Microvillus Inclusion Disease 

Updated: Oct 06, 2017
Author: Stefano Guandalini, MD; Chief Editor: Carmen Cuffari, MD 

Overview

Background

Microvillus inclusion disease (also referred to as congenital microvillus atrophy) is, with Tuft enteropathy, the best known disease of the intestinal epithelium causing intractable diarrhea of infancy, and a leading cause of secretory diarrhea in the first weeks of life. A group of infants with a familial enteropathy characterized by protracted diarrhea from birth and villus hypoplastic atrophy had been described in 1978 by Davidson et al.[1] The term microvillus atrophy was first used to identify the disease in 1982. The typical clinical presentation is watery profuse secretory diarrhea starting in the first hours of life. The peak age of onset is the early neonatal period. Although later-onset cases have been described, cases have never been described beyond the first 2-3 months of life.

Three variants of the disease have been identified: Microvillus inclusion disease, late-onset microvillus inclusion disease, and atypical microvillus inclusion disease.

In microvillus inclusion disease, diarrhea starts in the first few days of life and is immediately life threatening. Oral alimentation in nutritionally significant amounts is impossible. In late-onset microvillus inclusion disease, diarrhea starts later in life, usually in the second month. Diarrhea tends to be less severe than in the other form, and some alimentation is possible. A few cases have been termed atypical microvillus inclusion disease, in which the onset can be congenital or late, but the histologic picture is different.

The hallmark of the disease is the electron microscopic finding of disrupted enterocyte microvilli (ie, digitations of the apical membrane of the intestinal epithelial cell protruding into the lumen) and the appearance of characteristic inclusion vacuoles, the inner surfaces of which are lined by typical microvilli. Both lesions are seen only on electronic microscopy. In a notable percentage of consanguineous families, more than one child is affected; therefore, the disease appears to be transmitted as an autosomal recessive trait.

Pathophysiology

The pathogenesis of the disease, that had remained elusive for a long time, appears now to be associated with patient-unique, family-unique, and ancestry-unique mutations in the MYO5B gene, encoding the actin-based motor protein myosin Vb.

These mutations lead to severe perturbation of the microvillar cytoskeleton disrupting the transport of brush border components that have to be assembled at the apical membrane.

Biopsy samples from the small intestine of 2 infants with congenital microvillus inclusion disease were examined to analyze the membrane protein of the brush border. The samples demonstrated striking diminutions of the myosin bands. The genetic defect appears likely to cause abnormal binding of the myosin to the actin cable. In one patient with late-onset microvillus atrophy, the molecular defect involved a different protein, supposedly identified as vinculin.

Other studies have suggested an alternative hypothesis, namely that a defect in the autophagocytosis pathway[2] or an increase in enterocyte apoptosis and proliferation[3] explains the abnormalities observed in congenital microvillous disease.

Recently, Dutch investigators have found[4] that the mild variant of microvillus inclusion disease appears to be caused by loss of function of syntaxin 3 (STX3), an apical receptor involved in membrane fusion of apical vesicles in enterocytes. In fact, whole-exome sequencing of DNA from patients with variant microvillus inclusion disease revealed homozygous truncating mutations in STX3; and in addition, patient-derived organoid cultures and overexpression of truncated STX3 in CaCo2 cells recapitulated most characteristics of variant microvillus inclusion disease.

The postulated abnormality in the cytoskeleton causes a block in exocytosis, mainly of periodic acid-Schiff (PAS)–positive material (eg, polysaccharides, glycoproteins, glycolipids, neutral mucopolysaccharides). As a consequence, small secretory granules that contain a PAS-positive material accumulate in the apical cytoplasm of epithelial cells.

Substantial progress has been made in identifying the molecular nature of the secretory granules. A neutral, blood group antigen–positive glycosubstance that contains acetylated sialic acid accumulates in these granules. Acetylated sialic acid has been identified as a common component of the glycocalyx, suggesting that microvillus atrophy involves a defect in exocytosis of the glycocalyx or some of its components. To support this possibility, immunoreactivity against glycocalyx is found in secretory granules in microvillus atrophy.

The microvilli in the brush border are scanty, disorganized, and short.

Because of these alterations, mature enterocytes inefficiently absorb ions and nutrients, causing a malabsorption syndrome; however, the diarrhea is caused mainly by active secretion of water and electrolytes in the intestinal lumen (secretory diarrhea). The pathogenesis of the secretory diarrhea is unknown; it is assumed to result from an unbalance between decreased absorption and unaltered secretion. Data suggest that the morphologic changes of the disease result in a secondary decrease in the amount of messenger RNA (mRNA) encoding for apical membrane-transport systems.

Epidemiology

Frequency

United States

A cluster of cases from the Navajo reservation in northern Arizona suggests an incidence as high as 1 case per 12,000 live births.

