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Inducible nitric oxide synthase activity is expressed not only in inflamed but also in normal colonic mucosa in patients with ulcerative colitis: a potential prognostic marker
AJG – May, 2000
Letters to the Editor
Abdullah Sonsuz, M.D. Metin Basaranoglu, M.D. Division of Hepatology Department of Internal Medicine Cerrahpasa Medical Faculty University of Istanbul Istanbul, Turkey Gu¨lsen Ozbay, M.D. Cerrahpasa Medical Faculty University of Istanbul Istanbul, Turkey
REFERENCE 1. Brunt EM, Janney CG, Di Bisceglie AM, et al. Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions. Am J Gastroenterol 1999;94:2467–74. Reprint requests and correspondence: Metin Basaranoglu, M.D., Maresal Cakmak Mah., Mehtap Sok., Gu¨l apt, No⫽6/8, 34600, Gu¨ngo¨ren, Istanbul, Turkey. Received Nov. 29, 1999; accepted Dec. 13, 1999.
1371
Inducible Nitric Oxide Synthase Activity Is Expressed Not Only in Inflamed But Also in Normal Colonic Mucosa in Patients With Ulcerative Colitis: A Potential Prognostic Marker TO THE EDITOR: Determination of the activity and severity of ulcerative colitis (UC) is difficult and, at present, far from satisfactory. Current activity indices are based on patients’ symptoms (number of bowel movements per day, presence or absence of blood in the stool, patients’ overall condition), as well as on a few nonspecific laboratory parameters and on radiological and endoscopical studies. Endoscopic or posterior pathological examination typically shows a continuous and uniform inflamed mucosa, with no intermediate areas of normal mucosa. Recent studies have shown increased nitric oxide (NO䡠) production in UC (1–3). Nitric oxide is synthesized by the enzymes called NO synthases (NOS): endothelial (eNOS), neuronal (nNOS), which are both calcium-dependent, and
Figure 1. Calcium-independent and calcium-dependent NO synthase activity in inflamed and normal colonic mucosa from patients with UC. Inset: Western blot of iNOS. Frozen tissues were sonicated in an ice-cold buffer (pH 7.4) containing Tris HCl (50 mmol/L), sucrose (320 mmol/L), dithiothreitol (1 mmol/L), leupeptin (10 g/ml), soybean trypsin inhibitor (10 g/ml), and aprotinin (2 g/ml), followed by centrifugation at 10,000 g. NOS activity was determined in cell extracts under conditions of maximal activity, to assess indirectly the amount of enzyme. The samples were incubated at 37°C in a buffer KH2PO4 (50 mmol/L), MgCl2 (1 mmol/L), CaCl2 (0.2 mmol/L), L-valine (50 mmol/L), L-citrulline (1 mmol/L), L-arginine (20 mol/L), and dithiothreitol (1.5 mmol/L) containing L-[14C]-arginine. The reaction was terminated by removing the substrate with 1:1 H2O Dowex AF 500W-8 resin. The activity of the calcium-dependent NOS was calculated from the difference between L-[14C]-citrulline produced from control samples and samples containing 1 mmol/L ethylene glycol-bis (aminoethyl ether) N,N,N⬘-tetraacetic acid (EGTA); the activity of the calcium-independent isoform was determined from the difference between samples with EGTA and samples containing 1 mmol/L NG-monomethyl-L-arginine. *p ⬍ 0.05 vs control; #p ⬍ 0.05 vs noninflamed mucosa (Newman-Keuls). Characterization of NOS isoforms by Western blot: the proteins present in the supernatant were loaded and size-separated in 10% sodium dodecyl sulfate polyacrilamide gel electrophoresis (SDS-PAGE) (90 mA). The gels were blotted onto a PVDF membrane and incubated with specific polyclonal antibodies.
