Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Gastroenterology
Microvillous Inclusion Disease: How to Improve the Prognosis of a Severe Congenital Enterocyte Disorder
Halac, Ugur*; Lacaille, Florence*; Joly, Francisca†; Hugot, Jean-Pierre‡; Talbotec, Cécile*; Colomb, Virginie*; Ruemmele, Frank M*; Goulet, Olivier*
*Pediatric Gastroenterology, Hepatology and Nutrition Unit, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, France
†Gastroenterology and Nutritive Assistance Unit, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France
‡Pediatric Gastroenterology and Nutrition Unit, Robert-Debré Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
Received 29 May, 2010
Accepted 5 August, 2010
Address correspondence and reprint requests to Florence Lacaille, MD, Pediatric Gastroenterology, Hepatology and Nutrition Unit, Necker-Enfants Malades Hospital 149 rue de Sèvres, 75015 Paris, France (e-mail: firstname.lastname@example.org).
The authors report no conflicts of interest.
Background and Objective: Microvillous inclusion disease (MVID) is a rare congenital enterocyte disorder causing severe diarrhea and intestinal failure. The objective of this study was to analyze clinical evolution and the most frequent complications of MVID in children receiving parenteral nutrition (PN) and after small-bowel transplantation (SBTx) with the aim to improve treatment strategies and prognosis.
Patients and Methods: From 1995 to 2009, 24 patients (16 boys, median follow-up 4.7 years, range: from birth to 23.5 years) with MVID were admitted to our unit. The recorded parameters included growth, neurological development, liver and renal functions, bone disease, and outcome.
Results: Almost half of the children were from consanguineous families from the Mediterranean area. All of the patients completely depended on PN. Four children died of PN complications before 4 years of age. Before or without SBTx, growth failure was common (mean height −2.5 standard deviations [SD]), as was developmental delay (12/24), liver (20/22 with fibrosis) or kidney disease (3/23 with moderate renal insufficiency), and osteoporosis (6/24). Thirteen children underwent SBTx (9 isolated, 4 combined with liver Tx) at a median age of 3.5 years. Follow-up after SBTx was 0.4 to 14 years. Patient survival rates were 63% without SBTx and 77% with SBTx. After SBTx, 4 children experienced catch-up growth.
Conclusions: PN in MVID is difficult to manage and requires expertise. Despite improved results in expert centers, the risk of death or irreversible sequelae is higher with PN than after Tx. SBTx, despite being complicated, remains the only hope to improve the quality of life and long-term prognosis of these children.
Microvillous inclusion disease (MVID), a disease within the syndrome of intractable diarrhea in infancy, is a congenital enterocyte defect (1–4) that is responsible for severe and profuse diarrhea (up to 150–200 mL/kg/day) beginning at birth (3). It is a rare autosomal recessive disease, affecting a few hundred patients in Europe (5). The recently discovered molecular defect affects the MYO5B gene, coding for myosin Vb, a motor protein of the cytoskeleton involved in the regulation of polarized epithelial cell trafficking (6). Small-bowel biopsies show typical accumulation of periodic acid-Schiff (PAS)–positive secretory granules within the apical cytoplasm of immature enterocytes in the upper crypt (7). Transmission electron microscopy can further confirm the diagnosis, disclosing the typical “inclusions” of microvilli in the cytoplasm (8,9).
MVID causes total and irreversible intestinal failure. Except for 1 exceptional case (10), all of the published cases of patients were found to remain totally dependent on long-term parenteral nutrition (PN), without any improvement with age. Huge stool losses may be responsible for rapid, life-threatening dehydration (1,3,4). The management of PN in MVID is difficult, and complications are frequent because of severe diarrhea, acute episodes of dehydration, and metabolic imbalance (3). The neurological consequences of transient hypovolemic episodes, renal impairment, and nephrocalcinosis from insufficient hydratation, early liver disease due to the need for continuous infusion, growth failure, and infections are the most frequent outcomes (5,11). Three-quarters of 23 patients in an earlier multicenter survey died of sepsis, liver failure, or metabolic imbalance before 9 months of age (3). MVID is thus a dramatic disease with a poor prognosis. Small-bowel transplantation (SBTx) is the only curative treatment (11–14). However, the decision and timing of SBTx both are difficult to arrive at because of improvements in long-term PN in the last 15 years (15) and the complications in SBTx (16).
