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A MODEL FOR THE EXTRA-INTESTINAL MANIFESTATIONS OF
CHRONIC INTESTINAL PSEUDO-OBSTRUCTION (CIP)
©1997 William Alford, MSEE
Chronic Intestinal Pseudo-Obstruction (CIP) is a neuromuscular dysfunction of the gastrointestinal tract that presents with nausea, vomiting, abdominal pain, diarrhea, constipation, and abdominal distention associated with disturbed GI motility. A puzzling attribute of the disease is the frequent occurrence of many extra-intestinal symptoms (non-GI related). While not often addressed in the literature, many CIP patients have reported incidences of Raynaud's phenomena, leukopenia, pain in the lower back or upper right quadrant, pulmonary distress, hepatitis, chronic fatigue, arthritis, headaches, recurrent septicemia, neurological deficits, parasthesias, dysesthesias, frequent candidiasis, and various autoimmune disorders. Disturbances of the autonomic nervous system function can produce orthostatic hypotension (faintness on rising); disturbances of vision, perspiration, and motility; and venous pooling. Extreme allergies are also reported.
Since the extra-intestinal manifestations of CIP do not appear to be homogeneous, physicians are often confounded by the multiplicity of symptoms and hard put to determine which phenomena may be secondary to the other. The number of disparate symptoms may often unfortunately prejudice some physicians unfamiliar with CIP toward assuming a psychological origin much to the detriment of the patient. A hypothesis has been presented that places many of the kinds of varied symptomatology of CIP that are also shared by the Chronic Fatigue Syndrome (CFS) strictly in the neurological arena as manifestations of limbic dysfunction resulting from disturbances of the brain's prefrontal cortex (PFC) (Goldstein 1996). Impressive case reports of successful therapeutic interventions by a pharmacology based on this neurological model seem attractive, however such models often fail to adequately address causality.
This author's observation from attending many CIP support-group meetings as well as personal communications with patients has often revealed CIP onset following trauma from surgery, accidents, or preceding disease. Similarly, more than 50 per cent of all cases of IBS report a gastric infection that has resolved in the year prior to onset of the IBS.
Recent concerns for the septic complications of surgery for cardiopulmonary bypass that occur without an obvious source of infection have led to a greater appreciation of the gut as a point of origin. Coronary artery bypass grafting (CABG) is a fairly standard procedure these days with a mortality risk of 2.3% but with infectious complications of 6.4% within 6 months following surgery. A study of infections following CABG of 329 patients from January 1987 to March 1990 showed 58% of the infections to be of the respiratory tract with cultures from all of the patients growing enteric (gut origin) organisms (escherichia coli, klebsiella, enterobacter, haemophilus, candida) (Ford). In another collected review of 7,559 patients undergoing cardiac surgery, 49% of the infections were of enteric origin. Up to 54% of all cases in other retrospective studies of fungemia show no source of entry (Alverdy), and autopsies of patients dying with Multi Organ Failure due to sepsis can find no source for the infection in more than 30% of the cases (Deitch, 1992).
A notion that may at first seem odd to some is that the contents of the stomach and bowels are really outside the human body. Foodstuffs ingested by mouth only cross the intestinal barrier into the body following digestion. Undigested foodstuffs and the byproducts of digestion along with indigenous bacteria in the gut remain outside the human body throughout their transit from mouth to anus.
However, this region of contact in the gut is probably the most intimate contact that any animal has with its environment. The exterior skin of the body is multi-layered with an outer epidermis composed of several layers of dead cells which provides an effective protective barrier, whereas the separation of the interior of the body from the exterior environment in the gut is only by a single layer of living epithelial cells. Such a tenuous barrier cannot provide perfect isolation and may be vulnerable to several circumstances. If a breakdown in the gut muscosal barrier occurs, it can result in the passage of bacteria and bacterial components from the gut into the systemic circulation.