1372
Letters to the Editor
AJG – Vol. 95, No. 5, 2000
Table 1. Relationship Between Follow-up Endoscopic Examination and Previous Calcium-Independent NOS Activity in Noninflamed Mucosa Follow-up Study Patients (n)
Clinical Status
5 5
worse worse
Ca2⫹-Independent NOS Activity in First Colonoscopy (pmol/min 䡠 mg)
Second Colonoscopy similar (rectum and/or sigmoid) more extensive (transverse colon or pancolitis)
8.4 ⫾ 4.1 43.7 ⫾ 7.0*
Results are mean ⫾ SEM. * p ⬍ 0.01 (Newman-Keuls).
an inducible, calcium-independent isoform expressed during inflammatory reactions (iNOS) or after exposure to cytokines and/or lipopolysaccharide. This third isoform is a high-output source of NO䡠 and mediates cytotoxicity in many cell systems (4). Whereas control colonic tissue in healthy individuals does not show any iNOS activity, this isoform is present in UC (5). Several studies showed that iNOS is expressed only in inflamed mucosa in biopsy specimens from patients with UC, but not in macroscopically healthy tissue (6). Similar data have been obtained in experimental models (7). Using homogenates of colonoscopic biopsy specimens located in the rectum or sigmoid colon of 15 patients with UC (mean age: 33 ⫾ 6 yr, nine women and six men, and six age- and sex-matched controls), we found that a calciumindependent NO synthase activity is expressed not only in inflamed mucosa but also in normal mucosa in 12 patients (80%). This enzymatic activity corresponds to the iNOS protein, as shown by Western blot. Constitutive, calciumdependent NO synthase activity was not modified in areas of inflamed mucosa (Fig. 1). The production of NO䡠 in UC has been primarily ascribed to the action of iNOS (1, 5), although alternative sources include the reduction of nitrite by xanthine oxidase and ⫺ bacterial NO⫺ 3 /NO2 reductases (8). Such tremendous over䡠 production of NO is possibly linked with toxic dilation of the colon and could explain some cases of refractoriness to current clinical treatment. Our data indicate that this overproduction occurs not only in inflamed but also in “normal” mucosa from UC patients. To study the possible role of iNOS activity as a marker of progression, all of the patients were studied in a 12–24 month follow-up study. Of the 15 patients, 10 underwent a worsening in their clinical status despite 5-ASA treatment. Retrospective study demonstrated that all of these patients had increased values of calcium-independent NOS activity in noninflamed mucosa in the first study (25.8 ⫾ 9.1 pmol/ min 䡠 mg, p ⬍ 0.01, vs group with no clinical worsening). Endoscopical examination demonstrated extension of lesion to transverse colon or pancolitis in 50% of these patients, in correlation with the highest values of iNOS in noninflamed mucosa in the first study (Table 1). In addition, those five patients in whom iNOS was not detected in noninflamed mucosa did not undergo worsening of their clinical condition.
Conversely to the “standard” description of UC, the present data indicate that this is not a disease confined to inflamed mucosa. Our data indicating that the main highoutput source of NO䡠 is present in inflamed but also in “normal” mucosa in UC patients and that it correlates with extension of lesion provide further support for studies using inhibition of the induction and specific inhibition of the activity of expressed enzyme. Some in-course studies on the effect of selective inhibition of iNOS beyond its induction (9) should confirm this point (Menche´n et al., unpublished observations).
ACKNOWLEDGMENT Work supported by DGES PM97-0054 and PM98-0084. A. L. Colo´n, M.D. L. Menche´n, M.D. I. Lizasoain, M.D., Ph.D. J. C. Leza, M.D., Ph.D. P. Menche´n, M.D., Ph.D. V. Gonza´lez-Lara, M.D., Ph.D. M. A. Moro, Ph.D. P. Lorenzo, M.D., Ph.D. Department of Pharmacology Universidad Complutense Madrid, Spain Service of Gastroenterology Hospital General Universitario Gregorio Maran˜o´n Madrid, Spain
REFERENCES 1. Boughton-Smith NK, Evans SM, Hawkey CJ, et al. Nitric oxide synthase activity in ulcerative colitis and Crohn’s disease. Lancet 1993;342:338 – 40. 2. Lundberg JON, Hellstro¨m PM, Lundberg JM, et al. Greatly increased luminal nitric oxide in ulcerative colitis. Lancet 1994;344:1673– 4. 3. Rachmilewitz D, Stamler JS, Bachwich D, et al. Enhanced colonic nitric oxide generation and nitric oxide synthase activity in ulcerative colitis and Crohn’s disease. Gut 1995;36: 718 –23. 4. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: Physiology, pathophysiology and pharmacology. Pharmacol Rev 1991;43: 109 – 42. 5. Kimura H, Miura S, Shigematsu T, et al. Increased nitric oxide
AJG – May, 2000
6.
