Brief Article
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Sep 7, 2012; 18(33): 4557-4562
Published online Sep 7, 2012. doi: 10.3748/wjg.v18.i33.4557
Characteristics of intestinal pseudo-obstruction in patients with mitochondrial diseases
Yusuke Sekino, Masahiko Inamori, Eiji Yamada, Hidenori Ohkubo, Eiji Sakai, Takuma Higurashi, Hiroshi Iida, Kunihiro Hosono, Hiroki Endo, Takashi Nonaka, Hirokazu Takahashi, Tomoko Koide, Yasunobu Abe, Eiji Gotoh, Shigeru Koyano, Yoshiyuki Kuroiwa, Shin Maeda, Atsushi Nakajima
Yusuke Sekino, Masahiko Inamori, Eiji Yamada, Hidenori Ohkubo, Eiji Sakai, Takuma Higurashi, Hiroshi Iida, Kunihiro Hosono, Hiroki Endo, Takashi Nonaka, Hirokazu Takahashi, Tomoko Koide, Yasunobu Abe, Shin Maeda, Atsushi Nakajima, Gastroenterology Division, Yokohama City University School of Medicine, Yokohama 236-0004, Japan
Eiji Gotoh, Department of Medical Education, Yokohama City University School of Medicine, Yokohama 236-0004, Japan
Shigeru Koyano, Yoshiyuki Kuroiwa, Department of Neurology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan
Author contributions: Sekino Y, Inamori M, Iida H, Nonaka T and Nakajima A performed the majority of clinical and treatment data collection; Takahashi H, Koide T, Abe Y, Gotoh E, Kuroiwa Y and Maeda S were involved in the editing of the manuscript; Yamada E, Ohkubo H, Sakai E, Higurashi T, Hosono K and Endo H analyzed the clinical data and participated in the design and coordination of the study; Sekino Y, Inamori M, Iida H, Nonaka T, Koyano S and Nakajima A designed the study and wrote the manuscript.
Supported by Health and Labour Sciences Research Grants for Research on Intractable Diseases, awarded to Nakajima A, from the Ministry of Health, Labour and Welfare of Japan
Correspondence to: Dr. Masahiko Inamori, Gastroenterology Division, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. inamorim@med.yokohama-cu.ac.jp
Telephone: +81-45-7872640 Fax: +81-45-7843546
Received: December 30, 2011
Revised: March 9, 2012
Accepted: March 20, 2012
Published online: September 7, 2012

Abstract

AIM: To reveal the frequency, characteristics and prog-nosis of chronic intestinal pseudo-obstruction (CIP) in mitochondrial disease patients.

METHODS: Between January 2000 and December 2010, 31 patients (13 males and 18 females) were diagnosed with mitochondrial diseases at our hospital. We conducted a retrospective review of the patients’ sex, subclass of mitochondrial disease, age at onset of mitochondrial disease, frequency of CIP and the age at its onset, and the duration of survival. The age at onset or at the first diagnosis of the disorder that led to the clinical suspicion of mitochondrial disease was also examined.

RESULTS: Twenty patients were sub-classified with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), 8 with chronic progressive external ophthalmoplegia (CPEO), and 3 with myoclonus epilepsy associated with ragged-red fibers (MERRF). Nine patients were diagnosed with CIP, 8 of the 20 (40.0%) patients with MELAS, 0 of the 8 (0.0%) patients with CPEO, and 1 of the 3 (33.3%) patients with MERRF. The median age (range) at the diagnosis and the median age at onset of mitochondrial disease were 40 (17-69) and 25 (12-63) years in patients with CIP, and 49 (17-81) and 40 (11-71) years in patients without CIP. During the survey period, 5 patients (4 patients with MELAS and 1 with CPEO) died. The cause of death was cardiomyopathy in 2 patients with MELAS, cerebral infarction in 1 patient with MELAS, epilepsy and aspiration pneumonia in 1 patient with MELAS, and multiple metastases from gastric cancer and aspiration pneumonia in 1 patient with CPEO.

CONCLUSION: Patients with CIP tend to have disorders that are suspected to be related to mitochondrial diseases at younger ages than are patients without CIP.

