Digestive System Diseases

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Living organism needs food to satisfy its needs for substance and energy. Food has to be swallowed, prepared for digestion, digested, absorbed, and remnants eliminated. The extent and depth of pathologic conditions of digestive diseases were not appreciated by medicine for a long time, and that applied to cell transplantation/cell therapy as well. Digestive disorders attracted attention of cell transplantologists only after their role in the pathogenesis of neuro-degenerative diseases began to be explored. For this reason, there is not much experience with treatment of diseases of the digestive tube by cell transplantation with the exception of liver diseases that are discussed in a separate chapter, and to some degree chronic pancreatitis.


Gastrointestinal tract secretes several peptide hormones, and neurotransmitters, used for regulation and control of digestive tract.


The surface of digestive tract that amounts to approximately 100 m2 , as compared to the skin surface of less than 2 m2, is exposed to food coming from external environment, and is protected against infectious agents. In mouth there are components of saliva, such as mucins, IgA, and lysozym, in stomach HCl and pepsins have bactericidal properties, and then there are Peyer plaques in the intestines, which are a part of immunocompetent lymphatic tissue of digestive tract. Special ‘membraneous’ M-cells of mucosa enable an access of antigens in the intestinal lumen to Peyer plaques, which then react by release of IgA, i.e. oral immunization. In the intestinal mucosa a ‘secretory component’ is attached to IgA, that protects IgA against digestive enzymes. Another barrier against infectious agents represent macrophages of intestinal wall and Kupffer cells in sinusoids of liver.


Many chronic diabetics, suffering from diabetic complications as well, complain of severe parodontosis, not responsive to any stomatological treatment. After cell transplantation they all report dramatic improvement so that there is no need for any further dental treatment. Based on this a biological treatment of parodontosis was developed in cooperation with the 1st Stomatological Faculty in Moscow. It entailed the treatment of basic systemic disease(s) of the patient and a local treatment by ultrafiltrates of gum tissues.


Achalasia is due to a lowered count of ‘non-cholinergic-non-adrenergic’ neurons as well as decreased reactivity of such neurons to acetylcholine released by pre-ganglionic pathways. The result is a markedly increased pressure in lower esophageal sphincter, delayed relaxation during swallowing act, so that intra-sphincteric pressure is higher than in the stomach even during the receptive relaxation phase. The swallowed food is accumulated in esophagus, so that intraesophageal pressure keeps on growing and esophagus widens enormously. Peristaltic waves cease.


The reverse condition of esophageal hypomotility occurs in scleroderma, an autoimmune disease, with a neuronal defect in the early stages, that causes a disappearance of peristalsis in the lower esophageal segments. Here the contraction of esophageal sphincter is diminished so that a pathological esophageal reflux develops. For treatment of scleroderma see the chapter on ‘Autoimmune diseases’.


Atrophic gastritis is actually an atrophy of glands in fundus. There are IgG autoantibodies against parts of parietal cells and their products, infiltration by plasma cells and B-cells. The parietal cells atrophy, so that secretion of HCl substantially decreases: achlorhydria. Antibodies block the binding of vitamin B12 to intrinsic factor so that pernicious anemia eventually develops. There is a substantial reactive rise in gastrin release, and G-cells hypertrophy. The high level of gastrin brings on hyperplasia of enterochromaffin-like cells with receptors for gastrin, that are the main producers of histamine in the wall of stomach, and this hyperplasia can become carcinoid. The main risk of atrophic gastritis is an extensive mucosal metaplasia, a precancerous condition.


Peptic ulcer has been treated with cell transplantation of hypothalamus, placenta, stomach/intestine, mesenchyme, with success for many years. As it is a classic hypothalamic syndrome, obviously the cell transplant of hypothalamus is of major importance.


Chronic pancreatitis is an inflammatory process destroying exocrine and endocrine tissue, replacing them by fibrous tissue. In 80% it is due to chron. alcoholism. Tissue lesions are spread irregularly throughout parenchyma with protein drops and stones in major ducts, as well as atrophy and ductal stenosis. There is a decreased secretion of water and HCO3- in ducts, so that proteins precipitate in the lumen of ducts and protein drops and deposits are created. Calcium salts deposit into protein drops with creation of stones in small and large ducts. Trypsin is activated in the lumen of ducts and digests pancreatic tissue. Fetal precursor cell transplantation of exocrine pancreas, stomach/duodenum, intestine, liver, is advised along with placenta and adrenal cortex.


Malabsorption can involve any of three sources of energy: fats, proteins and carbohydrates, as well as vitamins, minerals, and trace elements. Fetal cell transplantation of exocrine pancreas, stomach/duodenum, small intestine, colon, liver, placenta, is highly advisable, although very seldom actually used.


Actual location of absorption varies by availability of specific resorption mechanisms in the respective portions of small intestine. Monosaccharides, i.e. glucose, galactose, are absorbed already at the beginning of duodenum. Disaccharides have to be first split by enzymes of the brush border into monosacharides. Polysaccharides, proteins and fats, have to come into contact with pancreatic juice first, so that their absorption takes place in the middle of jejunum and faster emptying of stomach can move their absorption into the distal jejunum or even into ileum. But some components, i.e. cobalamins or biliary acids, can be absorbed only in terminal ileum.