7.
8. 9.
production and inducible nitric oxide synthase activity in colonic mucosa of patients with active ulcerative colitis and Crohn’s disease. Dig Dis Sci 1997;42:1047–54. Kolios G, Rooney N, Murphy CT, et al. Expression of inducible nitric oxide synthase activity in human colon epithelial cells: Modulation by T lymphocyte derived cytokines. Gut 1998;43:56 – 63. Kiss J, Lamarque D, Delchier JC, et al. Time-dependent actions of nitric oxide synthase inhibition on colonic inflammation induced by trinitrobenzene sulphonic acid in rats. Eur J Pharmacol 1997;336:219 –24. Zhang Z, Naughton DP, Carty E, et al. Excess nitric oxide in ulcerative colitis may be generated by nitric oxide synthase independent pathways. Gut 1999;44:441. Zingarelli B, Cuzzocrea S, Szabo´ C, et al. Mercaptoethylguanidine, a combined inhibitor of nitric oxide synthase and peroxynitrite scavenger, reduces trinitrobenzene sulfonic acidinduced colonic damage. J Pharmacol Exp Ther 1998;287: 1048 –55.
Reprint requests and correspondence: Dr. Pedro Lorenzo, Department of Pharmacology, Universidad Complutense, Avda. Complutense, 28040 Madrid, Spain. Received Dec. 8, 1999; accepted Dec. 13, 1999.
Obesity Associated With Severe Acute Colonic Diverticulitis in the Young Adult TO THE EDITOR: Stollman and Raskin (1), in their superb diverticulitis “Practice Guideline,” noted increased surgical frequency in younger patients; but many readers may not be aware of other peculiar dangers. Both Konvolinka (2) and particularly, Schauer et al. (3), besides a high percentage of emergent surgeries in those ⬍40 yr, noted other striking features—almost universal obesity (even massive, “morbid”) (and maleness?), atypical localization of pain and tenderness (44% did not have left lower quadrant pain, even though in 82% the diverticula were limited to the sigmoid colon), and worse, preoperative misdiagnosis in 50%, sometimes requiring a new incision. I reviewed for the defense the case of a 25-yr-old, massively obese man (4) who suddenly developed a surgical abdomen with predominant RLQ tenderness after a 10-day course of lower abdominal pains and multiple physician visits. The truly massive obesity precluded using any existing CAT scanners. His hugeness rendered him radioopaque, so a gentle, water-soluble contrast enema couldn’t discern the actual site leaking contrast, (mistakenly believed to be appendix), but also missed the sigmoid diverticula. He was treated preoperatively with intensive antibiotics. The ER, gastroenterologist, surgeon, and radiologist all favored appendicitis. The first incision was RLQ. At his 6-h, difficult exploration, peritonitis secondary to a ruptured sigmoid diverticular abscess was encountered. A few hours postoperation, unable to be extubated and requiring high pressures for ventilation, this 25-yr-old patient died of sepsis and
Letters to the Editor
1373
multiorgan system failure. The family attorneys were uniformly successful. This case and surgical series (2, 3) suggest increased awareness of severe diverticulitis in the youthful obese, further complicated by obesity-related problems from diagnostic failure to tough surgical and postoperative sagas. (Dr. Peter Loeb, personal communication, 1999) has seen two nonfatal, very similar cases of patients in their 20s). David E. Langdon, M.D., F.A.C.P., F.A.C.G. University of Texas at Dallas Southwestern Medical School Dallas, Texas
REFERENCES 1. Stollman NH, Raskin JB. Diagnosis and management of diverticular disease of the colon in adults. Am J Gastroenterol 1999;94:3110 –21. 2. Konvolinka CW. Acute diverticulitis under age 40. Am J Surg 1994;167:562–5. 3. Schauer PR, Ramos R, Giatus AA, et al. Virulent diverticular disease in young obese men. Am J Surg 1992;162:443– 8. 4. Langdon DE. Acute diverticulitis and obesity in young adults. J Fam Pract 1996;42:623– 4. Reprint requests and correspondence: David E. Langdon, M.D., F.A.C.P., F.A.C.G., University of Texas at Dallas, Southwestern Medical School, 3120 Matlock Road, Suite 201, Arlington, TX 76015. Received Dec. 23, 1999; accepted Dec. 27, 1999.
