protracted diarrhea in infancy

Indian J Pediat 51: 55--63, 1984

Protracted diarrhea in infancy

B h u p i n d e r K. S a n d h u , M.R.C.P.and P e t e r J. Milla, M.R.C.P.

Protracted diarrhea may be defined as the passage o f four or more watery stools per day for a period of two weeks or more, dur ing which time the patient loses or fails to gain weight. Infants presenting with protracted diarrhea pose major problems in diagnosis and management . The diarrhea is often devastating and their general condi t ion so poor as to preclude intensive investigation. Whilst protracted diarrhea may be due to a wide variety of condit ions, in a small proportion a diagnosis canno t be made. Our know- ledge regarding the pathophysiology of the diarrhea in this latter group is f ragmentary and the mechanisms poorly understood.

Etiology of protracted diarrhea Protracted diarrhea may result from a

wide variety of etiologies (Table I) but in only some 60-70 percent o f the patients will a specific condi t ion be recognisable. L2 In the remaining 30 percent despite extensive investigation a diagnosis cannot be made and is termed idiopathic. Out of 82 infants presenting with protracted diarrhea, Larcher et al 2 were able to identify the cause in 59 (72%); the commones t diagnoses being coeliac disease (33.2%), disaccharide intolerance (12.2%) and cow's milk protein intolerance (11,3%). Other condi t ions found included pr imary sucrase-isomaltase deficiency, Shwachman ' s syndrome, ulcerative

institute of Child Health and the Hospital for Sick Children, Great Ormond Street, London.

Address for correspondence: Institute of Child Health, 31) Guilford Street, London WCIN I EH, U.K.

Table I. Differential diagnosis of protracted diarrhea in infancy

Causes Example

,4. B.

Idiopathic Secondary Acquired sugar intolerance Acquired protein intolerance Coeliac disease Pancreatic insufficiency

Extraintestinal infections

Intrauterine infections Surgical anomalies

Following abdominal surgery Selective inborn errors of absorption and digestion

Enterocolitis Immune deficiency states

Inflammatory bowel disease Tumours

Non accidental injury Endocrine

Lactose intolerance

Cow's mill soya, egg, fish, rice and chicken.

Cystic fibrosis, Shwach- man-Diamond syndrome, isolated pancreatic enzyme deficiency. Otomastoiditis, urinary tract infections, respira- tory tract infections. Cytomegalovirus. Hirschprung's disease. midgut malrotation. Short-gut syndrome

Congenital chloridorr- hea, glucose-galactose malabsorption, primary sucrase-isomaltase deficiency.

Severe combined immuno deficiency, x-linked hypogammaglobuline- mia, defective opsoni- sation. Ulcerative colitis, Crohn s disease. Neuroblastoma, histiocy- tosis. Laxatives. Adrenogenital syndrome, Addison's disease, thyro- toxicosis.

56 THE INDIAN JOURNAL OF PEDIATRICS Vol. 51, No. 408

Enteric Infection

Miscellaneous

Giardiasis, oacterial overgrowth. Acrodermatitis entero- pathica, intestinal lympr, hangiectasis, Abetali- poproteinemia, renal tubular acidosis, auto- immune disease, congenital idiopathic intestinal pseudo-obstruction.

colitis, ganglioneuroma, defective opsoniza- lion, staphylococcal pneumonia and Hirs- ehprung's disease. The overall mortality for the whole series was 5 percent, all four deaths were among infants with 'idiopathic protracted diarrhea', In India Arora et al ~ were able to identify the cause in 76 percent of the consecutive infants presenting to them with protracted diarrhea, the commonest factor being secondary disaccharide intolerance (32%) and milk protein intolerance (24%). The overall mortality rate was 16 percent.