Causes:

- stomach surgery due to a lowered stimulation of hormone secretion, and disturbed synchronization of secretion of pancreatic juices, gallbladder emptying, and choleresis,

- pancreatic diseases, such as chronic pancreatitis, mucoviscidosis, due to lack of important enzymes, i.e. lipase, trypsin, chymotrypsin, amylase, etc., and HCO3-, necessary for buffering of acid chime,

- atrophic gastritis with achlorhydria, where digestion is slowed down in stomach, and that makes colonization of small intestine by pathogenic bacteria easier. Stasis of intestinal contents due to diverticulosis or ‘blind-loop syndrome’ facilitates such colonization. Bacteria break the link between cobalamine and intrinsic factors and thereby cause a lack of cobalamine,

- lack of disaccharidases in the brush border: lack of lactase causes lactose intolerance,

- defects of specific transport systems in mucosa, e.g. Hartnup disease due to the defective transport system for neutral amino acids, or cystinuria due to the defective transport system for basic amino acids and cystin,

- global defects of mucosal digestion and absorption in diffuse mucosal diseases, such as coeliakia, tropical sprue, Crohn’s disease, Whipple disease, AIDS, salmonella enteritis, radiation enteritis,

- defective intracellular digestion of fats, i.e. production of chylomicrons, the basis of abetalipoproteinemia,

- disturbed blood circulation in intestines.


Saccharide malabsorption in small intestine leads to further metabolization in colon by bacteria with production of short-chain fatty acids and gases, and flatulence.


Fat malabsorption due to a lack of bile salts or a defect of micelle production, leads to malabsorption of fat-soluble vitamins A, D, E, K, because they reach the absorbing mucosa only in lipophilic environment and that requires the presence of micelles.


Coeliakia, with incidence 1:100, is handled easily nowadays with the availability of gluten-free food products, but many patients are candidates for the regeneration of intestinal mucosa by fetal precursor cell transplantation.


When autoimmune Crohn’s disease and ulcerative colitis stop responding to conservative treatment, cell transplantation should be carried out before proceeding with extensive surgical resection. Fetal precursor cell transplantation of liver, colon, intestine, adrenal cortex, thymus, skin, spleen, placenta, is recommended for ulcerative colitis and Crohn’s disease.


Among causes of constipation some are possibly treatable by fetal precursor cell transplantation:


Hirschsprung disease is a congenital lack of ganglion cells near anus which causes permanent spasm of involved portion of rectum with a lack of receptive relaxation and of recto-anal inhibition reflex: internal anal sphincter does not open when rectum is filled up.


Chagas disease is an infection by Trypanosoma cruci that destroys the nerves of intestinal ganglia and causes dilatation of colon, i.e. megacolon.


Clinical protocol for treatment of serious gastrointestinal diseases by fetal precursor cell transplantation:


This applies to:

1/ Malabsorption syndromes (‘MA’);

2/ Crohn’s Disease, Ulcerative Colitis & variants (‘CD’);

3/ Liver Cirrhosis, Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis, Chronic Hepatitis (‘LC’).


A proper preparation of the patient for fetal precursor cell transplantation is mandatory. A patient has to be brought into as good a clinical condition as possible by standard therapeutic means, while at the same time lowering the dosage of corticosteroids and other immunosuppressants to a necesary minimum, (or discontinuing them), and eliminating non-essential drugs.


Parameters to be followed in patients before and after fetal precursor cell xenotransplantation, and the frequency:


Basic: once a month or as often as necessary:

I / complete blood count

Ii / urinalysis

Iii / sedimentation rate

Iv / serum immunoglobulins

V / serum albumin

Vi/ serum electrolytes

Vii / serum calcium and phosphorus

Viii / prothrombin time

Ix / serum alkaline phosphatase

X serum transaminases: AST, ALT

Xi / serum bilirubin

Xii / serum cholesterol and lipoproteins

Xiii/ antinuclear antibodies, LE cell prep, Rheumatoid Factor

xiv/ total lymphocytes

xv/ T-lymphocytes (CD3)

xv i/ T-helpers (CD4) and T-suppressors (CD8) and CD4/CD8 ratio

xvii / NK (CD16)

xviii / B-lymphocytes (CD22 and CD19)

xix / serum complement, total (CH50) and C3 and C4

xx / serum gamma-Glutamyl transpeptidase


Special: once every 3 months or as often as necessary:

I / direct measurement of fecal fat (MA)

Ii / microscopic examination of stool (MA)

Iii / D-xylose absorption test (MA)

Iv / serum ferritin, serum iron levels (MA)

Vi / Schiling’s test of vitamin B12 absorption (MA)

VIi / Carbon 14-labeled glycocholic acid breath test (MA)

Vii / x-rays: an upper GI + small bowel series (MA, CD)

Vii i/ small bowel biopsy (MA)

Ix / upper gastrointestinal endoscopy (MA)

Xi / lactose tolerance test (MA)

Xi/ Chromium 51-labeled albumin test for intestinal protein loss (MA)

Xii / x-rays: barium enema, or double air-contrast barium enema (CD)

Xiii / fiberoptic sigmoidoscopy and total colonoscopy with biopsies (CD)

Xiv / C-reactive protein (CD)

Xv / liver scan (LC)

Xvi / liver ultrasound (LC)

Xvi i/ liver biopsy (LC)

Xix / endoscopic retrograde cholangio-pancreatography (LC, MA)


Frequency of office visits: 4 weeks and 48 hours before fetal precursor cell xenotransplantation, 24 hours and then once a week for the first month after fetal precursor cell xeno-transplantation, and once a month thereafter.