More than 500 different species of bacteria normally colonize the intestine in concentrations as high as 10/gram. As the bacteria grow they shed their outer shell. The pieces of this bacterial cell wall, made up of lipopolysaccharide (LPS) are present in large quantities (around 25 grams) in the gut from intact organisms as well as from the death of the bacteria and are known as endotoxins. While the normal gut can safely harbor this amount of endotoxin, it is so potent that it is toxic to humans in nanogram (10, or one billionth of a gram) quantities in systemic circulation.
It has begun to be appreciated that the gut's immunologic and barrier function may fail, allowing the indigenous bacteria to cross the epithelial mucosa lining the intestine to infect the mesenteric lymph nodes (MLNs) and other systemic organs by a process termed translocation. Some of the factors that can promote this translocation include: disruption of the normal ecologic balance of gut microflora by the use of oral antibiotics, bacterial overgrowth, bowel rest during TPN, an impaired immune system, increased intestinal permeability, trauma, ingestion of certain drugs or plant or animal compounds, or physical disruption of the gut mucosal barrier.
The immunoglobulin present in highest concentrations in the intestine is IgA. It is thought that this secretory IgA, or SIgA, prevents the absorption of antigens by binding to them in the lumen or the mucus coating, providing a barrier function. Patients with selective IgA deficiency have high levels of circulating immune complexes and antibodies after ingesting cow's milk. Reduced levels of SIgA result in a greater frequency of GIT infections and coupled with impaired RES, may predispose to systemic bacteremia. The production of SIgA is dependent on enteric antigen challenge which is absent with TPN, contributing to bacteremias in those patients (Alverdy 1985). The level of SIgA is inversely related to serum cortisol and so may be mediated by stressful life events. Recent work has shown that cortisol levels increase rapidly and remain at two- to threefold above baseline when LPS in levels as low as 4 ng/kg is injected into healthy adults (Lang, 1997).
It is well known that CIP often leads to bacterial overgrowth due to the failure of peristalsis to move the contents of the gut along in a timely manner. This undoubtedly leads to a larger colonic pool of endotoxin. In a 1988 study at LSU of patients with intestinal obstruction, MLNs were obtained at laparotomy and cultured to reveal that 59% of the patients with intestinal obstruction had bacteria in their MLNs, none of whom were clinically infected, in contrast to 4% of patients operated on for other reasons (Deitch 1989). Low level endotoxemia can be detected in 97% of patients undergoing abdominal surgery (Marshall 1987).
One test for intestinal permeability involves feeding a solution of lactulose and L-rhamnose to patients after an overnight fast. These two sugars have different molecular sizes and therefore pass into the systemic circulation at different rates. A measurement of the ratio of their levels in the urine can serve as a measure of the permeability of the gut. However, slow gut motility will lead to false results on this test. More reliable test results are obtained by using radioactive labeled tracers. Bacterial overgrowth can be determined by culture of the jejunal fluid obtained endoscopically and this procedure has been shown to be more reliable than hydrogen breath testing which also is impacted by delayed motility.
A study of the bacterial overgrowth and intestinal permeability in a group of children with immunodeficiency syndromes indicated that bacterial overgrowth of the small bowel (SBBO) is a common feature in such patients regardless of the source of the immune abnormality and that such patients have an increased gut permeability to macromolecules. All patients with gastrointestinal or atopic symptoms showed abnormal permeability (Pignata 1989).
Normal digestion reduces food compounds to a basic form with proteins degraded to their constituent amino acids before they are absorbed. With increased intestinal permeability, larger molecules (macromolecules) of incompletely digested food may easily pass into the systemic circulation and form soluble immune complexes which are thought to underlie various chronic allergic diseases in which the antigen is seldom ever identified (Paganelli 1979). Atopic (strange) diseases such as eczema, dermatitis, some forms of asthma, psoriatic arthritis, rhinitis, and others are frequently associated with high levels of circulating immune complexes. Arthritis and liver damage are known frequent complications of SBBO which sometimes occur after intestinal bypass surgery for morbid obesity and which resolve with antibiotic therapy. An interesting feature in these cases is that the macromolecule need not be specific, but only present in sufficient amounts (Bjarnason 1987).