Key Words: Chronic intestinal pseudo-obstruction, Criteria, Mitochondrial disease, Mitochondrial encephalopathy, Lactic acidosis, Stroke-like episodes, Chronic progressive external ophthalmoplegia


Citation: Sekino Y, Inamori M, Yamada E, Ohkubo H, Sakai E, Higurashi T, Iida H, Hosono K, Endo H, Nonaka T, Takahashi H, Koide T, Abe Y, Gotoh E, Koyano S, Kuroiwa Y, Maeda S, Nakajima A. Characteristics of intestinal pseudo-obstruction in patients with mitochondrial diseases. World J Gastroenterol 2012; 18(33): 4557-4562
INTRODUCTION

Intestinal pseudo-obstruction was first reported by Dudley et al[1] in 1958, and refers to an uncommon disabling motility syndrome characterized by severe symptoms and signs of intestinal obstruction (abdominal pain, abdominal distention, nausea, and vomiting) and radiographic evidence of a dilated bowel in the absence of any mechanical obstruction. Pseudo-obstruction is primarily considered a small-intestine motility disorder, but it may occur in any portion of the gastrointestinal tract[2-6]. Furthermore, pseudo-obstruction may occur as an acute disease (Ogilvie syndrome[7]) or as a chronic remitting or persistent disorder, and chronic intestinal pseudo-obstruction (CIP) can be caused by and complicate many disorders[2]. Primary CIP can be sub-classified into visceral myopathy, visceral neuropathy and idiopathic CIP based on its histopathological manifestations. According to its etiology, secondary CIP can be categorized as disease-induced (such as connective tissue disorders, muscular dystrophies, infiltrative diseases, mitochondrial diseases, generalized nerve disease, endocrine disease, metabolic disease and others)[8-12] or drug-induced (antidepressant and anti-anxiety drugs, phenothiazines and others)[13-16].

Although an algorithm for the diagnosis of CIP was proposed by Rudolph et al[2] in 1997, diagnostic criteria for CIP have not yet been established in Japan or worldwide. Recently, Iida et al[17] proposed the diagnostic criteria for CIP shown in Table 1 and reported a diagnostic sensitivity of 85.9%.

Table 1 Criteria for the diagnosis of chronic intestinal pseudo-obstruction.
Must include
One or more symptoms of ileus1 onset at least 6 mo prior to diagnosis
One or both of following for the last 12 wk: (1) Abdominal pain; (2) Abdominal bloating
Dilatation and/or air-fluid levels of the intestine on abdominal X-ray, echo and/or computed tomography imaging
No evidence of structural disease (including findings of upper endoscopy, lower endoscopy, computed tomography, barium enema, and small-bowel follow-through) that could explain dilatation and/or air-fluid levels of the intestine
Supportive criteria
Congenital and/or onset under 15 years old must be excluded. Only adult onset is included
Surgical history within the 6 mo prior to diagnosis must be excluded to rule out Ogilvie syndrome, except surgery for CIP
To define CIP at two levels: Primary CIP or secondary CIP. Primary CIP consists of three types: the muscular type, neurogenic type and idiopathic type; Secondary CIP consists of two types: the systemic sclerosis (SSc) type and unclassified type
Family accumulation may exist
Neuropathy such as problems with urination may exist
Some psychosocial disorder may be present

Mitochondrial diseases are a heterogeneous group of disorders associated with mutations or deletions of nuclear or mitochondrial DNA[18-22]. Genetic mutations or deletions result in multisystem involvement associated with defects in the oxidative phosphorylation system and impaired production of ATP. The degree of organ dysfunction is contingent on the energy requirement of the organ and the proportion of mutated mitochondrial DNA in the organ[18]. Encephalomyopathy and cardiomyopathy are frequently encountered manifestations of mitochondrial diseases, and recently, gastrointestinal dysmotility has received attention[23-26]. Chinnery et al[27] reported that over 15% of patients with mitochondrial diseases complain of dysphagia or constipation, and a small percentage of the cases with constipation develop intestinal pseudo-obstruction. Although Amiot et al[28] reported that 19% of 80 patients with CIP had mitochondrial defects, the relationship between CIP and mitochondrial disease has not yet been conclusively established.