Re: Pregnancy Outcomes in Celiac Women TO THE EDITOR: The study of Nø´rgård et al. (1) indicates that treatment of celiac women is important in the prevention of fetal growth retardation. The role of micronutrients during pregnancy has received attention recently (2). In my opinion celiac disease (CD) could be also a maternal risk factor for birth defects. A low plasma level of folic acid is a common finding in untreated CD (3). Screening of adult blood donors has suggested that the prevalence of CD in Europe and in the USA might be as high as 1 in 300 and over 25% of detected patients have folate deficiency (4, 5). There are two important biological effects of folic acid. First, folic acid acts as a cofactor for enzymes involved in DNA and RNA biosynthesis. Second, folic acid is involved in the supply of methyl groups to the methylation cycle. Plasma homocysteine levels are influenced by environmental (folate, vitamin B6 or vitamin B12 intake) as well as genetic factors. Hyperhomocysteinemia is frequently observed in women with recurrent miscarriages (6) and in mothers who gave birth to a child with a neural tube defect or an orofacial cleft (7). Recurrent abortion may be a presenting feature of adult CD (8, 9). Dickey et al. (10) reported that one (1.6%)
Letters to the Editor
Abdullah Sonsuz, M.D. Metin Basaranoglu, M.D. Division of Hepatology Department of Internal Medicine Cerrahpasa Medical Faculty University of Istanbul Istanbul, Turkey Gu¨lsen Ozbay, M.D. Cerrahpasa Medical Faculty University of Istanbul Istanbul, Turkey
REFERENCE 1. Brunt EM, Janney CG, Di Bisceglie AM, et al. Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions. Am J Gastroenterol 1999;94:2467–74. Reprint requests and correspondence: Metin Basaranoglu, M.D., Maresal Cakmak Mah., Mehtap Sok., Gu¨l apt, No⫽6/8, 34600, Gu¨ngo¨ren, Istanbul, Turkey. Received Nov. 29, 1999; accepted Dec. 13, 1999.