International

A survey completed in 1987 among centers known for their involvement in pediatric gastroenterology identified more than 30 cases worldwide. Additional cases were later published, including a series of 17 cases from the United Kingdom between 1990-2008[5] . Typical microvillus inclusion disease accounts for 80% of cases. The remaining 20% are due to mainly late-onset disease.

To better define this rare condition and its prevalence worldwide, an online MOLGENIS-based international patient registry has been constructed.[6] This easily accessible database currently contains detailed information of 137 patients with microvillus inclusion disease together with reported clinical/phenotypic details and 41 unique MYO5B mutations, several of which unpublished.

Mortality/Morbidity

The survival of patients with typical cases depends on total parenteral nutrition (TPN). Most infants of early series died when aged 3-9 months. The leading causes of death were dehydration, malnutrition, and sepsis.

Successful outcomes of small intestinal transplantation have been reported, and evidence suggests that an early transplant might be beneficial.[7, 8, 9] However, the prognosis remains poor, with most patients dying by the second decade of life as a result of complications of parenteral alimentation. Even patients who have undergone small-bowel transplantation have a mean 5-year survival rate of about 50%. Patients with late-onset or variant microvillus inclusion disease appear to have an improved prognosis.

Sex

A female preponderance has been observed among the published cases, with a female-to-male ratio of 2:1.

Age

The classic form of microvillus inclusion disease appears in the first 72 hours of life (usually on the first day) and is immediately life threatening. Late-onset microvillus atrophy starts after 6-8 weeks in a normal-appearing infant.

 

Presentation

History

Pregnancy and birth are usually normal in individuals with microvillus inclusion disease, and polyhydramnios is usually absent, in contrast to the clinical picture of patients with other causes of congenital secretory diarrhea. However, in some cases polyhydramnios and bowel dilation in the third trimester have been described.[10] In one case, a high fetal alpha-fetoprotein in the second trimester was observed.[11] Authors have speculated that the fetal alpha-fetoprotein elevation might possibly be caused by in utero body fluid leakage into the amniotic fluid through fetal enteropathy.

Severe diarrhea typically appears in the first days of life, usually within the first 72 hours, but a late-onset form is also known, with onset at 6-8 weeks of age. The stools are watery, and the stool output is 100-500 mL/kg/d when the infant is fed, a volume comparable to or higher than that observed in cholera. The diarrhea is of secretory type; therefore, it persists at a stable rate of 50-300 mL/kg/d despite fasting, and the electrolyte content of the stools is increased, without an osmotic gap. However, the mucosal atrophy causes osmotic diarrhea. For this reason, alimentation increases the fecal output. Because of the high output, patients can lose up to 30% of their body weight within 24 hours, resulting in profound metabolic acidosis and severe dehydration.[12]

The infant rapidly becomes dehydrated unless vigorous intravenous rehydration is started.

Microvillus inclusion disease is usually characterized by growth retardation and some developmental delay later in infancy. Associated abnormalities include Meckel diverticula, abdominal adhesions, inguinal hernias, renal dysplasia, an absent corpus callosum, and hydronephrosis. Recently, hepatic adenomas have also been described.[13]

Furthermore, microvillus inclusion disease has been reported in association with Down syndrome and aganglionic megacolon.

Physical

The infant appears severely dehydrated. Growth retardation and some developmental delay are usually present. No other specific findings can be detected. However, the disease is associated with other abnormalities, including Meckel diverticulum, mesenteric duct remnants, craniosynostosis, abnormal vertebrae, an absent corpus callosum, and hydronephrosis.

Causes

Microvillus inclusion disease is an autosomal recessive disease, the pathogenesis of which is illustrated in the section on pathophysiology.

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Measurements of stool electrolytes and osmolality enable rapid and accurate assessment of the pathogenesis of this important chronic diarrhea (osmolar vs secretory) and greatly narrow the differential diagnoses of microvillus inclusion disease.

In assessing the nature of diarrhea, remember that stool samples should be sent for electrolyte and osmolarity measurements only if patients have liquid stools.

Fecal electrolytes demonstrate a typical pattern of secretory diarrhea. Fecal sodium levels are high (approximately 60-120 mEq/L), and no osmotic gap is found. In patients with secretory diarrhea, the following formula applies: 2(Na concentration + K concentration) = stool osmolarity ± 50. In osmotic diarrhea, stool osmolarity exceeds 2(Na concentration + K concentration) by 100 or more.

In osmotic diarrhea, findings on stool microscopy are negative for WBCs, blood (exudative diarrhea), and fat (steatorrhea).

Secretory diarrhea occurs in the fasting state and is associated with large output losses that cause dehydration and metabolic acidosis.

The stool culture is likely negative in prolonged diarrhea, as well as in a diarrhea that lacks blood, a finding that suggests no invasive bacteria.

