AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 9, NUMBER 5/6
Sept/Nov 1992
PRENATAL PRESENTATION OF CONGENITAL CHLORIDE DIARRHEA: CLINICAL REPORT AND REVIEW OF THE LITERATURE Nancy C. Rose, M.D., Paige Kaplan, M.B. B.Ch., Steven Scott, R.D.M.S., Andrew Kousoulis, M.D., and Ronald Librizzi, D.O.
ABSTRACT
The finding of hydramnios refractory to pharmacotherapy and therapeutic amniocenteses was determined after delivery to be compatible with congenital chloride diarrhea. Review of the current literature and the prenatal presentation of this disorder are discussed.
CLINICAL REPORT The patient was a 28-year-old G3P2002 white female who was noted to have a rapidly increasing fundal height at 24 weeks gestation. Ultrasonographic evaluation showed hydramnios, with an amniotic fluid index of 44 cm. Biparietal diameter and limb measurements were all consistent with 24 weeks' gestation. Massively dilated small and large bowel were seen, and no other fetal anomalies were detected (Fig. 1). With the diagnosis of a presumptive small bowel obstruction, a therapeutic and diagnostic amniocentesis was performed. Toxoplasmosis, rubella, cytomegalovirus, herpes simplex titers revealed no evidence of active infection, and fetal chromosome analysis returned 46, XX without any apparent cytogenetic abnormalities. One week later, a reaccumulation of the amniotic fluid was seen on ultrasonographic evaluation, necessitating another therapeutic amniocentesis. The patient returned for biweekly therapeutic amniocenteses with removal of 750 to 2000 cc of fluid at each procedure, and underwent a total of 25 amniocenteses. Regular Gram stains and cultures of the amniotic fluid showed no evidence of bacterial growth.
In the early third trimester, the patient developed preterm labor and was treated with indomethacin, 25 mg every 6 hours, and terbutaline, 5 mg every 4 hours, for the duration of her pregnancy. At approximately 32 weeks' gestation, she was admitted in labor, and subsequently delivered a 2773 gm viable female infant with Apgar scores of 3 and 8 at 1 and 5 minutes, respectively. At birth, abdominal distention was present, with the infant appearing dehydrated. Her neurologic examination was appropriate for age. A neonatal abdominal sonogram confirmed dilated loops of small bowel filled with fluid. Copious clear fluid drained from the rectum. The initial diagnosis was a gastrointestinal-genitourinary fistula. A voiding cystourethrogram showed a normal bladder without fistulas and barium enema showed a normal colon with a small area of possible ileal stenosis. Cystoscopy, retrograde pyelography, vaginoscopy and sigmoidoscopy confirmed that the ureters, bladder, and colon were normal. A retrograde gastric enema showed an apparent high-grade obstruction of the ileocecal valve. The infant was persistently alkalotic and hypotensive. The first uncorrected serum chloride value was 90 mEq/liter. At 24 hours of life, the infant underwent an exploratory laparotomy for the presumed small bowel obstruction. Due to the dilated loops of jejunum and ileum encountered at surgery, biopsy of the intestine was done in consideration of Hirschsprung megacolon, and biopsies of the abdominal wall, skin, and right kidney were also taken. After surgery, respiratory function was increasingly impaired secondary to the rapidly dilating loops of bowel. At
Department of Obstetrics and Gynecology, Division of Reproductive Genetics, University of Pennsylvania Medical Center, Department of Clinical Genetics, Children's Hospital of Philadelphia, Department of Maternal-Fetal Medicine, Pennsylvania Hospital, Philadelphia, Pennsylvania, and Department of Ob/Gyn, West Jersey Hospital, Voorhees, New Jersey Reprint requests: Dr. Rose, Department of Obstetrics and Gynecology, Division of Reproductive Genetics, University of Pennsylvania Medical Center, Philadelphia, PA 19104 398
Copyright © 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
Downloaded by: NYU. Copyrighted material.
A case of congenital chloride diarrhea was diagnosed after delivery in a patient whose antenatal course was notable for massively dilated small and large bowel and persistent, severe hydramnios refractory to therapy. The pathophysiologic mechanism is a dysfunctional chloride-bicarbonate exchange in the brush border of the ileum. Antenatal presentation, prenatal diagnosis, and a review of the current literature are discussed.