The aim of this retrospective study was to report a series of 24 children with MVID and the most frequent complications to define how expert PN and timely SBTx may improve the disease prognosis.
PATIENTS AND METHODS
From 1995 to 2009, 27 patients with MVID were admitted in our unit. This report is an extension of a previous study (11) and does not include patients from the first multicenter survey (3). Twenty-four of these children, for whom enough information was available, are described here. Data on status (hospital-bound, at home), growth (standard deviation [SD] for height and weight), neurological development (developmental milestones, neurological symptoms), number of and reasons for hospital admission, number of central venous catheters (CVC), infections (number and origin), liver disease (clinical symptoms, serum enzyme levels, liver biopsy), renal function (creatinine blood level, glomerular filtration rate [GFR], ultrasound, kidney biopsy, if available), and skeletal complications (fractures, dual-energy x-ray absorptiometry) (17) were recorded. Neurological development was assessed by experienced neurologists and, when necessary, qualified ergo-physiotherapists. Renal function was evaluated by the GFR, measured by inulin or iohexol clearance or, when unavailable, calculated with the Schwartz formula. A normal result was defined as GFR >80 mL min/1.73 m2, moderate renal failure as GFR between 60 and 80 mL/min/1.73 m2, and severe renal failure as GFR <60 mL/min/1.73 m2.
PN formulae were registered, but data were missing in this retrospective collection, and PN composition and the origin of each component were largely variable during the 14-year study period. The indication of transplantation changed during this period. Until the late 1990s, it was a lifesaving procedure in children with progressive liver disease or extensive vascular thrombosis. Following the improvements in the technique, the indications were extended to other situations in which home PN could not be performed safely, such as recurrent life-threatening infections, episodes of dehydration, intolerance to PN cyclization, and permanent hospitalizations for medical or social reasons. Thus, due to the constant difficulties in managing home PN for this disease, MVID became for us an indication for early SBTx (11), limited only by the availability of organs. The Tx was either isolated SBTx, small bowel plus colon Tx, or combined liver and small bowel (with or without colon) Tx according to the Omaha procedure (18). Intestinal grafts were obtained from ABO-identical cadaveric donors. Proximal anastomosis of the small-bowel graft to the native duodenum or jejunum was performed, and the distal end of the graft was exteriorized as a stoma, which was taken down between 3 and 6 months after SBTx. The immunosuppression protocol included tacrolimus, steroids, azathioprine, and anti-interleukin-2-receptor monoclonal antibodies, as published previously (19).
The clinical characteristics of the 24 patients (16 boys) are reported in Table 1. The whole follow-up from the diagnosis took place in our unit for only 8 of them. One child was referred from another French hospital and 15 from other European countries. However, all of the transplanted patients were seen regularly after the procedure. At last follow-up or at the time of death, patients were 2 months to 24 years old (median 5 years). Almost half of them (11/24) were from consanguineous families from the Mediterranean area, especially Turkey (9/11). Two patients were siblings. In addition, 4 patients had a sibling who died of severe neonatal diarrhea, with or without a diagnosis of MVID. All of the patients developed severe intractable diarrhea in the first 2 months of life. MVID was diagnosed on the basis of typical clinical and histological findings between birth and 2 years of life, after a severe episode of dehydration in 20 patients.
