Chronic intestinal pseudo-obstruction

Chronic intestinal pseudo-obstruction (CIPO) is a severe functional digestive syndrome characterised by a derangement of gut propulsive motility which resembles mechanical obstruction. It may be associated with disabling and potentially life-threatening complications. CIPO can be secondary to a variety of diseases, but it is more frequently idiopathic. Most cases are sporadic, but familial forms have also been described. Based on histological features CIPO can be classified into three major entities: neuropathies, mesenchymopathies, and myopathies depending on the predominant involvement of enteric neurones, interstitial cells of Cajal (ICC) or smooth muscle cells, respectively. Mitochondriopathies may be responsible for a syndromic form of CIPO, i.e. mitochondrial neurogastrointestinal encephalomyopathy. Management of CIPO involves nutritional, pharmacological and surgical therapies, but the long-term outcome turns out to be poor in the vast majority of cases. The main pathogenetic and clinical features of the syndrome, together with current management recommendations are reviewed in this chapter.     

Chronic intestinal pseudo-obstruction

Chronic intestinal pseudo-obstruction (CIPO) is a disease characterized by episodes resembling mechanical obstruction in the absence of organic, systemic, or metabolic disorders. Pseudo-obstruction is an uncommon condition and can result from primary (40%) or secondary (60%) causes. The most common symptoms are nausea, vomiting, abdominal distension, abdominal pain and constipation or diarrhea. These symptoms are usually present many years before CIPO diagnosis. They can lead to severe electrolyte disorders and malnutrition. Principles for management of patients with CIPO are: to establish a correct clinical diagnosis in excluding mechanical obstruction; to perform a symptomatic and physiologic assessment of the gastrointestinal tract involved; to look for extra-intestinal manifestations, especially for myopathy and neuropathy; to discuss in some cases a surgery for full-thickness intestinal biopsies, and/or a neuromuscular biopsy in case of mitochondrial cytopathy suspicion. The management is primarily focused on symptom control and nutritional support to prevent weight loss and malnutrition. Treatment of CIPO includes prokinetic agents which may help to reduce gastrointestinal symptoms Courses of antibiotics may be needed in patients with symptoms suggestive of bacterial overgrowth. When necessary, enteral nutrition is preferred. In carefully selected patients, feeding jejunostomy with or without decompression gastrostomy may be tried. Long term parenteral nutrition should be reserved for patients who can not tolerate enteral nutrition. Intestinal transplantation can be discussed in selected patients.     

Chronic intestinal pseudo-obstruction]

Chronic intestinal pseudo-obstruction (CIPO) is a syndrome characterized by the presence of recurrent episodes of clinical intestinal obstruction in the absence of obstructive lesions. Although this syndrome is rare, it causes a high morbidity. It is caused by a disturbance of the intestinal motility, that results in a failure of the progression of the intestinal content. Basically, the failure of the intestinal motility is a consequence of muscular disorder, neurological disorder or both. Usually, CIPO is secondary to other systemic disease; however, in the last years, many cases of primary CIPO have been described. The use of new manometric tecniques and specific histological procedures have allowed to clarify the pathogenesis of some of these entities including mitochondrial diseases and paraneoplasic syndromes. Clinical manifestations of CIPO are diverse, depending on the location and extension of the motility disorder. As the diagnosis of this disease is usually not an easy task, patients frecuently undergo unnecesary surgical interventions, are diagnosed of psyquiatric disorders, or the correct diagnosis is delayed several years after the first symptoms arise. The aims of the treatment are to maintain the nutritional condition and to improve symptoms using nutritional measures, drugs or, eventually, endoscopical or surgical procedures.     