The aim of this study was to determine the frequency, characteristics, and prognosis of CIP in patients with mitochondrial diseases.

MATERIALS AND METHODS

Between January 2000 and December 2010, 33 patients were diagnosed with mitochondrial diseases at the Yokohama City University School of Medicine. Their clinical and treatment data were collected from their medical records and 2 patients were excluded due to insufficient clinical data.

Diagnosis of mitochondrial disease

The plasma and cerebrospinal fluid levels of lactate and pyruvate were measured at rest and then re-evaluated under exercise stress to ensure that the levels were within the normal ranges. Muscle biopsies and genetic analyses were performed in all patients. Examinations for other component disorders of mitochondrial dysfunction, such as glucose intolerance, electrocardiography, echocardiography, and brain magnetic resonance imaging were performed as needed.

Ethical approval

This study was conducted in accordance with the declaration of Helsinki, and with the approval of the Ethics Committee of Yokohama City University School of Medicine. We obtained written informed consents from each of the patients.

Statistical analysis

We conducted a retrospective review of each patient’s sex, subclass of mitochondrial disease, age at the onset of mitochondrial disease, age at the establishment of the diagnosis of mitochondrial disease, frequency of CIP and the age at onset, and the duration of survival. The age at onset or at the first diagnosis of the disorder that led to the clinical suspicion of mitochondrial disease was also examined. As controls, we collected the data of 57 patients who were diagnosed with progressive muscular dystrophy at the Yokohama City University School of Medicine between January 2007 and December 2011. Five of the patients were excluded due to insufficient clinical data.

RESULTS

Thirty-one patients with mitochondrial diseases underwent detailed assessment (Table 2). The subjects comprised 13 males and 18 females and were sub-classified as having mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS; n = 20), chronic progressive external ophthalmoplegia (CPEO; n = 8), or myoclonus epilepsy associated with ragged-red fibers (MERRF; n = 3). Of the 31 patients, 9 (28.1%) were diagnosed with CIP based on Nakajima’s criteria, including 8 of the 20 (40.0%) patients with MELAS, 0 of the 8 (0.0%) patients with CPEO, and 1 of the 3 (33.3%) patients with MERRF. One patient died of uncontrolled epilepsy and aspiration pneumonia 5 mo after the onset of intestinal pseudo-obstruction and did not fulfill the diagnostic criteria.

Table 2 Age at the oncet of mitochondrial disease and chronic intestinal pseudo-obstruction.
SexSubclassAge at the onset of mitochondrial disease, yrAge at the diagnosis of mitochondrial disease, yrAge at the diagnosis of CIP, yr
FMELASDifficulty in walking at 404040
MMELASGlucose intolerance at 135746
MMERRFDifficulty in walking at 415050
FCPEOPalpebral ptosis at 7181-
FMELASImpaired hearing at 4554-
MMELASImpaired hearing at 2429-
MCPEOPalpebral ptosis at 4069-
FCPEOImpaired eye movement at 3052-
FMELASImpaired hearing at 254043
MCPEOPalpebral ptosis at 4949-
FMERRFMuscular weakness at 4654-
MMELASImpaired hearing at 4752-
MMELASEpilepsy at 1118-
MCPEOGlucose intolerance at 4067-
MMELASImpaired hearing at 2431-
FMELASImpaired hearing at 121725
FMELASImpaired hearing at 5460-
FMELASEpilepsy at 4044-
MMELASGlucose intolerance and impaired hearing at 1818-
FMELAS-23-
FMELASChronic diarrhea at 2640-1
FMELASEpilepsy at 181826
FMELASDifficulty in walking and hearing at 636969
FMELASGlucose intolerance at 334255
MCPEOPalpebral ptosis at 1644-
MMELASEpilepsy at 2929-
FCPEOPalpebral ptosis at 1317-
FCPEOPalpebral ptosis at 5959-
MMELASEpilepsy at 212134
FMELASGlucose intolerance at 4648-
FMERRFDifficulty in walking at 2050-

The confirmable outcomes were as follows: in December 2010, 14 patients were receiving outpatient treatment, 12 patients had been transferred to chronic care facilities, and 5 patients (4 patients with MELAS and 1 with CPEO) had died. The cause of death was cardiomyopathy in 2 patients with MELAS, cerebral infarction in 1 patient with MELAS, epilepsy and aspiration pneumonia in 1 patient with MELAS, as previously described, and multiple metastases from gastric cancer and aspiration pneumonia in 1 patient with CPEO.