Increases in intestinal permeability precede clinical relapses of Crohn's disease with a predictive sensitivity of 81% (Wyatt, 1993). Systemic endotoxemia has been frequently documented in Crohn's disease and ulcerative colitis and correlates positively with the activity of the disease (Gardiner 1992).
CIP patients often exhibit anemia and this is sometimes attributed to malabsorption, but injections of endotoxin into laboratory animals produce a rapid and significant drop in plasma iron and zinc levels with iron levels falling to almost 25% of normal within 30 minutes as plasma levels of lactoferrin increased dramatically after 120 minutes (Gutteberg 1989).
High levels of non-specific auto-antibodies have been found in the blood of CIP patients and it has been suggested that this may serve as an indicator of disease involvement as well as raising the question of whether some forms of CIP are an auto-immune disease. Treatment with Leuprolide Acetate has led to reductions in these auto-antibody levels in some cases. However, a range of autoimmune antibodies which lack specificity that are directed at antigens expressed by enteric epithelial cells has been described with IBD (Jayanthi 1991) and injection of laboratory mice with endotoxin has been shown to produce auto-antibodies and soluble immune complexes in the blood, with individual mice showing marked differences in circulating immune complex responses (Bloembergen).
Low molecular weight LPS of some bacteria mimic the carbohydrate moieties of glycosphingolipids present on human cells. Campylobacter jejuni has been associated with the development of the neurological disorder known as Guillain-Barre Syndrome, and its LPS mimics gangliosides suggesting that cross-reactive antibodies may play an important role in GBS pathogenesis; high antibody titers to glycolipids of human peripheral nerve myelin have been detected in GBS patients (Moran 1996). Similarly, the O-chain of several forms of H pylori mimic the Lewis(x) and Lewis(y) blood group antigens and experimental oral infections in humans have yielded anti-Lewis antibodies suggesting an autoimmune phenomena (Appelmelk 1996). IgG autoantibodies against human antral gastric mucosa have been found in patients that are H pylori positive (Moran 1996) in as many as 65% of infected patients presenting with gastritis where the autoantibody status correlated with the presence and degree of inflammation (Negrini 1996). Endogenous LPS can also be modified in vivo by host substances and secretions resulting in the synthesis of new LPS structures that may mimic human glycolipids and also promote the generation of autoantibodies. Autoimmune disorders of uncertain significance have presented with high titers of antibodies against gastric parietal mucosa cells (Drenth 1995).
So, an argument could be made that a chronic hyperpermeability of the GIT that allows a corresponding chronic exposure in the peripheral circulation to what are normally sequestered protein fragments from food, bacterial endotoxins and their derivatives, as well as self protein released by the sloughing off of the gut epithelial lining during normal mucosal replenishment could lead to autoimmune disease and high levels of circulating autoimmune antibodies.
A 1979 experiment in London showed that while immune complexes were found in the serum of healthy adults after drinking milk, they were rapidly cleared from the circulation; but the levels were higher and more slowly cleared from the system in atopic subjects, producing bronchospasm and skin itching (Paganelli 1979). Paganelli, et. al., suggested that this may be caused by increased antigen entry due to increased gut permeability, and while this is certainly indicated; could the prolonged presence in the circulation be due to a failure of the clearance mechanism? Has the liver been fully appreciated as a contributor to CIP extra-intestinal effects?
If the first line of defense by the intestinal mucosal barrier protecting the organism is breached, then the second line of defense is the liver. Blood bearing digested nutrients leaves the gastrointestinal system and passes through the portal vein to the liver before it enters the systemic circulation. In the liver pass-through, blood filters through the hepatic sinusoids which are lined by Kupffer cells, the fixed macrophages of the liver. Like all other macrophages, these cells clear the blood by ingesting circulating debris. However, also like all other macrophages, they can secrete a number of factors known to alter hepatocyte function and influence other cell types systemically. These factors include: IL-1, tumor necrosis factor alpha (TNF-), PGE-2, toxic oxygen radicals, leukotrienes, platelet activating factor (PAF), interferon, colony stimulating factor, and lysosomal enzymes, all of which can have clinical significance. Some of these substances are pro-inflammatory, vasoactive, and toxic, while others may play roles in the immune defense mechanisms.