CONGENITAL CHLORIDE DIARRHEA/Rose, et al.
TRV SPINE
S328 19HZ DEPTII= 168 ATU :, PWR is 8dB 5@dB 8/2/1 GAIN- -6dB
48 hours of life a diverting ileostomy, placed just distal to the dilated bowel, was performed for decompression. When observed during surgery, the ileocecal valve obstruction appeared to be caused by dilated bowel compressing the normal valve. Neonatal management included replacement of a steady loss of 20 to 40 ml/hour of clear fluid from the rectum. Serial electrolyte studies on the ileostomy fluid noted the sodium to be 147 to 150 mEq/liter; chloride, 91 to 100 mEq/liter; potassium, 4.7 to 6.1 mEq/liter, and bicarbonate 12 to 15 mEq/liter. No creatinine was found in the fluid on several measurements. The persistent loss of sodium, potassium, chloride, and water into the bowel lumen with resultant abdominal distension and dehydration was considered to be a hypersecretory enteropathy, most likely congenital chloride diarrhea. Histologic examination noted ganglion cells throughout the bowel; the renal pathologic study revealed immature tissue of 32 weeks' gestation, dilated Bowman spaces, and dilated renal tubules. The juxtaglomerular apparatus was not hypertrophied. DISCUSSION Congenital chloride diarrhea is characterized by watery, profuse diarrhea with an increased chloride concentration. The onset of this disorder is intrauterine, complicated by hydramnios causing premature labor. No meconium is seen at delivery, presumably due to the dilute nature of the intraluminal bowel contents. In addition to the "diarrhea," the initial postnatal presentation includes dehydration, abdominal distention, hypochloremia, and hyponatremia, followed by hypokalemia. Hyperaldosteronism, confirmed on histologic examination by juxtaglomerular hyperplasia, is a secondary finding due to the persistent dehydration. A stool chloride level exceeding 90 mmol/liter is diagnostic.1 Congenital chloride diarrhea was first described by Gamble et al,2 who referred to the disorder as "congenital alkalosis with diarrhea." The description was modified by Perheenupta et al,3 noting that the alkalosis was not a congenital, but a secondary feature. The incidence is be-
tween 1 in 10,000 to 1 in 40,000 with no sex differentiation.4 It is an autosomal recessive condition, without a method to detect heterozygotes.4 There are approximately 50 reported cases, with about half of these originating from Finland, where an average of two new cases are diagnosed annually.1 The pathophysiology of congenital chloride diarrhea is a dysfunctional chloride-bicarbonate exchange in the brush border of the ileum (and possibly colon). This results in a marked loss of chloride in the stool. The resultant inability to resorb chloride against its concentration gradient is associated with a decrease in the bicarbonate loss in the bowel through its bicarbonate and chloride exchange mechanism. The decreased loss of bicarbonate acidifies the bowel contents, which limits the sodium and hydrogen exchange, impairing sodium resorption. Potassium and ammonia excretion increase in the bowel due to increased chloride loss in the stool. The increased osmotic gradient in the ileal fluid inhibits water resorption, leading to osmotic diarrhea. In Holmberg et al's1 series of 21 affected Finnish patients, all delivered prior to term, and 19 delivered at 34 weeks' gestation. Abdominal distention in the neonate is the primary reason for hospital admission.1 Several patients were believed to have an intestinal occlusion at birth, or an aganglionic segment of the colon. Four patients developed a volvulus, presumably secondary to the enlarged intestinal loops. Early signs may be overlooked: four patients were diagnosed as late as 6 months, wasted and inactive. To our knowledge, the oldest patient to present for diagnosis was a 31-year-old man with recurrent cramps and diarrhea exacerbated by a viral illness that made him anorexic.5 His longevity was attributed to his high salt diet and his mild manifestation of the disease. He did, however, develop chronic renal insufficiency. Pasternack et al6 noted a normal renal histologic picture in patients who had been treated with sodium chloride replacement since infancy. Biopsies in untreated patients have varying degrees of renal changes, including juxtaglomerular hyperplasia, interstitial fibrosis, and a characteristic vasculopathy, believed to be due to the persistent hypotension causing a secondary hyperaldosteronism.6 Classic juxtaglomerular changes seen with hypo- 399
Downloaded by: NYU. Copyrighted material.
