treatment of hypomotility disorders – GI tract (2) • Domperidone (Motilium): - anti-dopaminergic, increases acetyl-choline in myenteric plexus - increases gastric contractions - does not cross into CNS • Cisapride (Prepulsid): - increases release of acetylcholine from post-ganglionic neurons - increase motility in the stomach and small bowel

17. Mechanisms of treatment of hypomotility disorders – GI tract (3) • Erythromycin: - Motilin receptor + • Clonidine a2+ - increase absorption of water and electrolytes • Somatostatin: - Increases transit time • Fibers

18. GI Manifestations in Scleroderma • Systemic sclerosis (SSc) and CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal disease, sclerodactyly and telangectasia) - multisystem diseases • Affecting women 3 to 4 times more commonly than men, with symptoms occurring in their 20 to 40s. • A relatively rare disease with 10 new cases per 1 million adults per year. • Characterized by vasculitis of the small arteries and fibrosis of the skin and other organs.

19. Calcinosis Raynaud’s syndrome Sclerodactyly Telangectasia

20. Scleroderma-pathogenesis • Primarily, an early vascular lesion that manifests as mild changes in intestinal permeability, transport and absorption. • The second stage is neural dysfunction when early symptoms begin. • The third stage is smooth muscle atrophy, • The end stage lesion is muscle fibrosis, at which point pharmacologic restoration of function is no longer possible • A recent detection of circulating auto-antibodies to myenteric neurons and anti-muscarinic-3-acetylcholine receptors (M3R) suggests an autoimmune neuropathic etiology for scleroderma.

21. Scleroderma-GI Manifestations • Altered peristaltic activity with multiple secondary problems, including esophageal reflux, early satiety, nausea, vomiting, pseudo-obstruction, small intestinal bacterial overgrowth, malabsorption and ultimately malnutrition • The esophagus is the most commonly affected organ, between 70% and 90% • Smooth muscle atrophy leads to absent or low-amplitude esophageal contractions and weakening of the lower esophageal sphincter: - reflux of acid and retarded clearance of the refluxed material. - gastric emptying is commonly delayed, further increasing acid reflux • The result is severe symptomatic reflux and erosive esophagitis

22. Scleroderma-GI Manifestations • Dysphagia - secondary to dysmotility and reflux - less commonly due to stricture formation (occurring in 17% to 29% of patients) - Candida esophagitis • Due to the high risk of developing strictures, patients should be maintained on a proton pump inhibitor at a dose sufficient to suppress heartburn. • Gastro-esophageal reflux (GER) may contribute to pulmonary disease by microaspiration of acid and by vagal stimulation of esophageal acid causing bronchoconstriction

23. Scleroderma-GI Manifestations • Stomach: - delayed gastric emptying, which contributes to GER and subsequently to malnutrition. - iron deficiency anemia or severe bleeding secondary to telangectasia, including gastric antral vascular ectasia (GAVE)/watermelon stomach

24. Scleroderma-GI Manifestations • Malnutrition: - Malabsorptionrelated to small intestine bacterial overgrowth (SIBO), and to motility disorders of the gastrointestinal tract that may lead to early satiety and persistent nausea and vomiting. - If SIBO is suspected cycled antibiotics should be tried - In cases with refractory small bowel symptoms therapy withoctreotide 50 to 100 mg subcutaneously at bedtime, should be considered - enteral nutrition via jejunostomy or home parenteral nutrition.

25. Rheumatoid arthritis • Typical signs and symptoms include - morning stiffness - symmetrical polyarthritis - rheumatoid nodules - Rheumatoid Factor - radiographic erosions in hands and/or wrists

26. Rheumatoid arthritis - Felty’s syndrome: Hepatomegaly, abnormalities in liver function tests, and evidence of portal fibrosis causing portal hypertension - Vasculitis (less common than in other rheumatic diseases). - Necrotizing vasculitis of the mesenteric vessels may result in intestinal ischemia and perforation. Cholecystitis, appendicitis, and splenic infarctions have also been described

27. Rheumatoid arthritis- Treatment complications • Chronic administration of salicylates or NSAIDS

28. Am J Gastroenterol 2009; 104:728 – 738

29. Amyloidosis • Rheumatoid arthritis, FMF, IBD • In the past: chronic TB, osteomyelitis, Bronchiectasis • Infiltration of bowel wall / hypomotility

30. Cancer / GVHD • Metastasis to GI: - Breast, lung, ovary, melanoma • Sx: Bowel obstruction, bleeding • Leukemia: 10% severe GI complications direct involvement: bowel infiltration, chemotherapy related, immune deficiency - Leukemic typhlitis: neutropenic pts., post chemotherapy/antibiotics