Even minute doses of endotoxin produce significant changes in liver sinusoid cells. When a single non-lethal dose of endotoxin is injected into laboratory animals, leukocytes and platelets begin to adhere to the sinusoid lining with the blood flow significantly reduced. Healthy animals recover and develop tolerances to subsequent doses of endotoxin, however animals which have been sensitized and are in a hyperesponsive state have an exaggerated response to the endotoxin and even minute amounts are lethal (McCusky 1987). The priming of macrophages and neutrophils can occur with only one-tenth to one-hundredth of the amount of stimulus required to activate these same cells (Deitch 1992). An initial injury to the Kupffer cells lining the liver sinusoids may impair the ability of the liver to remove what are ordinarily innocuous amounts of endotoxin and this may lead to further hepatocyte damage. Pain in the upper right quadrant (URQ), a hallmark symptom of CIP, could sometimes be due to transient liver swelling from activation by food macromolecules. Liver swelling causes steady aching pain in the URQ, but since the liver has no pain receptors, it is caused by stretching of the liver capsule. Such swelling occurs routinely in acute hepatitis, with alcoholics following a binge, and following injury (Gislason, 1997).
Activation of the Kupffer cells leads to secretion of tumor necrosis factor alpha (TFN-), IL-1, hepatocyte stimulating factor, oxygen radicals, lysosomal enzymes, leukotrienes, and procoagulants. TNF- is a regulatory peptide that can produce most of the biological effects of LPS by itself. It has been characterized as a pro-inflammatory protein and has particular relevance in its ability to recruit circulating inflammatory cells to sites of local tissue inflammation (van Deventer) as well as increasing the permeability of epithelial tight junctions of the GIT (Breese). Increased gut permeability has been linked to neutrophil infiltration and to the production of reactive oxygen metabolites, both of which further degrade tight-junction integrity (Dugan 1995).
If TNF alone is injected, it releases another cascade of mediators such as IL-1, IL-6, leukotrienes, and Platelet Activating Factor (PAF); neutrophil counts decrease precipitously, with the neutrophils becoming activated to release elastase and lactoferrin. TNF- has been found in high concentrations in the stools of children with Crohn's disease, although serum concentrations are low even in patients with very active disease. TNF- is implicated in severe rheumatoid arthritis, which shares immunopathological features with Crohn's disease. Treatment with anti-TNF- antibody has anti-inflammatory effects here as well as reducing or preventing colitis and complete (but transient) remission in Crohn's disease (van Deventer,). IL-1 has CNS effects contributing to GI stasis (Goldstein, 1993).
When LPS was injected in laboratory mice in sub-lethal doses (250 g/kg), systolic blood pressure dropped continuously to approximately 70% of baseline. The animals exhibited severe leukopenia when single high doses were given. LPS enhances the expression of inducible nitric oxide (NO) synthase, leading to the generation of higher levels of NO which is known to relax vascular smooth muscle with corresponding induction of hypotension (Higashi). In hypotensive states, a significant depression of the RES function occurs and decreased liver perfusion is often seen. It has been speculated that low blood pressure can promote endotoxin absorption as well (Nolan, 1975). The enzyme that produces NO is present in the gut where NO acts as a neurotransmitter involved in the regulation of peristalsis (Goldstein, p 161, 1993). A role for excessive NO production in the motility disturbances of the gut has been shown by endotoxin challenge that significantly reduced the spontaneous duodenal intestinal contractions (Whittle 1993). Injecting rats with LPS induced iNOS mRNA expression and enzyme activity in intestinal tissue within two hours. Circulating NO/NO remains elevated for at least 24 hours after LPS injection indicating an enhanced production of NO for a prolonged period (Unno 1997). When LPS is administered to experimental animals, it causes derangement of intestinal barrier function that seems to be dependent on the induction of iNOS, leading to bacterial translocation as well as increased intestinal permeability to various hydrophilic solutes. The macromolecular fluorescent probe, FD4, readily demonstrates increased permeability, and hyperpermeability to this type of macromolecule (mol wt. 4000 daltons) suggests a barrier dysfunction of sufficient magnitude to permit the absorption into the submucosa of potent microbially derived proinflammatory compounds which could contribute to systemic inflammatory responses. This hyperpermeability and translocation is reduced greatly by the selective iNOS inhibitor, aminoguanidine, which has also ameliorated colonic inflammation in a model of chronic inflammatory bowel disease (Unno 1997). The overproduction of NO has been implicated as a factor in the development of ileus during endotoxemia (Wirthlin 1996). The prolonged overexposure to NO after LPS challenge may lead to inhibition of mitochondrial respiration, ATP depletion, and increase of [Ca], and ultimately loss of cellular viability (Unno 1997).