All of the children were totally dependent on PN. A large volume, on average 170 mL/kg/day, was needed to ensure adequate electrolyte balance. Seven patients received PN 24 hours per day during at least their first year of life. Among the 11 nontransplanted children, 2 died before 6 months and 9 were discharged on home PN only after 6 months of age. In all, 4 children (17%) died of PN complications between 2 months and 3.5 years of age. Thirteen children (54%) underwent SBTx, at a median age of 3.5 years (range 1–12 years), after a mean waiting time of 1.5 years (1 month–2.5 years). Eight of these 13 children (62%) were hospital bound up to SBTx. All of the children could be discharged after SBTx. The comparison between the duration of hospitalization before or without or after SBTx is difficult in this retrospective study because part of the follow-up was done outside of our unit.
Except in the first 2 children, the colon was transplanted simultaneously with the small bowel to allow better fluid resorption. Three transplanted children (23%) died, 1 in the operating room, 1 at 4 years after combined liver and SBTx, of liver failure secondary to small-bowel removal due to rejection, and the third 2 years after SBTx, of sepsis. The small-bowel graft was removed in 4 other children (31%) because of rejection 2 to 9 years after SBTx. Two of them are on the waiting list for retransplantation: 1 receives home PN and the other underwent combined liver and SBTx 4 years later. Median follow-up after SBTx is 3.5 years (ranging from 3 months to 14 years) (Table 1). The patient survival rate is 63% without SBTx and 77% with SBTx. Seven transplanted children (54%) are living with a functional graft and have been weaned off PN. The number of CVC implanted in the 24 children during their time on PN varied from 2 to 15 (mean 4.6 CVC per child). The reasons for CVC removal and replacement were infection (24/24), technical failure (7/24), and thrombosis (4/24). In the majority of cases (17/24), septic episodes were attributed to infected CVC with positive blood cultures. After SBTx, the CVC was removed eventually during the first year in all of the children. Growth parameters are included in Table 1. At the last follow-up, median height was measured in children receiving PN at −2.5 SD and weight −1 SD. For transplanted patients weaned off PN, growth at the last follow-up was −2 SD for median height and −0.8 SD for weight. Four children experienced catch-up growth. In the whole group, neurological development was normal in only 12 children (50%) and delayed in the others, moderately to severely in 3 of them. Gross neurological examination was normal in all of them, except for 1 severe strabismus. At the last follow-up, 5 children were still preschool age; 8 children could not follow the normal education system and needed special care; and 1 of the young adults obtained a low-qualification professional degree. Three patients (2 of them hospital bound from birth and without family support) had psychiatric problems and needed medications at times. One of them lost his graft from chronic rejection and obvious lack of compliance.
Liver disease manifested as episodes of intrahepatic cholestasis, as clinical symptoms of portal hypertension or cirrhosis, or as the finding of fibrosis on biopsy. One-fourth (6/24) of children experienced several episodes of intrahepatic cholestasis, 3 before and 3 only after SBTx. They presented permanent and severe pruritus, intermittent jaundice, and mild hepatomegaly. The gamma-glutamyl transpeptidase (GGT) activity was normal, whereas transaminases were mildly elevated, conjugated bilirubin increased, and the level of serum bile acids was high. Liver biopsy revealed lobular cholestasis, without inflammation, and mild to moderate portal fibrosis (Table 2). In 2 cases in whom transmission electron microscopy was performed, no microvillous inclusions were seen at the canalicular membrane. After SBTx, pruritus was controlled by treatments used in other types of intrahepatic cholestasis in children: rifampicin, ursodeoxycholic acid, nasobiliary drainage, ileal exclusion (surgical exclusion of the last 30 cm of ileum and direct ileocolic anastomosis), and external biliary drainage (by using a conduit between the gallbladder and the skin). Pruritus was also relieved by graft removal (rejection) in 2 children; in these cases, liver biopsy disclosed severe fibrosis. In 2 other children, follow-up biopsy after SBTx showed moderate ductopenia without significant fibrosis. This specific MVID-associated liver disease has already been reported (20,21). Four other children presented more usual PN-associated cirrhosis and received a liver and SBTx. All of them had jaundice sometime before SBTx, but without any itching and with elevated GGT. Altogether, liver biopsies were investigated in 22/24 children (mean of 2.5 biopsies per patient). Almost all of the patients (20/22) had some fibrosis, severe (F3 or cirrhosis) in 8 of them (40%). Three children developed gallstones during their first year and 1 had acute cholecystitis. Liver biopsies were not taken after isolated SBTx in children without cholestasis.