In radiographic examinations for the 9 patients with CIP, small intestinal distention was observed in 6 patients, and large intestinal distention was observed in 1 patients. Both small and large intestinal distention was observed in 2 patients.

The median age (range) at the establishment of the diagnosis of mitochondrial disease was 40 (17-69) years in patients with CIP and 49 (17-81) years in patients without CIP. The median age (range) at the onset or at the first diagnosis of the disorder that led to the suspicion of mitochondrial disease was 25 (12-63) years in patients with CIP and 40 (11-71) years in patients without CIP.

The symptoms of CIP were treated with laxative agents, antidiarrheal drugs, antiflatulence agents, mosapride, dimethicone, pantothenic acid, daikenchuto (Chinese herbal medicine), neostigmine or distigmine, and none of the patients required surgery (Table 3).

Table 3 Characteristics of chronic intestinal pseudo-obstruction in patients with mitochondrial diseases.
SexSubclassType of abdominal discomfortArea of dilated intestineTreatment
FMELASNausea, vomiting, diarrhea, constipationSmall intestinePEG, neostigmine
MMELASDiarrheaSmall intestineAntidiarrheal drug
MMERRFPain, diarrhea, distensionSmall and large intestinesMosapride, dimethicone, antiflatulent, daikenchuto, pantothenic acid
FMELASDiarrhea, constipation, distensionSmall and large intestinesMosapride, daikenchuto, magnesium oxide
FMELASNausea, vomiting, diarrhea, constipation, painSmall intestinePEG, antiflatulent, magnesium oxide, antidiarrheal drug
FMELASNausea, vomiting, constipation, painSmall intestineProstarmon, magnesium oxide, dimethicone, daikenchuto, mosapride, neostigmine, sodium picosulfate hydrate
FMELASNausea, vomiting, distensionSmall intestineMagnesium oxide, daikenchuto
FMELASNausea, vomitingLarge intestineDaikenchuto, sennoside
MMELASNausea, vomiting, diarrhea, distensionSmall intestineDaikenchuto, mosapride, magnesium oxide, lansoprazole, neostigmine, dimechicone

As controls, we collected the data of 57 patients with progressive muscular dystrophy (Table 4). The patients consisted of 2 patients with Duchenne muscular dystrophy, 7 patients with Becker muscular dystrophy, 4 patients with limb-girdle muscular dystrophy, 1 patient with facio-scapulo-humeral muscular dystrophy and 43 patients with myotonic dystrophy (5 patients were excluded due to insufficient clinical data). The median age (range) at the establishment of the diagnosis of progressive muscular dystrophy was 34.5 (1-67) years and the median age (range) at the onset of progressive muscular dystrophy was 25 (1-62) years. Only 2 of the patients died, while the others were alive at the last hospital visit. Although progressive muscular dystrophy has been considered as one of the etiologies of CIP, none of the patients with progressive muscular dystrophy in this study fulfilled the diagnostic criteria of CIP.

Table 4 Characteristics of chronic intestinal pseudo-obstruction in patients with progressive muscular dystrophy.
SubclassNo. of patientsNo. of femalesAge at the onset1Age at the diagnosis1
Duchenne muscular dystrophy2012 (1-3)
Becker muscular dystrophy7010 (1-30)19 (6-43)
Limb-girdle muscular dystrophy4122.5 (5-40)49 (10-53)
Facio-scapulo-humeral muscular dystrophy11NSNS
Myotonic dystrophy381830 (5-62)39 (12-67)
Total522025 (1-62)34.5 (1-67)
DISCUSSION