Pitfalls in diagnosing mitochondrial neurogastrointestinal encephalomyopathy

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase and is characterized by external ophthalmoparesis, gastrointestinal dysmotility, leukoencephalopathy, and neuropathy. The availability of new therapeutic options (peritoneal dialysis, allogeneic stem cell transplantation, enzyme replacement) makes it necessary to diagnose the disease early, which is not always achieved due to the difficulty in recognizing this disorder, especially in case of atypical presentation. We describe three MNGIE patients with atypical onset of the disease. In the first patient the main symptoms were long-standing chronic fever, recurrent acute migrant arthritis, and gastrointestinal disorders mimicking autoimmune or inflammatory intestinal diseases; the second patient complained only of exercise intolerance and muscle cramps, and the third patient had a CIDP-like polyneuropathy. This study stresses the insidious heterogeneous clinical onset of some cases of MNGIE, expands the spectrum of the phenotype, and suggests considering MNGIE in the differential diagnosis of enteropathic arthritis, isolated exercise intolerance, and inflammatory polyneuropathies not responsive to the usual treatment. A better understanding of the clinical heterogeneity of MNGIE is necessary in order to diagnose atypical cases and promote early diagnosis, which is now absolutely necessary in view of the new available therapies.     

Chronic Intestinal Pseudo-obstruction with Mitochondrial Diseases

Chronic intestinal pseudo-obstruction (CIPO) is a rare disorder of intestinal dysmotility characterized by chronic symptoms, including vomiting and abdominal pain, associated with bowel obstruction without any mechanical obstructive causes. We herein report a case of mitochondrial diseases with recurrent duodenal obstruction that was initially diagnosed as superior mesenteric artery syndrome (SMAS) for a few years but was later diagnosed as CIPO. Since CIPO is known to be associated with mitochondrial diseases, it should be considered in the differential diagnosis of patients with mitochondrial diseases presenting with recurrent intestinal obstruction.     

Octreotide treatment of chronic intestinal pseudoobstruction secondary to connective tissue diseases

Chronic intestinal pseudoobstruction (CIPO) is a rare syndrome that may occur in association with connective tissue diseases (CTD). Effective management is a major challenge. We report 3 cases in which subcutaneous octreotide was efficacious in the treatment of digestive symptoms in CIPO. In 2 of the 3 cases, previous treatment with domperidone, cisapride, or erythromycin had been unsuccessful. All 3 patients underwent a regimen of oral antibiotics along with octreotide to stimulate small bowel motility. The effects of octreotide were evident within 48 hours after the first injection in all patients. In 2, the efficacy seemed to decrease after 1 week and 6 months respectively, but increasing the dosage led to another remission. CIPO in CTD is a severe condition that can evolve regardless of the underlying disease activity. Octreotide appears to be efficacious in improving both clinical symptoms and manometric patterns. When its therapeutic effect diminishes, increasing the dosage can be useful.     

Chronic intestinal pseudo-obstruction

Chronic intestinal pseudo-obstruction （CIPO） is a severe digestive syndrome characterized by derangement of gut propulsive motility which resembles mechanical obstruction, in the absence of any obstructive process. Although uncommon in clinical practice, this syndrome represents one of the main causes of intestinal failure and is characterized by high morbidity and mortality. It may be idiopathic or secondary to a variety of diseases. Most cases are sporadic, even though familial forms with either dominant or recessive autosomal inheritance have been described. Based on histological features in- testinal pseudo-obstruction can be classified into three main categories：neuropathies, mesenchymopathies, and myopathies, according on the predominant involvement of enteric neurones, interstitial cells of Cajal or smooth muscle cells, respectively. Treatment of intestinal pseu- do-obstruction involves nutritional, pharmacological and surgical therapies, but it is often unsatisfactory and the long-term outcome is generally poor in the majority of cases.     

Mitochondrial neurogastrointestinal encephalomyopathy: evidence of mitochondrial DNA depletion in the small intestine