The GFR in patients on PN, measured in 6 of them and calculated in the others, was >80 mL/min/1.73 m2 in 20 children (83%), whereas 3 patients had moderate renal failure (data lacking in 1 child) (Table 3). Nephrocalcinosis was observed in 2 children and renal stones in 4, 1 of whom experienced life-threatening sepsis from urinary tract infection. Three patients underwent renal biopsy. The findings were normal in 2, but 1 had membranous glomerulonephritis and severe nephronic reduction, for which combined kidney and SBTx is being discussed. After SBTx, measured or calculated GFR was within normal ranges in 11/12 and indicated moderate renal failure in 1 patient.
Significant osteoporosis (z, score <−2 SD) was identified by bone densitometry in one-fourth of the non- or not-yet transplanted patients (6/24). Three of them experienced bone fractures before SBTx and none afterward. The absorptiometry data after SBTx are also few to draw conclusions.
In addition, 2 siblings developed pulmonary complications. The first child was born prematurely, had bronchodysplasia, and needed oxygen for several months. Her sister was born full-term, experienced severe neonatal respiratory distress, and died after 2 months. It is worth noting that their older sibling, not reported here, also died of severe dehydration from neonatal diarrhea and had pulmonary disease.
MVID, together with intestinal epithelial dysplasia (tufting enteropathy) and “syndromatic” (or “phenotypic”) diarrhea, is a defined cause of congenital enterocyte disorder (22,23). It is a rare but dramatic disease, with major management difficulties. Its clinical and histological characteristics were well described many years ago (5,9,24). The first large series of 23 patients recorded a mortality rate of three-quarters in the first year of life (3). A later-onset form of MVID (symptoms appear 3 months after birth) has been described in few patients, who had a better prognosis (5): 1 patient, the only reported case, could be weaned off PN (10), but in the vast majority of cases, the children are definitively and totally dependent on PN.
Major improvements have occurred in the long-term management of PN in specialized centers (15), with an excellent survival rate among children with intestinal failure (about 90% after 14 years of follow-up) (11,15). However, the outcome depends mainly on the primary disease, and MVID clearly belongs to the most severe cases. In our series, many children had such severe daily electrolyte losses that they had to be maintained on 24-hour PN because of dehydration after a 2-hour PN pause. In general, we first aim to exactly quantify the “baseline” electrolyte losses in stools. We use a rectal tube to collect the stools for 24 hours, which allows for the adjustment of intravenous electrolytes. Further adjustments are made on the basis of blood and urine electrolytes. This method is repeated when an acute event happens (eg, sudden increase in diarrhea). Care should be taken not to “overcompensate” the losses, which otherwise can lead to further increase in secretory diarrhea.
Nonetheless, dehydration episodes occurred, although their number and severity were difficult to assess retrospectively. As reported previously (25), we suspect that the developmental delay in half of the children is, in part, due to episodes of dehydration, either severe before the diagnosis or repeated and milder but, nonetheless, significant for the developing brain. Moreover, long and frequent hospitalizations had a negative impact on development and familial environment. Renal disease also originates probably from repeated episodes of dehydration. Renal stones are not a common complication of PN and neither is renal failure (26). However, 3 of our patients had significant renal insufficiency, and clearance was <100 mL/mn/1.73 m2 in more than half of them. Few kidney biopsies were available to draw conclusions, especially about possible specific lesions associated with MVID. After SBTx, renal function cannot improve with nephrotoxic immunosuppressive drugs. With a rather short follow-up, however, we did not observe it to worsen. These patients will have to be monitored carefully on this aspect in the future. The growth of these children on PN was worse than the average in our center where growth failure was rare on long-term PN (15). We showed recently that a catch-up growth was uncommon after SBTx and also that patients with MVID had more severe pre-SBTx growth failure than others (median: −2.6 for MVID patients compared to −0.9 for others) (16). Difficult PN management, numerous pre-Tx events (hospitalizations, infections, etc), and perhaps late referral are some of the plausible explanations.