Although mitochondrial diseases have been considered as a potential cause of secondary CIP, the frequency of CIP in patients with mitochondrial diseases has not yet been well established. Gastrointestinal dysmotility (including CIP) may be caused by the accumulation of intracellular long-chain fatty acids, activation of extramitochondrial fatty acid oxidation pathways and excessive generation of reactive oxygen species leading to visceral myopathy, possibly as a result of impaired mitochondrial beta-oxidation[29]. Betts et al[30] reported that profound COX deficiency was found in the smooth muscle layers of all regions of the gastrointestinal tract in patients with the m.3243A>G mutation despite scarce evidence of morphologic abnormalities within the gastrointestinal tissues of these patients. Parsons et al[31] also reported that 80% of patients with MELAS and more than 60% of m.3243A>G carriers have 1 or more autonomic symptoms; gastrointestinal symptoms were especially common in the MELAS group, occurring in 66% of these patients and in almost 40% of the mutation carriers. In mitochondrial diseases, mitochondrial neurogastrointestinal encephalopathy (MNGIE), which is an uncommon autosomal recessive syndrome caused by the reduced activity of thymidine phosphorylase due to a mutation of the nuclear DNA, has also been reported to be particulary associated with CIP along with other symptoms such as malnutrition, progressive external ophthalmoplegia, ptosis, peripheral neuropathy, and leukoencephalopathy[32-34]. Although we have never encountered patients with MNGIE, this study revealed that patients with mitochondrial diseases develop complicating CIP at a relatively high frequency (28.1%), especially patients with MELAS (40.0%). We also examined the clinical data of patients with progressive muscular dystrophy, which is also a known cause of CIP, as controls and found that CIP occurs less frequently in patients with progressive muscular dystrophy than in patients with mitochondrial diseases (0% vs 28.1%).

Patients with CIP tend to have disorders, such as glucose intolerance, epilepsy, hearing impairment and palpebral ptosis,that are suspected to be related to mitochondrial diseases at younger ages than are patients without CIP. None of the patients in our study presented with CIP as the initial symptom of mitochondrial disease. This trend indicates that some patients with mitochondrial dysfunction will develop gastrointestinal dysmotility with disease progression, eventually leading to the development of CIP.

The frequency of CIP among patients with relatively mild mitochondrial dysfunction who do not need advanced treatment at a hospital may also be smaller than that noted in this study. Most patients with mitochondrial diseases die of cardiomyopathy and encephalopathy before the development of severe CIP, and this finding is consistent with a previous report indicating that the degree of organ dysfunction depended on the energy requirement of the organ. Although CIP was not a major cause of death in patients with mitochondrial diseases, it often resulted in impaired oral intake or tube feeding and eventually the critical loss of the activities of daily life. Early detection and treatment of gastrointestinal dysmotility, including CIP, and the maintenance of the nutritional status may be efficacious in the management of patients with mitochondrial diseases.

There is still no sufficiently effective treatment for CIP today. A number of medicines were used in this study, and none were especially effective when comparing these treated patients with CIP patients without mitochondrial diseases. Surgery has been reported to be effective in patients with normal small intestinal motility[35], although surgery was not performed in this study (8 of 9 patients with CIP in this study had small intestine dysmotility).

Selection bias is one of the major limitations of our study. Patients receiving outpatient treatment at a university hospital like ours may have more severe symptoms than general patients presenting to primary care practitioners may have. This limitation could have resulted in an over-estimation of the CIP prevalence in patients with mitochondrial diseases. In addition, the 31 patients with mitochondrial diseases in this study included 20 patients with MELAS (64.5%), 8 patients with CPEO (25.8%) and 3 patients with MERRF (9.7%), indicating a larger prevalence of MELAS patients in our study compared with that from an epidemiological study conducted in Japan (64.5% vs 25.5%)[36]. This selection bias may also have contributed to an over-estimation of the CIP prevalence. Moreover, patients with MELAS often use antiepileptic drugs regularly, which may cause drug-induced intestinal pseudo-obstruction. In our study, 5 patients with CIP regularly used antiepileptic drugs (phenytoin, carbamazepine, carbamazepine and sodium valproate, and for 2 patients, carbamazepine and clonazepam). Although it may be difficult to precisely distinguish between mitochondrial and drug-induced gastrointestinal symptoms, the regular use of these antiepileptic drugs alone rarely results in CIP, and mitochondrial dysfunction was considered the main cause of the severe intestinal dysmotility of these 5 patients.