Pathophysiology of protracted diarrhea Intolerance to disaccharides, cow's milk

protein, gluten or other proteins such as soya bean may be associated with small intestinal enteropathy and is often preceded by an attack of acute gastroenteritis. It has been suggested that an acute infective insult may be the prime event in sensitizing the small intestine to foreign proteins. 2 A wide variety of dietary proteins including cow's milk, wheat, eggs, soya, fish, rice and chicken have now been shown to be capable of inducing enteropathy and gastrointestinal symp- toms. 4,5,6 The presence of minor immunodeficiency seems important 6,7 in the pathogenesis of the enteropathy and may also con- tribute to the presence of bacterial infection, bacterial overgrowth of the small intestine being especially common in malnourished

children, s-II The ability of bacteria to adhere to the mucosal surface of the small intestine is probably essential for colonisation and for their ability to produce disease. Candy et al found increased adhesion of Esctt coil (01- K1-H7) to mucosal cells from infants with protracted diarrhea compared to children with acute diarrhea, and healthy infants and adults.t2 In addition enterobacteria isolated from the jejunum or stools of patients with protracted diarrhea adhered to far greater numbers of their own buccal epithelial cells compared with healthy adults, suggesting that bacterial adhesion may play an important role in the pathogenesis of protracted diarrhea. The presence of IgA deficiency 6 and other minor immune defects appear important in this process and may be present as either an inherited defect or as a consequence of malnutrition. This may explain why following acute enteric infection only some children develop protracted diarrhea.

Bacteria may cause diarrhea by a variety of mechanisms including small intestinal mucosal invasion, elaboration of toxins and metabolism of luminal substrates to produce toxic metabolites. A variety of toxins elaborated by bacteria commonly found in the duodenum of infants with protracted diarrhea (Esch.coli, Clostridium perfringens, Kleb pneumoniae) have been shown to cause active secretion and inhibition of intestinal fluid and electrolyte absorption in the experimental animal. L315 A number of intraluminal substrates may be metabolised by bacteria )o produce products of patho- physiological importance, such as deconjugated bile acids (deoxycholate or cheno- deoxycholate) and hydroxy fatty acids. Deoxycholate is known to induce secretion in the small and large intestine of the experimental animal; at high concentration bile acids produce obvious mucosal damage whilst at low concentration in the jejunum

SANDHU AND MILLA : PROTRACTED DIARRI-FEA 57

Na+K+ATPase is inhibited, 16"|8 and in the colon adenylate cyclase is activated. 19-2~ Hydroxy fatty acids similarly activate Colonic adenylate cyclase. 21 Deconjugated bile salts in particular have been found in the duodenalcontents of some infants wi th protracted diarrhea and clearly may con- tribute to the diarrheal process. 22,~3

More recently auto-immune processes have been shown to play a role in the pathogenesis of protracted diarrhea in some infants. Savage eta[ 24 have reported 2 cases and Walker-Smith 25 one case of protracted diarrhea in whom autoantibodies to intestinal enterocytes were present as part of a polyendocrinopathy syndrome.

The pathophysiology of the progression of the diarrheal illness which may be trivial at onset, to a severe and life threatening disease is presently unexplained, but it is likely that as suggested by the above factors the mechanisms involved are complex and mul- tifactorial. It at least seems clear that a vicious cycle of malabsorption--malnutrition--is responsible for the perpetuation of the diarrhea in many cases.

Idiopathic protracted diarrhecL A specific diagnosis cannot be esta-

blished despite extensive investigations in an appreciable proportion of patients with protracted diarrhea particularly in those. presenting at or some after birth. |~26-2s Candy et a127 reported 24 children with protracted 'cholera like' diarrhea from 10 families, in which at least one sibling was affected. In two families the siblings were from 1st cousin marriages. In addition to gastrointestinal anomalies, extraintestinal anomalies were common. The mortality was high, 21 (87.5%) infants died after an illness that lasted between 12 days and 6 yr, despite periods of prolonged intravenous feeding and the administration of a wide variety of