The kidney may be vulnerable since overproduction of nitric oxide may lead to impairment of cGMP-associated vasodilatation and disrupt autoregulation of the renal vascular bed (Inan 1997). In fact, there is a new appreciation that polycystic kidney disease (PKD) may be an emerging infectious disease in a vulnerable human subpopulation since analysis of kidney cyst fluid confirmed the presence of 3-hydroxy fatty acids characteristic of endotoxin (Miller-Hjelle 1997), and like in the liver, a cytokine response, which is thought to play important roles in the pathophysiology of chronic kidney disorders, including glomerulonephritis, occurs in the kidney from bacterial endotoxin in which TNF-alpha acts as a primary cytokine capable of stimulating additional cytokines, including IL-6 (Kayama).
Other recent work has shown endotoxins to have a direct effect on the pituitary gland. Endotoxin in very small quantities (400 ng/kg i.v.) increased plasma GH, ACTH, cortisol, and prolactin, while it decreased luteinizing hormone (LH) pulse frequency in sheep. It also led to increases of ACTH and LH in vitro (Coleman 1993). This is mindful of John Mathias' work showing that an increase of LH significantly alters the migrating myoelectric complex of the small intestine (Ducker 1993) as well as his suggestion that the successful use of Leuprolide Acetate in ameliorating the symptoms of Functional Bowel Disease might involve the autonomic centers of the CNS (Ducker 1993).
When peripheral macrophages are activated by low doses of LPS given i.p., IL-1 beta is produced and acts as a hormonal signal to stimulate corticotropin-releasing hormone (CRH) secretion. Brain endothelial cells are activated as well to produce IL-1, IL-6, prostaglandins, and other substances that affect CRH neurons which show IL-1 induced IL-1 production, thereby amplifying and prolonging the intracerebral IL-1 signal to activate the hypothalamic-pituitary-adrenal (HPA) axis producing changes in thermoregulation and the chronic low fever associated with endotoxin (Tilders 1994). Furthermore, it has been shown that low levels of CRH can sensitize the pituitary gland to the direct ACTH releasing activity of IL-1 and therefore could represent an interactive point between the nervous, endocrine, and immune systems whereby a mild psychological or physical stress may have a profound impact on inflammatory responses (Payne 1994). A single exposure to IL-1 beta can produce long term changes in the HPA axis of adult male rats with a delayed and long-lasting hyperproduction, hyperstorage, and hypersecretion of vasopressin from hypothalamic CRH neurons that results in hyper-responsiveness of the HPA axis to subsequent stimuli. (Schmidt 1995).
Research in Sudden Infant Death Syndrome (SIDS) has shown that i.v. injected endotoxins isolated from SIDS baby feces alter rabbit catecholamine levels with sharp rises in adrenaline and noradrenaline. Behavioral changes ranging from reduced appetite to diarrhea occurred when the same toxins were injected into any areas of the GIT, but without the changes in catecholamine level observed from the i.v. injections, leading to speculation that conditions that might promote this toxin’s release from a hyperpermeable gut could result in SIDS (Siarakas). Similar mechanisms could alter catecholamine levels in CIP patients.