Figure 1. Transverse view of fetal abdomen, demonstrating markedly dilated loops of bowel at 26 weeks' gestation.
AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 9, NUMBER 5/6
400
the need for exploratory laparotomy in these children otherwise suspected of an obstructive enteropathy.
REFERENCES
1. Holmberg C, Perheenupta J, Launiala K, Hallman N: Congenital chloride diarrhea. Arch Dis Child 52:255-267, 1977 2. Gamble JL, Fahey KR, Appleton J, MacLachan EA: Congenital alkalosis with diarrhea, j Pediatr 26:509-518, 1945 3. Perheenupta J, Eklund J, Kojo N: Familial chloride diarrhea ("congenital alkalosis with diarrhea"). Acta Paediat Scand 159 (Suppl):119-120, 1965 4. Norio R, Peeheenupta J, Launiala K, Hall N: Congenital chloride diarrhea: An autosomal recessive disease. Clin Genet 2:182-192, 1971 5. Wall BM, Williams HH, Cooke CR: Chloride resistant metabolic alkalosis in an adult with congenital chloride diarrhea. Am J Med 85:570-572, 1988 6. Pasternack A, Perheenupta J: Hypertensive angiopathy in congenital chloride diarrhea. Lancet 2:1047-1049, 1966 7. Restaino I, Kaplan BS, Kaplan P, et al: Renal Dysgenesis in a monozygotic twin. Association with an in utero exposure to indomethacin. Am J Med Genet 39:252-257, 1991 8. Hartikainen-Sorri AL, Tuimala R, Koivisto M: Congenital chloride diarrhea: possibility for prenatal diagnosis. Acta Paediatr Scand 69:807-808, 1980 9. Patel PJ, Kolawole TM, BaAqueel HS, Al'Jisi N: Antenatal sonographic findings in congenital chloride diarrhea. J Clin Ultrasound 17:115-118, 1989 10. Kirkinen P, Jouppila P: Prenatal ultrasonic findings in congenital chloride diarrhea. Prenat Diagn 4:457—461, 1984 11. Nyber DA, Hastrup W, Watts H, et al: Dilated fetal bowel. A sonographic sign of cystic fibrosis. J Ultrasound Med 6:257,1987
Downloaded by: NYU. Copyrighted material.
volemia were not observed in our patient, whose fluid balance was corrected within a short time of birth. It is postulated that the indomethacin therapy, given in an attempt to control the hydramnios during gestation, may cause reversible or irreversible kidney changes, such as the dilated Bowman spaces and renal tubules, noted in this case as well as in others.7 Prenatal diagnosis of this disorder has been described by Hartikainen-Sorri et al.8 A significant increase in bilirubin is found in the amniotic fluid of patients with congenital chloride diarrhea who do not have Rh incompatibility. The enzyme beta-glucuronidase converts bilirubin to its unconjugated form, which is resorbed through the fetal enterohepatic circulation and by the maternal circulation. Because of disturbed resorption, an increase in bilirubin is found in the amniotic fluid. Alpha-fetoprotein can also be increased in this disorder, since it normally remains in the gastrointestinal tract long enough to be partially degraded by intestinal enzymes. In congenital chloride diarrhea, it is transported much more rapidly through the bowel by osmotic diarrhea and is not degraded.8 However, the sensitivity of these tests have not been determined. Ultrasonographic prenatal diagnosis of this condition has been described.910 Massively dilated loops of bowel with a normal-appearing stomach and esophagus may reflect congenital chloride diarrhea rather than an obstructive process. In the latter, there may also be a secondary dilation of the stomach and upper intestinal tract.10 The differential diagnoses for dilated fetal bowel loops detected on ultrasound include Hirschsprung disease, bowel atresia, intestinal volvulus, and meconium ileus.9 Generalized bowel dilation and hydramnios can occur in cysticfibrosis,11but can also be associated with meconium ileus and calcifications. An amniocentesis to detect chloride levels, alpha-fetoprotein, and bilirubin would help diagnose congenital chloride diarrhea and perhaps avert
Sept/Nov 1992
Sept/Nov 1992
PRENATAL PRESENTATION OF CONGENITAL CHLORIDE DIARRHEA: CLINICAL REPORT AND REVIEW OF THE LITERATURE Nancy C. Rose, M.D., Paige Kaplan, M.B. B.Ch., Steven Scott, R.D.M.S., Andrew Kousoulis, M.D., and Ronald Librizzi, D.O.