1371
Inducible Nitric Oxide Synthase Activity Is Expressed Not Only in Inflamed But Also in Normal Colonic Mucosa in Patients With Ulcerative Colitis: A Potential Prognostic Marker TO THE EDITOR: Determination of the activity and severity of ulcerative colitis (UC) is difficult and, at present, far from satisfactory. Current activity indices are based on patients’ symptoms (number of bowel movements per day, presence or absence of blood in the stool, patients’ overall condition), as well as on a few nonspecific laboratory parameters and on radiological and endoscopical studies. Endoscopic or posterior pathological examination typically shows a continuous and uniform inflamed mucosa, with no intermediate areas of normal mucosa. Recent studies have shown increased nitric oxide (NO䡠) production in UC (1–3). Nitric oxide is synthesized by the enzymes called NO synthases (NOS): endothelial (eNOS), neuronal (nNOS), which are both calcium-dependent, and
Figure 1. Calcium-independent and calcium-dependent NO synthase activity in inflamed and normal colonic mucosa from patients with UC. Inset: Western blot of iNOS. Frozen tissues were sonicated in an ice-cold buffer (pH 7.4) containing Tris HCl (50 mmol/L), sucrose (320 mmol/L), dithiothreitol (1 mmol/L), leupeptin (10 g/ml), soybean trypsin inhibitor (10 g/ml), and aprotinin (2 g/ml), followed by centrifugation at 10,000 g. NOS activity was determined in cell extracts under conditions of maximal activity, to assess indirectly the amount of enzyme. The samples were incubated at 37°C in a buffer KH2PO4 (50 mmol/L), MgCl2 (1 mmol/L), CaCl2 (0.2 mmol/L), L-valine (50 mmol/L), L-citrulline (1 mmol/L), L-arginine (20 mol/L), and dithiothreitol (1.5 mmol/L) containing L-[14C]-arginine. The reaction was terminated by removing the substrate with 1:1 H2O Dowex AF 500W-8 resin. The activity of the calcium-dependent NOS was calculated from the difference between L-[14C]-citrulline produced from control samples and samples containing 1 mmol/L ethylene glycol-bis (aminoethyl ether) N,N,N⬘-tetraacetic acid (EGTA); the activity of the calcium-independent isoform was determined from the difference between samples with EGTA and samples containing 1 mmol/L NG-monomethyl-L-arginine. *p ⬍ 0.05 vs control; #p ⬍ 0.05 vs noninflamed mucosa (Newman-Keuls). Characterization of NOS isoforms by Western blot: the proteins present in the supernatant were loaded and size-separated in 10% sodium dodecyl sulfate polyacrilamide gel electrophoresis (SDS-PAGE) (90 mA). The gels were blotted onto a PVDF membrane and incubated with specific polyclonal antibodies.
1372
Letters to the Editor
AJG – Vol. 95, No. 5, 2000
Table 1. Relationship Between Follow-up Endoscopic Examination and Previous Calcium-Independent NOS Activity in Noninflamed Mucosa Follow-up Study Patients (n)
Clinical Status
5 5
worse worse
Ca2⫹-Independent NOS Activity in First Colonoscopy (pmol/min 䡠 mg)
Second Colonoscopy similar (rectum and/or sigmoid) more extensive (transverse colon or pancolitis)
8.4 ⫾ 4.1 43.7 ⫾ 7.0*
Results are mean ⫾ SEM. * p ⬍ 0.01 (Newman-Keuls).
an inducible, calcium-independent isoform expressed during inflammatory reactions (iNOS) or after exposure to cytokines and/or lipopolysaccharide. This third isoform is a high-output source of NO䡠 and mediates cytotoxicity in many cell systems (4). Whereas control colonic tissue in healthy individuals does not show any iNOS activity, this isoform is present in UC (5). Several studies showed that iNOS is expressed only in inflamed mucosa in biopsy specimens from patients with UC, but not in macroscopically healthy tissue (6). Similar data have been obtained in experimental models (7). Using homogenates of colonoscopic biopsy specimens located in the rectum or sigmoid colon of 15 patients with UC (mean age: 33 ⫾ 6 yr, nine women and six men, and six age- and sex-matched controls), we found that a calciumindependent NO synthase activity is expressed not only in inflamed mucosa but also in normal mucosa in 12 patients (80%). This enzymatic activity corresponds to the iNOS protein, as shown by Western blot. Constitutive, calciumdependent NO synthase activity was not modified in areas of inflamed mucosa (Fig. 1). The production of NO䡠 in UC has been primarily ascribed to the action of iNOS (1, 5), although alternative sources include the reduction of nitrite by xanthine oxidase and ⫺ bacterial NO⫺ 3 /NO2 reductases (8). Such tremendous over䡠 production of NO is possibly linked with toxic dilation of the colon and could explain some cases of refractoriness to current clinical treatment. Our data indicate that this overproduction occurs not only in inflamed but also in “normal” mucosa from UC patients. To study the possible role of iNOS activity as a marker of progression, all of the patients were studied in a 12–24 month follow-up study. Of the 15 patients, 10 underwent a worsening in their clinical status despite 5-ASA treatment. Retrospective study demonstrated that all of these patients had increased values of calcium-independent NOS activity in noninflamed mucosa in the first study (25.8 ⫾ 9.1 pmol/ min 䡠 mg, p ⬍ 0.01, vs group with no clinical worsening). Endoscopical examination demonstrated extension of lesion to transverse colon or pancolitis in 50% of these patients, in correlation with the highest values of iNOS in noninflamed mucosa in the first study (Table 1). In addition, those five patients in whom iNOS was not detected in noninflamed mucosa did not undergo worsening of their clinical condition.