BACKGROUND & AIMS: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease clinically defined by gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy, white-matter changes in brain magnetic resonance imaging, and mitochondrial abnormalities. Loss-of-function mutations in thymidine phosphorylase gene induce pathologic accumulations of thymidine and deoxyuridine that in turn cause mitochondrial DNA (mtDNA) defects (depletion, multiple deletions, and point mutations). Our study is aimed to define the molecular basis of gastrointestinal dysmotility in a case of MNGIE. METHODS: By using laser capture microdissection techniques, we correlated histologic features with mtDNA abnormalities in different tissue components of the gastrointestinal wall in a MNGIE patient and ten controls. RESULTS: The patient's small intestine showed marked atrophy and mitochondrial proliferation of the external layer of muscularis propria. Genetic analysis revealed selective depletion of mtDNA in the small intestine compared with esophagus, stomach, and colon, and microdissection analysis revealed that mtDNA depletion was confined to the external layer of muscularis propria. Multiple deletions were detected in the upper esophagus and skeletal muscle. Site-specific somatic point mutations were detected only at low abundance both in the muscle and nervous tissue of the gastrointestinal tract. Analysis of the gastrointestinal tract from 10 controls revealed a non-homogeneous distribution of mtDNA content; the small intestine had the lowest levels of mtDNA. CONCLUSION: Atrophy, mitochondrial proliferation, and mtDNA depletion in the external layer of muscularis propria of small intestine indicate that visceral myopathy is responsible for gastrointestinal dysmotility in this MNGIE patient.     

Chronic primary intestinal pseudo-obstruction from visceral myopathy.

Chronic intestinal pseudo-obstruction is an uncommon syndrome characterized by relapsing episodes suggesting intestinal obstruction during which no mechanical causes are identified to account for symptoms. Etiologic factors may be manifold. Among them a number of neurologic conditions, gastrointestinal smooth muscle myopathies, endocrino-metabolic and autoimmune diseases, and the use of selected drugs stand out. We report a case of chronic intestinal pseudo-obstruction originating in a sporadic, primary intestinal myopathy that corresponds to no type thus far described. A histological study of the intestinal wall showed disrupted muscle bundles and the presence of interstitial edema. Myocytes had severe degenerative changes, and no alterations were seen in submucosal and myenteric plexus neurons. The activity of enzyme complexes in the mitochondrial respiratory chain, and of thymidine phosphorylase was normal. No mitochondrial DNA changes were seen.     

Chronic intestinal pseudo-obstruction in systemic lupus erythematosus

Background/Aims—Chronicintestinal pseudo-obstruction (CIPO) reflects a dysfunction of thevisceral smooth muscle or the enteric nervous system. Gastrointestinalmanifestations are common in systemic lupus erythematosus (SLE)but CIPO has not been reported. Features of CIPO are reported in fivepatients with SLE.
Methods—From 1988 to1993, five patients with SLE or SLE-like syndrome were hospitalised forgastrointestinal manometric studies. CIPO was the onset feature in twocases. Antroduodenal manometry (three hours fasting, two hours fed) wasperformed in all patients, and oesophageal manometry in four.
Results—Intestinalhypomotility associated with reduced bladder capacity and bilateralureteral distension was found in four patients and aperistalsis of theoesophagus in three. Treatment, which consisted of high dosecorticosteroids, parenteral nutrition, promotility agents, andantibiotics, led to remission of both CIPO and urinary abnormalities inall cases. Antroduodenal manometry performed in two patients afterremission showed increased intestinal motility. One patient died, andpostmortem examination showed intestinal vasculitis.
Conclusions—CIPO inSLE is a life threatening situation that can be reversed by treatment.It may be: (a) a complication or onsetfeature of the disease; (b) secondary tosmooth muscle involvement; (c) associatedwith ureteral and vesical involvement; (d)the result of intestinal vasculitis.

Keywords:chronic intestinal pseudo-obstruction; systemiclupus erythematosus

     

Generalized megaviscera of lupus： Refractory intestinal pseudo-obstruction, ureterohydronephrosis and megacholedochus