pharmacological agents. Candy et a/27 termed this condition 'lethal familial protracted diarrhea'. Two other reports have described familial protracted diarrhea also with a high mortality rate. 26-~ The family histories were compatible with an autosomal recessive mode of inheritance, but studies by David- s o n eta126 and Milla eta129 suggested that this was a heterogenous group of conditions. Milla et aF 9 studied transport of water electrolytes and hexoses in the proximal je junum and colon of 6 infants with lethal familial protracted diarrhea. In 5 of the 6 infants the je junum was in a marked secretory state, in the 6th water absorption was markedly reduced. Absorpiion of glucose and fructose was markedly impaired in all the infants as was the glucose evoked trans- mural potential. In the proximal jejunum glucose failed to induce an increase in Na + and water adsorption in 3 of the patients. Estimation of the activity of the two transport enzymes Na+K+ATPase and adenylate cyclase showed a marked reduction o f Na+K+ATPase activity in the 5 infants with marked secretion, the adenylate cyclase activity was variable. Colonic transport in these infants appeared normal suggesting that the diarrhea was due to small intestinal secretion overwhelming the reabsorptive capacity of the colon. In the families studied by Davidson et a126 all suffered from a crypt hypoplastic villous atrophy. Trans- port studies in. the proximal jejunum showed glucose absorption to be reduced and the response o fNa + absorption to both glucose andphenylalanine impaired. In two of the three patients studied there was net secretion of water and sodium in the basal state; the clinical course of the third patient was milder and ,cle.arly different. In both studies, in addition to the active secretory process the defect in glucose absorptiofi could be accounted for-by either abnormal

58 T H E I N D I A N J O U R N A L O F P E D I A T R I C S Vol. 51 , No. 4 0 8

Na + coupled organic solute translocation at the apical cell membrane or by a defect in Na + extrusion at the baso-lateral cell membrane. In the infants studied by MiUa et a129 at least the latter was playing a role. However the findings of both studies could be accounted for if the enterocytes populating the villous were immature and retained their 'crypt-like' characteristics. Thus a defect in cell differentiation and replication may also play a role and this may be either an acquired or inherited defect.

The non familial cases of idiopathic protracted diarrhea may have a better outlook. Larcher et al z were able to show that 83 percent of their idiopathic group were not familial and in those (74%) in which diarrhea presented some time after birth (mean age 4.9 wk) the prognosis was extremely good (mortality 0%) and it was unusual for I/V nutrition to be required. Nearly all were managed on a diet based on comminuted chicken 3~ and thrived. Rossi et a131 have studied the extent and duration of small intestinal mucosal injury in 30 infants including 18 infants in whom no specific diagnosis could be established. Various degrees of villous atrophy were present in all the patients, and persisted for an average period of 6 months in 16 patients of the 23 who had repeat biopsies. Twelve infants required parenteral feeding and all were given an elemental diet. No mortality occurred during management and follow up, and weight and height velocities were satisfactory in the vast majority.

In vestigations Investigation of a patient with protracted

diarrhea should be carded out in a logical fashion (Table II). The examination of three stools usually excludes a specific bacterial or parasitic enteric infection but giardia lam- blia and sometimes other enteropathogens

Table II. Investigation o f protracted d iar rhea

Condition Preliminary Further screening screening and specific

investigations

Sugar intolerance Stool PH and re- Sugar loading tests ducing substances, with chromato-

graphy,. Cow's milk protein Cow's milk efimi- Rechalltnge with intolerance nation cow's milk and

small intestinal biopsy.

Coeliac disease Small intestinal Gluten free diet biopsy followed by biopsy.

controlled gluten challenge.

Cystic fibrosis Sweat test Pancreatic function test and repeat sweat tesL

Extraintestinal White cell diffren- Full infection infections tial screen including

investigation of sinuses.

Intrauterine infec- igM and TORCH Specific lgM and tions screen culture for viruses. Surgical anomalies Abdominal X-ray Barium studies.

rectal biopsy for Hirschprong's disease.