ABSTRACT
The finding of hydramnios refractory to pharmacotherapy and therapeutic amniocenteses was determined after delivery to be compatible with congenital chloride diarrhea. Review of the current literature and the prenatal presentation of this disorder are discussed.
CLINICAL REPORT The patient was a 28-year-old G3P2002 white female who was noted to have a rapidly increasing fundal height at 24 weeks gestation. Ultrasonographic evaluation showed hydramnios, with an amniotic fluid index of 44 cm. Biparietal diameter and limb measurements were all consistent with 24 weeks' gestation. Massively dilated small and large bowel were seen, and no other fetal anomalies were detected (Fig. 1). With the diagnosis of a presumptive small bowel obstruction, a therapeutic and diagnostic amniocentesis was performed. Toxoplasmosis, rubella, cytomegalovirus, herpes simplex titers revealed no evidence of active infection, and fetal chromosome analysis returned 46, XX without any apparent cytogenetic abnormalities. One week later, a reaccumulation of the amniotic fluid was seen on ultrasonographic evaluation, necessitating another therapeutic amniocentesis. The patient returned for biweekly therapeutic amniocenteses with removal of 750 to 2000 cc of fluid at each procedure, and underwent a total of 25 amniocenteses. Regular Gram stains and cultures of the amniotic fluid showed no evidence of bacterial growth.
In the early third trimester, the patient developed preterm labor and was treated with indomethacin, 25 mg every 6 hours, and terbutaline, 5 mg every 4 hours, for the duration of her pregnancy. At approximately 32 weeks' gestation, she was admitted in labor, and subsequently delivered a 2773 gm viable female infant with Apgar scores of 3 and 8 at 1 and 5 minutes, respectively. At birth, abdominal distention was present, with the infant appearing dehydrated. Her neurologic examination was appropriate for age. A neonatal abdominal sonogram confirmed dilated loops of small bowel filled with fluid. Copious clear fluid drained from the rectum. The initial diagnosis was a gastrointestinal-genitourinary fistula. A voiding cystourethrogram showed a normal bladder without fistulas and barium enema showed a normal colon with a small area of possible ileal stenosis. Cystoscopy, retrograde pyelography, vaginoscopy and sigmoidoscopy confirmed that the ureters, bladder, and colon were normal. A retrograde gastric enema showed an apparent high-grade obstruction of the ileocecal valve. The infant was persistently alkalotic and hypotensive. The first uncorrected serum chloride value was 90 mEq/liter. At 24 hours of life, the infant underwent an exploratory laparotomy for the presumed small bowel obstruction. Due to the dilated loops of jejunum and ileum encountered at surgery, biopsy of the intestine was done in consideration of Hirschsprung megacolon, and biopsies of the abdominal wall, skin, and right kidney were also taken. After surgery, respiratory function was increasingly impaired secondary to the rapidly dilating loops of bowel. At
Department of Obstetrics and Gynecology, Division of Reproductive Genetics, University of Pennsylvania Medical Center, Department of Clinical Genetics, Children's Hospital of Philadelphia, Department of Maternal-Fetal Medicine, Pennsylvania Hospital, Philadelphia, Pennsylvania, and Department of Ob/Gyn, West Jersey Hospital, Voorhees, New Jersey Reprint requests: Dr. Rose, Department of Obstetrics and Gynecology, Division of Reproductive Genetics, University of Pennsylvania Medical Center, Philadelphia, PA 19104 398
Copyright © 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
Downloaded by: NYU. Copyrighted material.
A case of congenital chloride diarrhea was diagnosed after delivery in a patient whose antenatal course was notable for massively dilated small and large bowel and persistent, severe hydramnios refractory to therapy. The pathophysiologic mechanism is a dysfunctional chloride-bicarbonate exchange in the brush border of the ileum. Antenatal presentation, prenatal diagnosis, and a review of the current literature are discussed.