Dilated dysfunction involving multiple visceral organs has been reported in patients with systemic lupus erythematosus （SLE）. Chronic intestinal pseudoobstruction （CIPO） resulting from intestinal smooth muscle damage has presented in conjunction with ureterohydronephrosis and, more rarely, biliary dilatation （megacholedochus）. While the molecular pathogenesis is largely unknown, observed histopathologic features include widespread myositis, myocyte necrosis in the intestinal muscularis propria with subsequent atrophy and fibrosis, preserved myenteric innervations and little vasculitis. High dose immunosuppression usually results in resolution of symptoms with recovery of smooth muscle function, indicative of an autoimmune etiology. We report a patient with SLE who presented with intestinal pseudo-obstruction, ureterohydronephrosis and megacholedochus, and present images that illustrate megaviscera simultaneously involving all 3 visceral organs. Since the co-manifestation of all 3 is unusual and has been reported only once previously, we have termed this rare clinical syndrome generalized megaviscera of lupus （GML）. Although the SLE disease-activity parameters responded to aggressive immunomodulative therapy in our patient, clinical evidence of peristaltic dysfunction persisted in all involved viscera. This is a variation from the favorable outcomes reported previously in SLE patients with GML and we attribute this poor clinical outcome to disease severity and, most importantly, delayed clinical presentation. Since inflammation followed by atrophy and fibrosis are key aspects in the pathogenesis and natural history of GML, the poor response in our patient who presented late in the clinical course may be the result of ＇burnt out＇ inflammation with irreversible end-stage fibrosis. Thus, early recognition and timely initiation of treatment may be the key to recover visceral peristaltic function in patients with GML.     

干燥综合征合并慢性假性肠梗阻的临床特征分析

背景:干燥综合征(SS)合并慢性假性肠梗阻(CIPO)临床上较罕见,早期易误诊漏诊。目的:通过分析SS合并CIPO的临床特征,以期为SS合并CIPO的诊治提供参考。方法:纳入2005年1月～2012年12月于浙江省嘉兴市第一医院住院或门诊确诊的SS合并CIPO患者3例,采集患者临床资料,回顾性分析SS合并CIPO患者的临床特征。结果:3例SS合并CIPO患者中,1例以CIPO为首发症状,3例抗核抗体(+)、3例抗SSA抗体(+)、1例抗SSB抗体(+)、1例抗线粒体抗体(+)、1例抗平滑肌抗体(+),3例患者均有雷诺现象,1例双下肢有可触性紫癜,3例均有高球蛋白血症和IgG、IgM、IgA增高,3例患者接受大剂量糖皮质激素联合免疫抑制剂治疗,治疗反应良好。结论:CIPO是SS的一种罕见并发症,早期诊断、及时使用大剂量糖皮质激素联合免疫抑制剂治疗对于控制病情至关重要。     

Chronic intestinal pseudo-obstruction

Chronic intestinal pseudo-obstruction (CIPO) is a syndrome defined by the presence of chronic intestinal dilation and dysmotility in the absence of mechanical obstruction or gross inflammatory disease. Specific diseases may affect any level of the brain-gut axis. For most patients, the diagnosis relies upon a combination of historical, laboratory, manometric and histological features. Recent advances into the autoimmune nature of etiologies such as Chagas' disease and paraneoplastic dysmotility and into the genetic basis of mitochondrial neurogastrointestinal encephalomyopathy, multiple endocrine neoplasia IIB and Hirschsprung's disease have greatly refined our understanding and diagnosis of these disorders. At present, medical therapy of CIPO remains limited. Current and future developments in pharmacologic agents targeting specific enteric neurotransmitters and motility patterns hold much promise for improving the care of the patients afflicted with this complex and often debilitating syndrome.     

Deoxyuridine accumulation in urine in thymidine phosphorylase deficiency (MNGIE)

We report the presence of the unusual nucleoside deoxyuridine in the urine of a patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) (MIM 603041) due to thymidine phosphorylase (TP:EC 2.4.2.4) deficiency. Thymidine, uracil and thymine were also elevated. We propose that inhibition of thymidylate synthetase by TMP leads to the accumulation of dUMP which may be degraded to deoxyuridine or metabolised to dUTP. Incorporation of dUTP into mtDNA may explain the multiple deletions characteristic of TP deficiency.     

Autonomic dysfunction presenting as orthostatic intolerance in patients suffering from mitochondrial cytopathy

Background

Disturbances in autonomic nervous system function have been reported to occur in patients suffering from mitochondrial cytopathies. However, there is paucity of literature on the occurrence of orthostatic intolerance (OI) in these patients. We report on a series of patients diagnosed with mitochondrial cytopathy who developed features of autonomic dysfunction in the form of OI.