Chronic exposure to endotoxins induces emphysematous lung injury in some animal models. Rabbits injected with E. coli LPS develop changes in the polymorphonuclear leukocytes (PMN) which results in the release of greater quantities of immature PMN that are less deformable and are sequestered in the lungs as a result of the difference between the PMN size and microcapillary size leading to leukopenia (Klut 1996). Leukopenia can also be produced by the elevated TNF and LTB4 which can act as chemoattractants contributing to the lung leuko-sequestration and injury (Simons RK, Maier RV, Lennard ES, 1987). Gut decontamination lowered the endotoxin pool in laboratory animals and resulted in a lowering of the LPS, TNF and subsequent lung injury when intestinal ischemia was induced (Sorkine 1997).
Thus, evidence is available that the gastrointestinal tract may be involved in injury at remote sites due to translocation of bacteria and endotoxins and their derivatives that may be reflected by the numerous extra-intestinal complications reported by patients with CIP and other inflammatory bowel diseases. It seems reasonable that a vicious cycle is possible with an initial insult to the gut producing hyperpermeability and the resulting cascade of macromolecules, bacteria, endotoxins, and chemical mediators further increasing the permeability and inflammation leading to continued permeability and hypomotility, potentiating the further translocation of intestinal endotoxin and so on in a circle of self-sustaining events.
Summary:
A hypothesis can be presented that offers biological explanations for many of the extra-intestinal manifestations of CIP. The slow transit of intestinal contents characteristic of CIP is known to produce small bowel bacterial overgrowth (SBBO). SBBO causes increased intestinal permeability which could allow a greater presentation of gut endotoxins (LPS) to overwhelm the liver's clearance ability, spilling endotoxins into the peripheral circulation with the corresponding characteristic soreness of lymph nodes, mild fever, and redness of all mucosal membranes (mouth, vagina, and rectum); and lowering of serum iron and zinc. Pain in the URQ may result from transient liver swelling. Atopic diseases can result from the simultaneous release of incompletely digested food macromolecules (in particular, incomplete proteins) by the hyperpermeable gut. Such chronic exposure in the peripheral circulation to normally sequestered protein fragments could lead to autoimmune disease and high levels of circulating autoimmune antibodies. The chronic mild endotoxemia likely causes an elevated TNF and IL-1, enhancing neutrophil chemoattraction and infiltration and further increasing permeability and inflammation.Changes in pituitary and other brain hormones and functions as well as activation of the HPA axis may occur with new homeostasis set-points involving CRH neurons. Excess NO due to LPS activation of NO synthase leads to hypotension, GIT barrier dysfunction, GIT dysmotility, and kidney dysfunction. Elevated TNF and LTB4 can cause the release of immature PMN into the bloodstream which are sequestered in the lungs reflecting the leukopenia and emphysematous lung destruction.
Resources:
TNF can be measured in a sandwich-type enzyme-linked immunosorbent assay (ELISA), from T Cell Science, Cambridge, Massachusetts, or Asahi Chemical Industry America, Inc., 350 Fifth Ave., NY, NY 10118.
Plasma endotoxin concentrations can be quantitated by the chromogenic limulus amebocyte lysate (LAL) technique in the LS-1 kit (Seikagaku Corporation, Tokyo, Japan), (Whittaker M.A. Bioproducts, Walkersville, MD). Associates of Cape Cod, Inc. has several choices of LAL test kits: 800-848-3248, http://www.acciusa.com/, e-mail--accinc@acciusa.com
Intestinal SIgA can be measured by stool sample by Diagnos-Techs, Inc., 6620 So 192nd Pl., J-104, Kent, WA 98032-1948, 800-87-TESTS (800-878-3787). They have a very elaborate and informative Laboratory Manual dealing with many non-invasive tests relating to intestinal function available to physicians on request.
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