In conclusion, patients with mitochondrial diseases (especially MELAS) sometimes develop CIP. In cases characterized by the adequate control of fetal mitochondrial dysfunctions such as cardiomyopathy and encephalopathy, CIP may present as a prominent problem. The possibility of the development of gastrointestinal dysmotility, including CIP, should be considered at all stages of the clinical course of all patients with mitochondrial diseases.

COMMENTS
Background

Chronic intestinal pseudo-obstruction (CIP) is characterized by severe symptoms and signs of intestinal obstruction without mechanical obstruction. Although mitochondrial diseases have been considered as a potential cause of secondary CIP, the frequency, characteristics, and prognosis of CIP in patients with mitochondrial diseases has not yet been well established.

Research frontiers

Mitochondrial diseases are a heterogeneous group of disorders associated with mutations in or deletions of nuclear or mitochondrial DNA. The degree of organ dysfunction depends on the energy requirements of the organ and on the proportion of mitochondrial DNA in the organ. In the treatment of mitochondrial patients with CIP, current research now focuses on how mitochondrial dysfunction develops into CIP and what the differences between the patients with CIP and without CIP are.

Innovations and breakthroughs

The relationship between CIP and mitochondrial diseases has not yet been firmly established. In the present study, authors conducted a retrospective review of each patient’s sex, subclass of mitochondrial disease, age at the onset of mitochondrial disease, age at the establishment of the diagnosis of mitochondrial disease, frequency of CIP and the age at its onset, and the duration of survival. The age at the onset or at the first diagnosis of the disorder that led to the clinical suspicion of mitochondrial disease was also examined.

Applications

The study results suggest that patients who have certain disorders, such as glucose intolerance, epilepsy, hearing impairment and palpebral ptosis, that are suspected to be related to mitochondrial diseases at younger ages tend to develop gastrointestinal dysmotility with disease progression, eventually leading to the development of CIP.

Terminology

CIP is an uncommon disabling motility syndrome characterized by severe symptoms and signs of intestinal obstruction (abdominal pain, abdominal distention, nausea and vomiting) and radiographic evidence of dilated bowels in the absence of any mechanical obstruction; Mitochondrial diseases are a heterogeneous group of disorders associated with mutations in or deletions of nuclear or mitochondrial DNA.

Peer review

This is a good descriptive study in which the authors retrospectively reviewed the frequency, characteristics and prognosis of chronic intestinal pseudo-obstruction in mitochondrial patients. The study revealed that patients with CIP tend to have disorders that are suspected to be related to mitochondrial diseases at younger ages than patients without CIP.

Footnotes

Peer reviewer: Francis Seow-Choen, Professor, Seow-Choen Colorectal Centre, Mt Elizabeth Hospital, 290 Orchard Road Paragon Shopping Centre 06-06, Singapore 238859, Singapore