Serum electrolyte levels may be very useful in the management but add little information to establish a diagnosis.

Cystic fibrosis, the most common cause of pancreatic insufficiency, is best confirmed or ruled out by performing the sweat test.

Other Tests

Findings from duodenal biopsy must not be considered diagnostic. Histologic results of duodenal biopsy samples can range from essentially normal to mildly abnormal, showing the following:

  • Thin mucosa caused by hypoplastic villus atrophy

  • Diffuse villus atrophy (loss of villus height)

  • Crypt hypoplasia

The diagnosis rests on findings demonstrated by electron microscopy (see Histologic Findings).

Rectal biopsy findings demonstrate microvillous involutions and an increased number of secretory granules. This test has been proposed as a relatively easy method for making an early diagnosis.

Histologic Findings

Electron microscopy demonstrates well-preserved crypt epithelium with abundant microvilli. Villus enterocytes are severely abnormal, particularly toward the apices of the short villi. The microvilli are depleted in number, short, and irregularly arranged. Some of the enterocytes contain the typical microvillus involutions, which are intracellular vacuoles where microvilli are observed lining the inner surface. A striking feature is a number of small, membrane-bound vesicles containing electron-dense material.

A few cases have been described in which the classic microvillous inclusions are shadowed by other features, such as large aggregates of electron lucent, vermiform membranous vesicles in enterocyte cytoplasm.[14, 15]

PAS staining of the intestinal biopsy sample reveals PAS-positive material in the apical cytoplasm. The normal linear staining of the glycocalix is absent. PAS accumulates in low crypts in atypical microvillus atrophy, in upper crypts in congenital microvillus atrophy, and in low villi in late-onset microvillus atrophy.

Anti-CD10 immunohistochemistry shows a marked enlargement of the stained band that appears doubled compared with controls.[16, 17] CD10 is a neutral membrane-associated peptidase; thus, abnormal stain findings with PAS or anti-CD10 immunohistochemistry are expressions of the abnormalities in microvillar structure.

 

Treatment

Medical Care

Several drugs have been tried to counteract the massive secretory diarrhea in patients with microvillus atrophy; however, none has proven effective. At present, the only available therapy is total parenteral nutrition (TPN). Agents tentatively given to induce a better growth of the intestinal mucosa (eg, epithelial growth factor, colostrum) are ineffective. Antisecretagogue agents (eg, somatostatin, octreotide, loperamide, chlorpromazine) can reduce the stool output, but the clinical significance of this effect is marginal.

Surgical Care

Successful transplantation of the small intestine may allow for the patient's survival without TPN. Transplantation appears to be the only option for patients who do not fare well with long-term TPN (eg, because of sepsis, liver damage, lack of vascular access). Although only small series have been reported, evidence suggests that early small-bowel transplantation should be performed.

The analysis of 16 patients who underwent a small-bowel transplantation[18] shows anyway a lower death rate compared to those who did not (23% versus 37%) after an average 3.5 years observation period (but variable between 3 mo and 14 y). In all of the cases, apart from the first 2, the colon had been transplanted too.

Diet

In most patients with early-onset MVID, no intake by mouth is possible. In the late-onset variant, minimal oral intake may be possible.

Except for rare, documented exceptions, no improvement of the condition is observed. Food intolerance remains complete in the overwhelming majority of patients described.

Long-term nutritional support is accomplished with TPN.

For patients in whom transplantation is successful, a gradual return to a normal diet is considered possible.

 

Medication

Medication Summary

Several drugs, including epidermal growth factor, octreotide, glutamine, and chlorpromazine, have been tried to counteract the massive secretory diarrhea in patients with microvillus atrophy. However, none have been proven effective.

 

Follow-up

Complications

Acute episodes of dehydration and metabolic decompensation are common complications. Neurological and psychological symptoms (eg, developmental delay) may be related to the hypovolemia-related temporary ischemia.[19] Impaired renal function and nephrocalcinosis may also occur. Infectious complications of the central line that result in sepsis are the most frequent causes of death, followed by liver failure.[12]

Multiple hepatic adenomas have recently been described in a child with microvillus inclusion disease.[13]

Prognosis

The prognosis is poor. If patients are untreated, the disease is rapidly fatal because of dehydration and malnutrition.

If patients are treated with total parenteral nutrition (TPN), their prognosis entirely depends on the complications of this approach. These complications include cholestasis with subsequent liver damage leading to cirrhosis, catheter-related sepsis due to infection with bacterial or fungal agents, and progressive lack of vascular access.

The limited experience accumulated in a few centers worldwide reflects an overall survival rate of approximately 50% at 5 years after small-bowel transplantation; this is a much better outcome than is seen with other indications for intestinal transplantation.[9]

Children with late-onset congenital microvillous atrophy usually have less severe diarrhea; with age they can reduce the requirements of TPN to 1-2 per week.