Congenital chlori- Stool electrolytes Intestinal perfu- dorrhea and PH sion studies. Inflammatory Barium studies Endoscopy, biopsy bowel disease of affected region. Immune deficiency Lympocyte counL Full immunologi- states immunoglobulins cal screen. Tumours Ultrasound exami- Gastro intestinal

nation, IVP polypeptides, cate- cholamines.

Enteric infection Stool microscopy Duodenal aspirate. and culture toxin assays e.g. CI.

difficile.

may be t0uno only in the duodenal aspirate or duodenal biopsy. Examination of stool material by electron microscopy or counter immuno-electrophoresis may demonstrate a primary or coincidental viral infection. A full blood count and an infection screen should be performed to exclude extraintestinal infection including occult infection such as mastoiditis. 32 Early in the course of the disease surgical conditions should be

SANDHU AND MILLA : PROTRACTED DIARRH~.A 59

sought as these may be immediately remedi- able. Radiographs with contrast material are necessary, and if there is any suspicion of Hirschprung's disease rectal biopsies should be taken.

Evaluation of the histology and enzyme activity of proximal small intestinal mucosa by peroral small intestinal biopsy should be done when coeliac disease, acquired cow's milk protein enteropathy, abetalipop- roteinemia, intestinal lymphangiectasia and primary disaccharidase deficiency are suspected. Althouzh ulcerative colitis and granulomatous ileocolitis are very rare in the first year of life, colitis due to food allergic disease is not and may be the commonest cause of inflammatory bowel disease in infancy. 33 Endoscopy and barium studies should be considered in suspicious cases, Steatorrhea is usually clinically obvious but pancreatic function testing may be necessary to exclude pancreatic insufficiency. In over 95 percent of cases of cystic fibrosis a sweat test is all that is necessary. Shwach- man's syndrome might be suggested by a combination of metaphyseal dysosteosis and defective neutrophil numbers and function. Immunodeficiency is an important factor and when a good nutritional state has been restored, specific tests of immune function should be carried out. Tests of both B and T cell function should be employed including immunoglobulins, complement levels, tests of opsonization and neutrophil killing and PHA response. Thyroid hor- mone, calcitonin, VIP, gastrin and catechola- mine levels may be abnormal in endocrine disorders associated with diarrhea or tumors secreting ectopic polypeptides. Familial chloride losing diarrhea should be suspected in every case of diarrhea starting from birth especially where there is a history of polyhydramnious. In the older infant a stool C I - concentration which exceeds the

sum of stool Na + and K + concentration is highly suggestive of the diagnosis.

Treatment

In all infants with protracted diarrhea any dehydration and electrolyte imbalance should first be corrected. Then ifa diagnosis is not readily apparent dietary treatment using an oligoantigenic formula should be started whilst the results of laboratory investigations are awaited. In our experience a chiken based formula has been most suc- cessful. Comminuted chicken provides a hypoallergenic protein source and essential fatty acids. 3~ Carbohydrate and fat are gradually added in the form of a glucose polymer, Gastrocoloreen and long chain triglycerides as are vitamins and a mineral supplement. This formula provides all the essential nutrients required for optimal growth. It has relatively low osmolarity, is -well tolerated by infants, is relatively cheap and is very effective 2.3~ It is essential if the chicken based formula is to be used that scrupulous attention is paid to details of its composition. Clear and detailed instruc- tions for its use are provided by Francis. 3~ Coconut oil may be substituted for Pros- parol. 3 Pregestamil (Mead Johnson) can also be successfully employed as an elemental diet and is based on a casein hydrolysate. If there is not a rapid response to dietary manipulations, parental nutrition (PN) should be started at an early age and may be life saving in marasmic children. 3435 There is no good evidence that 'resting the bowel' of infants with diarrhea has any therapeutic benefit. Children on PN should receive some oral feed as intraluminal substrates exert a trophic effect on the small intestinal mucosa the effect being mediated by certain GI hormones 36 and thus minimizes the atrophy that occurs on PN when no oral


leeds are given. Specific management of secondary protracted diarrhea is according to the specific diagnosis made (see Table I).