Methods

This was a single‐center report on a series of 6 patients who were followed in our clinic for orthostatic intolerance. All of these patients had a diagnosis of mitochondrial cytopathy on the basis of muscle biopsy and were being followed at a center specializing in the treatment of mitochondrial disorders. This study was approved by our local institutional review board. Each of the patients had suffered from symptoms of fatigue, palpitations, near syncope, and syncope. The diagnosis of OI was confirmed by head‐up tilt test. Collected data included demographic information, presenting symptoms, laboratory data, tilt‐table response, and treatment outcomes.

Results

Six patients (3 females) were identified for inclusion in this report. The mean age of the group was 48 ± 8 years (range, 40–60 years). All of these patients underwent head‐up tilt table testing and all had a positive response that reproduced their clinical symptoms. Among those having an abnormal tilt‐table pattern, 1 had a neurocardiogenic response, 1 had a dysautonomic response, and 4 had a postural orthostatic tachycardia response. All but 1 patient reported marked symptom relief with pharmacotherapy. The patient who failed pharmacotherapy received a dual‐chamber closed‐loop pacemaker and subsequently reported marked improvement in her symptoms with elimination of her syncope.

Conclusions

Orthostatic intolerance might be a significant feature of autonomic nervous system dysfunction in patients suffering from mitochondrial cytopathy. Copyright © 2010 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose.     

Chronic intestinal pseudo-obstruction associated with biliary tract dilatation in a patient with systemic lupus erythematosus

We present the case of a 57-year old female patient diagnosed with systemic lupus erythematosus (SLE) along with glomerulonephritis and chronic intestinal pseudo-obstruction (CIPO). Dilatation of bile and pancreatic ducts not associated with malignant or litiasic obstruction is reported. The combination of bile duct associated with CIPO in a patient with lupus has not been previously reported in the literature and it probably suggests a smooth muscle dysmotility.     

Mitochondrial diseases represent a risk factor for valproate‐induced fulminant liver failure

Abstract: We report on 3 siblings (2 females and 1 male) with chronic progressive external ophthalmoplegia (CPEO), compatible with inherited mitochondrial cytopathy. The younger of the two sisters died at the age of 37 due to progressive respiratory failure. The older one presented with a status epilepticus at the age of 39 and was treated with valproate. Five months after the start of treatment, she developed fulminant liver failure and died. The brother has suffered from CPEO since early childhood but has had so far no other symptoms of a mitochondrial disease. A muscle biopsy from the younger sister revealed ragged‐red fibers and decreased activities of complex I and IV of the respiratory chain but no pathogenic mutations in the mitochondrial tRNA genes or in several locations in the coding region of the mitochondrial genome. In the older sister's liver (obtained post‐mortem), mitochondrial DNA was fragmented and could not be investigated. The clinical presentation and the biochemical findings suggest that all 3 siblings suffered from a mitochondrial cytopathy. Since mitochondrial cytopathies and valproate‐induced fulminant liver failure are both rare events, an association between them is likely. Mitochondrial diseases should therefore be considered as a risk factor for valproate‐induced liver failure and be excluded before treatment with valproate.     

汞中毒92例临床分析

目的 总结经血、尿毒检确诊为汞中毒的92例患者的临床诊治特点,以提高该病的诊治水平.方法 对2000年1月至2010年4月我院住院诊治的92例汞中毒患者的原因、临床表现、诊治及预后情况进行回顾性分析.结果 92例(男37例,女55例)患者平均发病年龄33.1(2～65)岁,因职业性接触、生活性接触(医源性、生活、误服或自杀)含汞物质所致,主要经呼吸道、消化道和皮肤吸收而中毒.其受累系统有神经系统,表现为记忆力减退50例(54.3%)、乏力34例(37.0%)、四肢麻木25例(27.2%)、眩晕头痛22例(23.9%)、感觉异常20例(21.7%)、细小震颤(指端、舌尖、眼睑)15例(16.3%)、失眠多梦12例(13.O%);消化系统:恶心16例(17.4%)、腹痛14例(15.2%)、口腔炎5例(5.4%);关节肌肉:肌痛16例(17.4%)、关节酸痛5例(5.4%);心血管系统:胸闷、心悸6例(6.5%);泌尿系统:水肿9例(9.8%);其他系统:多汗20例(21.7%).经驱汞治疗后,患者各系统症状、体征逐渐缓解,其消化系统和心血管系统症状2周内缓解;神经系统症状3个月内缓解;肾脏损害恢复较慢,在6个月内也可临床完全缓解.结论 汞中毒临床表现多样,易被误诊、漏诊,故需进一步提高对此病的认识.及时脱离汞中毒环境,并行驱求治疗,预后较好.