S- Editor Gou SX L- Editor A E- Editor Li JY

References
1.  Dudley HA, Sinclair IS, McLaren IF, McNair TJ, Newsam JE. Intestinal pseudo-obstruction. J R Coll Surg Edinb. 1958;3:206-217.  [PubMed]  [DOI]
2.  Rudolph CD, Hyman PE, Altschuler SM, Christensen J, Colletti RB, Cucchiara S, Di Lorenzo C, Flores AF, Hillemeier AC, McCallum RW. Diagnosis and treatment of chronic intestinal pseudo-obstruction in children: report of consensus workshop. J Pediatr Gastroenterol Nutr. 1997;24:102-112.  [PubMed]  [DOI]
3.  Sutton DH, Harrell SP, Wo JM. Diagnosis and management of adult patients with chronic intestinal pseudoobstruction. Nutr Clin Pract. 2006;21:16-22.  [PubMed]  [DOI]
4.  Connor FL, Di Lorenzo C. Chronic intestinal pseudo-obstruction: assessment and management. Gastroenterology. 2006;130:S29-S36.  [PubMed]  [DOI]
5.  Yamanaka Y, Sakakibara R, Asahina M, Uchiyama T, Liu Z, Yamamoto T, Ito T, Suenaga T, Odaka T, Yamaguchi T. Chronic intestinal pseudo-obstruction as the initial feature of pure autonomic failure. J Neurol Neurosurg Psychiatry. 2006;77:800.  [PubMed]  [DOI]
6.  Anuras S. Intestinal pseudo-obstruction syndrome. Annu Rev Med. 1988;39:1-15.  [PubMed]  [DOI]
7.  Ogilvie H. Large-intestine colic due to sympathetic deprivation; a new clinical syndrome. Br Med J. 1948;2:671-673.  [PubMed]  [DOI]
8.  Park JS, Kim HA, Lee KJ, Suh CH. Intestinal pseudo-obstruction caused by neuromyopathy in a patient with systemic sclerosis. Mod Rheumatol. 2012;Jan 31; Epub ahead of print.  [PubMed]  [DOI]
9.  Masaki T, Sugihara K, Nakajima A, Muto T. Nationwide survey on adult type chronic intestinal pseudo-obstruction in surgical institutions in Japan. Surg Today. 2012;42:264-271.  [PubMed]  [DOI]
10.  Kim J, Kim N. Intestinal pseudo-obstruction: initial manifestation of systemic lupus erythematosus. J Neurogastroenterol Motil. 2011;17:423-424.  [PubMed]  [DOI]
11.  Zhang J, Fang M, Wang Y, Mao J, Sun X. Intestinal pseudo-obstruction syndrome in systemic lupus erythematosus. Lupus. 2011;20:1324-1328.  [PubMed]  [DOI]
12.  Hokama A, Kishimoto K, Nakamoto M, Kobashigawa C, Hirata T, Kinjo N, Kinjo F, Kato S, Fujita J. Endoscopic and histopathological features of gastrointestinal amyloidosis. World J Gastrointest Endosc. 2011;3:157-161.  [PubMed]  [DOI]
13.  Sharma A, Naraynsingh V, Goalan R, Teelucksingh ST. Severe intestinal pseudo-obstruction following withdrawal from over-the-counter steroid abuse. J Postgrad Med. 2011;57:218-220.  [PubMed]  [DOI]
14.  Young RP, Wu H. Intestinal pseudo-obstruction caused by diltiazem in a neutropenic patient. Ann Pharmacother. 2005;39:1749-1751.  [PubMed]  [DOI]
15.  Fauville JP, Hantson P, Honore P, Belpaire F, Rosseel MT, Mahieu P. Severe diltiazem poisoning with intestinal pseudo-obstruction: case report and toxicological data. J Toxicol Clin Toxicol. 1995;33:273-277.  [PubMed]  [DOI]
16.  Camarero-Temiño V, Mercado-Valdivia V, Hijazi-Prieto B, Abaigar-Luquin P. Intestinal pseudo-obstruction secondary to persistent constipation due to lanthanum carbonate. Nefrologia. 2012;32:129.  [PubMed]  [DOI]
17.  Iida H, Inamori M, Sekino Y, Sakamoto Y, Yamato S, Nakajima A. A review of the reported cases of chronic intestinal pseudo-obstruction in Japan and an investigation of proposed new diagnostic criteria. Clin J Gastroenterol. 2011;4:141-146.  [PubMed]  [DOI]
18.  Fayssoil A. Heart diseases in mitochondrial encephalomyopathy, lactic acidosis, and stroke syndrome. Congest Heart Fail. 2009;15:284-287.  [PubMed]  [DOI]