Liver disease is clearly a feature of MVID because 6 patients presented peculiar cholestasis with severe pruritus, similar to progressive familial and benign recurrent intrahepatic cholestasis (PFIC and BRIC). This specific MVID-associated liver disease has been described recently by us and others (20,21), and we are further characterizing it. The treatment is difficult, and surgical solutions aimed at disrupting the enterohepatic cycle, used in PFIC and BRIC, are not satisfactory after SBTx because they decrease the absorption capacity of the transplanted small bowel. Future works on the role of myosin Vb in bile excretion will probably give us some insights into the mechanism of this aspect of MVID. Other patients, however, presented more common PN-associated liver disease, with early severe histological lesions, including fibrosis and cirrhosis. The prolonged inability to cycle PN and episodes of infection and dehydration are certainly aggressive factors affecting the liver, perhaps in conjunction with particular genetic susceptibility (15,27). The maintained inability to provide enteral feeding is probably another important risk factor in the development of such cholestatic liver disease. Protection of the liver on PN includes not only the control of these factors but also, when indicated, the use of new fish oil emulsions (28,29).
Significant osteoporosis before SBTx was most probably also a consequence of PN, complicating the care after SBTx, when steroids are mandatory. Pulmonary disease was reported here for the first time in siblings; however, we cannot conclude whether it was related to MVID or to another genetic factor in this consanguineous family.
Many of the complications described here are irreversible (developmental delay), will probably worsen (renal disease, osteoporosis), or improve insufficiently (growth failure) after SBTx. It is, therefore, of paramount importance for the overall prognosis that as soon as the diagnosis of MVID is suspected, these children be referred to specialized centers with expertise in long-term PN and MVID to optimize their management. Before SBTx, we attempted, albeit not always successfully, to implement nutritional recommendations for all of the children, and we shared these recommendations with the primary gastroenterologists of patients living outside France. After SBTx, patients followed a specific protocol outlined in Paris, which was also shared with the primary medical team of children. These guidelines have changed over time thanks to published data and growing experience (16).
SBTx is a difficult procedure, with significant mortality and morbidity and limited experience and follow-up, in comparison to the Tx of other organs (30,31). Nevertheless, and notwithstanding the small number, more transplanted patients than nontransplanted ones have survived. We recently reported the results of our 13-year experience with SBTx for different causes of intestinal failure, including MVID (32). The patient survival rate was similar to that of MVID and other intestinal diseases (63% vs 68%), but the graft survival rate was better (54% vs 42%). Of major importance for overall quality of life, many children could be discharged after SBTx. In general, in children receiving long-term PN, defining the optimal timing for SBTx is not easy because of its risks and the relatively good quality of life on uncomplicated home PN (15). However, PN in MVID is always complicated, and home PN is possible relatively late in life. Although our updated results on SBTx in MVID are worse than reported previously (11) due to late graft losses, we still think that because of potentially severe and irreversible complications on PN, MVID is an indication for SBTx as early as possible (11–33). In our patients, only the unavailability of donors prevented the performance of SBTx before 3.5 years of age. That is why we think that the child should be listed as soon as there is a reasonable chance of locating a donor (eg, 6 months of age).
In conclusion, MVID is one of the most severe congenital intestinal disorders. Its long-term prognosis depends highly on an early therapeutic program, from expert PN management to SBTx. Early referral of these patients will help decrease the severe complications of PN. It is hoped that further improvements in SBTx will lead to constant enhancement in patients' quality of life. Genetic counseling for families with an affected sibling or a history is also crucial.
We thank Prof Jacques Schmitz for his great help in reviewing this work. We also thank all of the colleagues who referred these patients and with whom their follow-up was shared.
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This article has been cited 3 time(s).
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