In cases where a specific diagnosis cannot be made or diarrhea continues to pose a major problem a number of therapeutic agents may be tried in addition to therapy with PN or oral oligoantigenic feeds. These include cholestyramine, corticosteroids, prostaglandin synthetase inhibitors, phenotha- zincs and opioid analogues. In our experience phamacological agents may at times be life saving in protracted diarrhea and in severe situations have a place in the management of the diarrheal state. However their role in acute diarrheal states remains controversial and is at best only adjunctive to maintenance of hydration and nutrition.

Tamer et ai 37 used oral cholestyramine to treat seven patients with intractable diarrhea and suggested that the mode of action of the drug may be through binding of exotoxin or unconjugated bile acids in the intestinal lumen. However cholestyramine therapy may be associated with serious side effects including intestinal obstruction, hyperchloremic acidosis, hypernatremia and steatorrhea and its use should be con- fined to those cases in which bile acid malabsorption has been established. Steroids may have an effect by enhancing active intestinal absorption of electrolytes and water perhaps by stimulation of Na-K- ATPase activity, as They do not inhibit intestinal secretion. 3~ Endogenous prostaglandin synthesis plays a role in the intestinal regula- tion of basal salt and water absorption. Salicylates and indomethacin may enhance basal a'bsorption by interfering with pros- tagland in synthesis, lndomethacin has however proved relatively ineffective in inhibiting cholcraloxinc induced secretion in both in rivo "u~ and in vitro studies. 41

Antisecretory agents may be of benefit to

children whose diarrhea continues despite nil by mouth and we have successfully used loperamide to treat some children with severe protracted diarrhea. 42 Fig. illus- trates the effect of this drug on the daily stool volume of one of these children. Lopera- mide is an opioid which if given orally has a very restricted access to the central nervous system and is thus safer to use than other opioids, but over-dosage may result in ileus. Until recently it antidiarrheal action was thought to be mediated solely via an effect on intestinal motility. However, in viva studies in both man 43 and the experimental animal 44.45 have shown that loperamide has potent antisecretory activity against a variety of secretagogoues including cholera toxin, prostaglandin E2 and deoxycholic acid. Loperamide is however totally ineffective in modifying the osmotic effects ofhypertonic mannitol. 45 Despite much recent work the mechanism of action of opioids on water and electrolyte movement across the intestinal epithelium remains obscure save that opioid receptors are involved, and known pathways of cyclic nucleotide metabolism are unaffected. 46.47 Loperamide binds to purified Calcium Dependent Regulator protein (CDR) in the presence of Ca 2+ but this binding unlike the antisecretory effect of Ioperamide is not affected by the opioid antagonist Naloxone (Sandhu, Hyland and Milla, unpublished observations) and its relevance is at the moment unclear.

The phenothiazine, choloropromazine has been shown to clearly reduce intestinal secretion in cholera 4s and it is currently thought to do this by inhibiting CDR. 49.~ However its effects on the CNS, particularly sedation limit its usefulness as a therapeutic tool.

As our understanding of the patho- physiological mechanisms involved in protracted diarrhea increases it may be possible

SANDHI)' AND MILLA : PROTRACTED DIARRHEA 61

"6 .9o U3

2 4 t 6 8 , 10 12 14 t

Time (doys) Loperomide (8 mg124hours) LoperQmJde sto, rt s top

r 1

16

Fig. 1. The effect of loperamide on the daily stool volume of an infant with severe protracted diarrhea.

to develop and institute appropriate therapy and take preventive measures b a s e d on rational scientific principals more effectively.

Acknowledgement

We are indebted to our friend, mentor and colleague the late Professor John Harries, without whose guidance and encouragement our work outlined here would not have been possible. BS gratefully acknowledges financial support from Janssen Pharmaceuticals Ltd.

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protracted diarrhea in infancy

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