Conversely to the “standard” description of UC, the present data indicate that this is not a disease confined to inflamed mucosa. Our data indicating that the main highoutput source of NO䡠 is present in inflamed but also in “normal” mucosa in UC patients and that it correlates with extension of lesion provide further support for studies using inhibition of the induction and specific inhibition of the activity of expressed enzyme. Some in-course studies on the effect of selective inhibition of iNOS beyond its induction (9) should confirm this point (Menche´n et al., unpublished observations).
ACKNOWLEDGMENT Work supported by DGES PM97-0054 and PM98-0084. A. L. Colo´n, M.D. L. Menche´n, M.D. I. Lizasoain, M.D., Ph.D. J. C. Leza, M.D., Ph.D. P. Menche´n, M.D., Ph.D. V. Gonza´lez-Lara, M.D., Ph.D. M. A. Moro, Ph.D. P. Lorenzo, M.D., Ph.D. Department of Pharmacology Universidad Complutense Madrid, Spain Service of Gastroenterology Hospital General Universitario Gregorio Maran˜o´n Madrid, Spain
REFERENCES 1. Boughton-Smith NK, Evans SM, Hawkey CJ, et al. Nitric oxide synthase activity in ulcerative colitis and Crohn’s disease. Lancet 1993;342:338 – 40. 2. Lundberg JON, Hellstro¨m PM, Lundberg JM, et al. Greatly increased luminal nitric oxide in ulcerative colitis. Lancet 1994;344:1673– 4. 3. Rachmilewitz D, Stamler JS, Bachwich D, et al. Enhanced colonic nitric oxide generation and nitric oxide synthase activity in ulcerative colitis and Crohn’s disease. Gut 1995;36: 718 –23. 4. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: Physiology, pathophysiology and pharmacology. Pharmacol Rev 1991;43: 109 – 42. 5. Kimura H, Miura S, Shigematsu T, et al. Increased nitric oxide
AJG – May, 2000
6.
7.
8. 9.
production and inducible nitric oxide synthase activity in colonic mucosa of patients with active ulcerative colitis and Crohn’s disease. Dig Dis Sci 1997;42:1047–54. Kolios G, Rooney N, Murphy CT, et al. Expression of inducible nitric oxide synthase activity in human colon epithelial cells: Modulation by T lymphocyte derived cytokines. Gut 1998;43:56 – 63. Kiss J, Lamarque D, Delchier JC, et al. Time-dependent actions of nitric oxide synthase inhibition on colonic inflammation induced by trinitrobenzene sulphonic acid in rats. Eur J Pharmacol 1997;336:219 –24. Zhang Z, Naughton DP, Carty E, et al. Excess nitric oxide in ulcerative colitis may be generated by nitric oxide synthase independent pathways. Gut 1999;44:441. Zingarelli B, Cuzzocrea S, Szabo´ C, et al. Mercaptoethylguanidine, a combined inhibitor of nitric oxide synthase and peroxynitrite scavenger, reduces trinitrobenzene sulfonic acidinduced colonic damage. J Pharmacol Exp Ther 1998;287: 1048 –55.
Reprint requests and correspondence: Dr. Pedro Lorenzo, Department of Pharmacology, Universidad Complutense, Avda. Complutense, 28040 Madrid, Spain. Received Dec. 8, 1999; accepted Dec. 13, 1999.