CONGENITAL CHLORIDE DIARRHEA/Rose, et al.
TRV SPINE
S328 19HZ DEPTII= 168 ATU :, PWR is 8dB 5@dB 8/2/1 GAIN- -6dB
48 hours of life a diverting ileostomy, placed just distal to the dilated bowel, was performed for decompression. When observed during surgery, the ileocecal valve obstruction appeared to be caused by dilated bowel compressing the normal valve. Neonatal management included replacement of a steady loss of 20 to 40 ml/hour of clear fluid from the rectum. Serial electrolyte studies on the ileostomy fluid noted the sodium to be 147 to 150 mEq/liter; chloride, 91 to 100 mEq/liter; potassium, 4.7 to 6.1 mEq/liter, and bicarbonate 12 to 15 mEq/liter. No creatinine was found in the fluid on several measurements. The persistent loss of sodium, potassium, chloride, and water into the bowel lumen with resultant abdominal distension and dehydration was considered to be a hypersecretory enteropathy, most likely congenital chloride diarrhea. Histologic examination noted ganglion cells throughout the bowel; the renal pathologic study revealed immature tissue of 32 weeks' gestation, dilated Bowman spaces, and dilated renal tubules. The juxtaglomerular apparatus was not hypertrophied. DISCUSSION Congenital chloride diarrhea is characterized by watery, profuse diarrhea with an increased chloride concentration. The onset of this disorder is intrauterine, complicated by hydramnios causing premature labor. No meconium is seen at delivery, presumably due to the dilute nature of the intraluminal bowel contents. In addition to the "diarrhea," the initial postnatal presentation includes dehydration, abdominal distention, hypochloremia, and hyponatremia, followed by hypokalemia. Hyperaldosteronism, confirmed on histologic examination by juxtaglomerular hyperplasia, is a secondary finding due to the persistent dehydration. A stool chloride level exceeding 90 mmol/liter is diagnostic.1 Congenital chloride diarrhea was first described by Gamble et al,2 who referred to the disorder as "congenital alkalosis with diarrhea." The description was modified by Perheenupta et al,3 noting that the alkalosis was not a congenital, but a secondary feature. The incidence is be-
tween 1 in 10,000 to 1 in 40,000 with no sex differentiation.4 It is an autosomal recessive condition, without a method to detect heterozygotes.4 There are approximately 50 reported cases, with about half of these originating from Finland, where an average of two new cases are diagnosed annually.1 The pathophysiology of congenital chloride diarrhea is a dysfunctional chloride-bicarbonate exchange in the brush border of the ileum (and possibly colon). This results in a marked loss of chloride in the stool. The resultant inability to resorb chloride against its concentration gradient is associated with a decrease in the bicarbonate loss in the bowel through its bicarbonate and chloride exchange mechanism. The decreased loss of bicarbonate acidifies the bowel contents, which limits the sodium and hydrogen exchange, impairing sodium resorption. Potassium and ammonia excretion increase in the bowel due to increased chloride loss in the stool. The increased osmotic gradient in the ileal fluid inhibits water resorption, leading to osmotic diarrhea. In Holmberg et al's1 series of 21 affected Finnish patients, all delivered prior to term, and 19 delivered at 34 weeks' gestation. Abdominal distention in the neonate is the primary reason for hospital admission.1 Several patients were believed to have an intestinal occlusion at birth, or an aganglionic segment of the colon. Four patients developed a volvulus, presumably secondary to the enlarged intestinal loops. Early signs may be overlooked: four patients were diagnosed as late as 6 months, wasted and inactive. To our knowledge, the oldest patient to present for diagnosis was a 31-year-old man with recurrent cramps and diarrhea exacerbated by a viral illness that made him anorexic.5 His longevity was attributed to his high salt diet and his mild manifestation of the disease. He did, however, develop chronic renal insufficiency. Pasternack et al6 noted a normal renal histologic picture in patients who had been treated with sodium chloride replacement since infancy. Biopsies in untreated patients have varying degrees of renal changes, including juxtaglomerular hyperplasia, interstitial fibrosis, and a characteristic vasculopathy, believed to be due to the persistent hypotension causing a secondary hyperaldosteronism.6 Classic juxtaglomerular changes seen with hypo- 399
Downloaded by: NYU. Copyrighted material.