19.  Chiyonobu T, Noda R, Yoshida M, Fujiki A, Ishii R, Nukina S, Fujita K, Goto Y, Morimoto M. Intestinal pseudo-obstruction in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) associated with phenytoin therapy. Brain Dev. 2008;30:430-433.  [PubMed]  [DOI]
20.  DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med. 2003;348:2656-2668.  [PubMed]  [DOI]
21.  Pulkes T, Liolitsa D, Eunson LH, Rose M, Nelson IP, Rahman S, Poulton J, Marchington DR, Landon DN, Debono AG. New phenotypic diversity associated with the mitochondrial tRNA(SerUCN) gene mutation. Neuromuscul Disord. 2005;15:364-371.  [PubMed]  [DOI]
22.  Hanna MG, Nelson IP. Genetics and molecular pathogenesis of mitochondrial respiratory chain diseases. Cell Mol Life Sci. 1999;55:691-706.  [PubMed]  [DOI]
23.  Garone C, Tadesse S, Hirano M. Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. Brain. 2011;134:3326-3332.  [PubMed]  [DOI]
24.  Giordano C, d'Amati G. Evaluation of gastrointestinal mtDNA depletion in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Methods Mol Biol. 2011;755:223-232.  [PubMed]  [DOI]
25.  Granero Castro P, Fernández Arias S, Moreno Gijón M, Alvarez Martínez P, Granero Trancón J, Álvarez Pérez JA, Lamamie Clairac E, González González JJ. Emergency surgery in chronic intestinal pseudo-obstruction due to mitochondrial neurogastrointestinal encephalomyopathy: case reports. Int Arch Med. 2010;3:35.  [PubMed]  [DOI]
26.  Oztas E, Ozin Y, Onder F, Onal IK, Oguz D, Kocaefe C. Chronic intestinal pseudo-obstruction and neurological manifestations in early adulthood: considering MNGIE syndrome in differential diagnosis. J Gastrointestin Liver Dis. 2010;19:195-197.  [PubMed]  [DOI]
27.  Chinnery PF, Turnbull DM. Mitochondrial medicine. QJM. 1997;90:657-667.  [PubMed]  [DOI]
28.  Amiot A, Tchikviladzé M, Joly F, Slama A, Hatem DC, Jardel C, Messing B, Lombès A. Frequency of mitochondrial defects in patients with chronic intestinal pseudo-obstruction. Gastroenterology. 2009;137:101-109.  [PubMed]  [DOI]
29.  Gilbert J, Ibdah JA. Intestinal pseudo-obstruction as a manifestation of impaired mitochondrial fatty acid oxidation. Med Hypotheses. 2005;64:586-589.  [PubMed]  [DOI]
30.  Betts J, Barron MJ, Needham SJ, Schaefer AM, Taylor RW, Turnbull DM. Gastrointestinal tract involvement associated with the 3243A& gt; G mitochondrial DNA mutation. Neurology. 2008;70:1290-1292.  [PubMed]  [DOI]
31.  Parsons T, Weimer L, Engelstad K, Linker A, Battista V, Wei Y, Hirano M, Dimauro S, De Vivo DC, Kaufmann P. Autonomic symptoms in carriers of the m.3243A& gt; G mitochondrial DNA mutation. Arch Neurol. 2010;67:976-979.  [PubMed]  [DOI]
32.  Bariş Z, Eminoğlu T, Dalgiç B, Tümer L, Hasanoğlu A. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): case report with a new mutation. Eur J Pediatr. 2010;169:1375-1378.  [PubMed]  [DOI]
33.  Hirano M, Nishino I, Nishigaki Y, Martí R. Thymidine phosphorylase gene mutations cause mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Intern Med. 2006;45:1103.  [PubMed]  [DOI]
34.  Slama A, Lacroix C, Plante-Bordeneuve V, Lombès A, Conti M, Reimund JM, Auxenfants E, Crenn P, Laforêt P, Joannard A. Thymidine phosphorylase gene mutations in patients with mitochondrial neurogastrointestinal encephalomyopathy syndrome. Mol Genet Metab. 2005;84:326-331.  [PubMed]  [DOI]
35.  Glia A, Akerlund JE, Lindberg G. Outcome of colectomy for slow-transit constipation in relation to presence of small-bowel dysmotility. Dis Colon Rectum. 2004;47:96-102.  [PubMed]  [DOI]
36.  Makino M, Nonaka I. Epidemiology of mitochondrial disease. Annual Review Shinkei. 1999;406-412.  [PubMed]  [DOI]