GI involvement in systemic diseases

Dr. Eran IsraeliDr. Eran Israeli

General principles Common!!

The GI manifestation is due to the same

mechanism (e.g. neuropathy, infiltration of

mucosa)

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

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)

General principles -3

Different mechanisms of disease may only cause a limited “repertoire” of symptoms:

Dysphagia: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

General principles -4

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

GI Involvement in Diabetes MellitusGI Involvement in Diabetes Mellitus

GI Manifestations in DMGI 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

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

Pathogenesis

Autonomic Neuropathy Hyperglycemia

Dysbalance of the autonomicnervous system:

Disordered motor function of the GI tract .

In IDDM autonomic neuropathy : 20-40%

Most commonly affects sympathetic nervous system

Cholinergic denervation causes relaxation

No response to a2+ (usually increases absorption): malabsorption

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

Diabetes Mellitus-2Diabetes Mellitus-2 Esophagus: low LES pressure Decreased peristalsis Esophagitis, candidiasis, dysphagia Stomach: Low peristalsis, gastroparesis, pylorospasm,

nausea, vomiting, bezoars

Diabetes Mellitus -3Diabetes Mellitus -3 Small bowel: Sympathetic denervation: malabsorption,

diarrhea, bacterial overgrowth Colon: Constipation or diarrhea Rectum: Low pressure of internal sphincter, incontinence

Diabetes Mellitus-4Diabetes Mellitus-4

Radiculopathy – upper abdominal pain

Stomach - gastric atrophy, macrocytic anemia

(IF deficiency), hypochlorydria

Gallbladder - Cholelithiasis

Liver - steatosis, hepatomegaly,

steatonecrosis

Mechanisms of treatment of hypomotility disorders – GI tract Diabetes mellitus: control of hyperglycemia Metoclopramide (Pramin):Metoclopramide (Pramin):

- antidopaminergic, increases acetyl-choline in myenteric plexus

- central effect on vomiting center

- vagus excitation

- increases gastric contractions

- pyloric relaxation Side effectsSide effects: CNS, increased prolactin

Domperidone (Motilium):Domperidone (Motilium): - anti-dopaminergic, increases acetyl-choline in myenteric plexus - increases gastric contractions - does not cross into CNS Cisapride (Prepulsid): Cisapride (Prepulsid): - increases release of acetylcholine from post-

ganglionic neurons - increase motility in the stomach and small bowel

Mechanisms of treatment of hypomotility disorders – GI tract (2)

Mechanisms of treatment of hypomotility disorders – GI tract (3) Erythromycin:Erythromycin:

- Motilin receptor +

Clonidine Clonidine 22++

- increase absorption of water and electrolytes SomatostatinSomatostatin:

- Increases transit time FibersFibers

GI Manifestations in SclerodermaGI 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.

Sclerodactyly

Calcinosis

Telangectasia

Raynaud’s syndrome

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.

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

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

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

Scleroderma-GI Manifestations

Malnutrition:

- Malabsorption related 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 with octreotide 50 to 100 mg subcutaneously at bedtime, should be considered

- enteral nutrition via jejunostomy or home parenteral nutrition.

Rheumatoid arthritis

Typical signs and symptoms include

- morning stiffness

- symmetrical polyarthritis

- rheumatoid nodules

- Rheumatoid Factor

- radiographic erosions in hands and/or wrists

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

Rheumatoid arthritis- Treatment complications Chronic administration of salicylates or NSAIDS

Am J Gastroenterol 2009; 104:728 – 738

Rheumatoid arthritis, FMF, IBD In the past: chronic TB, osteomyelitis,

Bronchiectasis Infiltration of bowel wall / hypomotility

AmyloidosisAmyloidosis

Cancer / GVHD Metastasis to GI: - Breast, lung, ovary, melanoma Sx: Bowel obstruction, bleeding LeukemiaLeukemia: 10% severe GI complications direct involvement: bowel infiltration,

chemotherapy related, immune deficiency - Leukemic typhlitis: neutropenic pts., post chemotherapy/antibiotics