Figure 1. Transverse view of fetal abdomen, demonstrating markedly dilated loops of bowel at 26 weeks' gestation.
AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 9, NUMBER 5/6
400
the need for exploratory laparotomy in these children otherwise suspected of an obstructive enteropathy.
REFERENCES
1. Holmberg C, Perheenupta J, Launiala K, Hallman N: Congenital chloride diarrhea. Arch Dis Child 52:255-267, 1977 2. Gamble JL, Fahey KR, Appleton J, MacLachan EA: Congenital alkalosis with diarrhea, j Pediatr 26:509-518, 1945 3. Perheenupta J, Eklund J, Kojo N: Familial chloride diarrhea ("congenital alkalosis with diarrhea"). Acta Paediat Scand 159 (Suppl):119-120, 1965 4. Norio R, Peeheenupta J, Launiala K, Hall N: Congenital chloride diarrhea: An autosomal recessive disease. Clin Genet 2:182-192, 1971 5. Wall BM, Williams HH, Cooke CR: Chloride resistant metabolic alkalosis in an adult with congenital chloride diarrhea. Am J Med 85:570-572, 1988 6. Pasternack A, Perheenupta J: Hypertensive angiopathy in congenital chloride diarrhea. Lancet 2:1047-1049, 1966 7. Restaino I, Kaplan BS, Kaplan P, et al: Renal Dysgenesis in a monozygotic twin. Association with an in utero exposure to indomethacin. Am J Med Genet 39:252-257, 1991 8. Hartikainen-Sorri AL, Tuimala R, Koivisto M: Congenital chloride diarrhea: possibility for prenatal diagnosis. Acta Paediatr Scand 69:807-808, 1980 9. Patel PJ, Kolawole TM, BaAqueel HS, Al'Jisi N: Antenatal sonographic findings in congenital chloride diarrhea. J Clin Ultrasound 17:115-118, 1989 10. Kirkinen P, Jouppila P: Prenatal ultrasonic findings in congenital chloride diarrhea. Prenat Diagn 4:457—461, 1984 11. Nyber DA, Hastrup W, Watts H, et al: Dilated fetal bowel. A sonographic sign of cystic fibrosis. J Ultrasound Med 6:257,1987
Downloaded by: NYU. Copyrighted material.
volemia were not observed in our patient, whose fluid balance was corrected within a short time of birth. It is postulated that the indomethacin therapy, given in an attempt to control the hydramnios during gestation, may cause reversible or irreversible kidney changes, such as the dilated Bowman spaces and renal tubules, noted in this case as well as in others.7 Prenatal diagnosis of this disorder has been described by Hartikainen-Sorri et al.8 A significant increase in bilirubin is found in the amniotic fluid of patients with congenital chloride diarrhea who do not have Rh incompatibility. The enzyme beta-glucuronidase converts bilirubin to its unconjugated form, which is resorbed through the fetal enterohepatic circulation and by the maternal circulation. Because of disturbed resorption, an increase in bilirubin is found in the amniotic fluid. Alpha-fetoprotein can also be increased in this disorder, since it normally remains in the gastrointestinal tract long enough to be partially degraded by intestinal enzymes. In congenital chloride diarrhea, it is transported much more rapidly through the bowel by osmotic diarrhea and is not degraded.8 However, the sensitivity of these tests have not been determined. Ultrasonographic prenatal diagnosis of this condition has been described.910 Massively dilated loops of bowel with a normal-appearing stomach and esophagus may reflect congenital chloride diarrhea rather than an obstructive process. In the latter, there may also be a secondary dilation of the stomach and upper intestinal tract.10 The differential diagnoses for dilated fetal bowel loops detected on ultrasound include Hirschsprung disease, bowel atresia, intestinal volvulus, and meconium ileus.9 Generalized bowel dilation and hydramnios can occur in cysticfibrosis,11but can also be associated with meconium ileus and calcifications. An amniocentesis to detect chloride levels, alpha-fetoprotein, and bilirubin would help diagnose congenital chloride diarrhea and perhaps avert
Sept/Nov 1992