Obesity Associated With Severe Acute Colonic Diverticulitis in the Young Adult TO THE EDITOR: Stollman and Raskin (1), in their superb diverticulitis “Practice Guideline,” noted increased surgical frequency in younger patients; but many readers may not be aware of other peculiar dangers. Both Konvolinka (2) and particularly, Schauer et al. (3), besides a high percentage of emergent surgeries in those ⬍40 yr, noted other striking features—almost universal obesity (even massive, “morbid”) (and maleness?), atypical localization of pain and tenderness (44% did not have left lower quadrant pain, even though in 82% the diverticula were limited to the sigmoid colon), and worse, preoperative misdiagnosis in 50%, sometimes requiring a new incision. I reviewed for the defense the case of a 25-yr-old, massively obese man (4) who suddenly developed a surgical abdomen with predominant RLQ tenderness after a 10-day course of lower abdominal pains and multiple physician visits. The truly massive obesity precluded using any existing CAT scanners. His hugeness rendered him radioopaque, so a gentle, water-soluble contrast enema couldn’t discern the actual site leaking contrast, (mistakenly believed to be appendix), but also missed the sigmoid diverticula. He was treated preoperatively with intensive antibiotics. The ER, gastroenterologist, surgeon, and radiologist all favored appendicitis. The first incision was RLQ. At his 6-h, difficult exploration, peritonitis secondary to a ruptured sigmoid diverticular abscess was encountered. A few hours postoperation, unable to be extubated and requiring high pressures for ventilation, this 25-yr-old patient died of sepsis and
Letters to the Editor
1373
multiorgan system failure. The family attorneys were uniformly successful. This case and surgical series (2, 3) suggest increased awareness of severe diverticulitis in the youthful obese, further complicated by obesity-related problems from diagnostic failure to tough surgical and postoperative sagas. (Dr. Peter Loeb, personal communication, 1999) has seen two nonfatal, very similar cases of patients in their 20s). David E. Langdon, M.D., F.A.C.P., F.A.C.G. University of Texas at Dallas Southwestern Medical School Dallas, Texas
REFERENCES 1. Stollman NH, Raskin JB. Diagnosis and management of diverticular disease of the colon in adults. Am J Gastroenterol 1999;94:3110 –21. 2. Konvolinka CW. Acute diverticulitis under age 40. Am J Surg 1994;167:562–5. 3. Schauer PR, Ramos R, Giatus AA, et al. Virulent diverticular disease in young obese men. Am J Surg 1992;162:443– 8. 4. Langdon DE. Acute diverticulitis and obesity in young adults. J Fam Pract 1996;42:623– 4. Reprint requests and correspondence: David E. Langdon, M.D., F.A.C.P., F.A.C.G., University of Texas at Dallas, Southwestern Medical School, 3120 Matlock Road, Suite 201, Arlington, TX 76015. Received Dec. 23, 1999; accepted Dec. 27, 1999.
Re: Pregnancy Outcomes in Celiac Women TO THE EDITOR: The study of Nø´rgård et al. (1) indicates that treatment of celiac women is important in the prevention of fetal growth retardation. The role of micronutrients during pregnancy has received attention recently (2). In my opinion celiac disease (CD) could be also a maternal risk factor for birth defects. A low plasma level of folic acid is a common finding in untreated CD (3). Screening of adult blood donors has suggested that the prevalence of CD in Europe and in the USA might be as high as 1 in 300 and over 25% of detected patients have folate deficiency (4, 5). There are two important biological effects of folic acid. First, folic acid acts as a cofactor for enzymes involved in DNA and RNA biosynthesis. Second, folic acid is involved in the supply of methyl groups to the methylation cycle. Plasma homocysteine levels are influenced by environmental (folate, vitamin B6 or vitamin B12 intake) as well as genetic factors. Hyperhomocysteinemia is frequently observed in women with recurrent miscarriages (6) and in mothers who gave birth to a child with a neural tube defect or an orofacial cleft (7). Recurrent abortion may be a presenting feature of adult CD (8, 9). Dickey et al. (10) reported that one (1.6%)