Abstract：

Objective To summarize the clinical features of mercury poisoning diagnosed by blood and urine tests for improving the diagnosis and treatment of the disease.Methods Poisoning causes,clinical manifestations,diagnosis,treatment and prognosis were retrospectively reviewed in 92 in-patients with mercury poisoning in our hospital from January 2000 to April 2010.Results Of the 92 patients,37 were male and 55 were female with an average age of 33.1(2-65)years old.The mercury poisoning was caused by occupational exposure and non-occupational exposure,such as iatrogenic exposure,life exposure and wrong intake or suicidal intake of mercury-containing substances,mainly through respiratory tract,digestive tract and skin absorption.The most common clinical symptoms were as the followings:nervous system symptom,such as memory loss in 50 eases(54.3%),fatigue in 34(37.0%),numb limb in 25 (27.2%),dizziness and headache in 22(23.9%),cacesthesia in 20(21.7%),fine tremor(finger tip,tongue tip,eyelids)in 15(16.3%),insomnia and more dreams in 12(13.0%);gastrointestinal symptoms:nausea in 16 (17.4%),abdominal pain in 14(15.2%),stomatitis in 5(5.4%);joint and muscle symptoms:muscle pain in 16(17.4%),joint pain in 5(5.4%);cardiovaseular system:chest tightness,hean palpitations in 6(6.5%);urinary system:edema in 9(9.8%);other system:hidrosis in 20(21.7%).After the treatment with sodium dimercaptopropane sulfonate (DMPS),the symptoms were gradually alleviated.Their gastrointestinal,cardiovascular symptoms were alleviated within 2 weeks;neurological symptoms were alleviated within 3 months;kidney damage showed a slower recovery and could be completely'alleviated within 6 months.Conclusions Because of its diverse clinical symptoms,the mercury poisoning was easy to misdiagnosis and missed diagnosis:therefore the awareness of the disease should be further enhanced.Leaving from the poisoning environment timely and giving appropriate treatment with DMPS will lead to a satisfactory prognosis.     

Intestinal transplantation in children with chronic intestinal pseudo-obstruction

BACKGROUND: Children with chronic intestinal pseudo-obstruction (CIPO) often require total parenteral nutrition (TPN) which puts them at risk of liver failure and recurrent line infections. Intestinal transplantation has become a therapeutic option for TPN dependent children with intestinal failure who are failing management with TPN. AIMS: To investigate the outcome of children with CIPO referred for intestinal transplantation. METHODS: A retrospective review was carried out of records and diagnostic studies from 27 patients with CIPO referred for intestinal transplantation. RESULTS: Five children were not listed for transplantation: two because of parental decision, two because of suspicion of Munchausen syndrome by proxy, and one because he tolerated enteral nutrition. Six are still TPN dependent and awaiting transplantation. Eight children died awaiting transplantation. Eight children underwent transplantation. Three died (two months, seven months, and four years after transplant). Five children are alive with a median follow up of 2.6 years (range two months to six years). All transplanted children were able to tolerate full enteral feedings. The postoperative course was complicated by dumping syndrome, Munchausen syndrome by proxy, narcotic withdrawal, and uncovering of achalasia. Conclusion-Intestinal transplantation may be a life saving procedure in children with CIPO. Early referral and thorough pretransplant evaluation are keys to successful transplantation.