Colonic pseudo-obstruction in sickle cell disease. (Case Report).

Abstract: A young Arab woman with sickle cell-[[beta].sup.o]-thalassemia disease developed acute colonic pseudo-obstruction that became chronic but showed some response to hydroxyurea. There was no evidence of microvascular or macrovascular occlusion. We also report the case of an Arab man with sickle cell anemia who presented with acute colonic pseudo-obstruction from which he recovered completely within a few days. Although the development of pseudo-obstruction in these two cases seems to have been a complication of sickle cell anemia, its pathogenesis remains unclear. There are several reports of ischemic and inflammatory disorders of the colon complicating sickle cell disease; however, these two cases represent the first descriptions of large-bowel pseudo-obstruction in this hemoglobinopathy.

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Sickle cell disease is a genetically determined hemoglobinopathy that results in chronic hemolytic disease and recurrent vaso-occlusive events affecting the skeleton, abdominal viscera, and other organs. Abdominal pain with or without transient distention and gut hypotonia is the usual manifestation of an abdominal crisis. We describe two cases of sickle cell disease with colonic pseudo-obstruction. In the first case of sickle cell-[beta]-thalassemia disease, the patient developed intestinal (predominantly colonic) obstruction, which persisted and became chronic after a bout of acute chest syndrome. The second patient with sickle cell anemia presented during one of several admissions with an acute colonic pseudo-obstruction, which resolved completely after conservative management. We think that these two patients represent the first descriptions of colonic pseudo-obstruction in sickle cell disease.

Case Reports

Patient 1

A 39-year-old unmarried Omani woman was diagnosed with sickle cell-[[beta].sup.o]-thalassemia disease when she first presented at the age of 7 years. Her painful skeletal crises, which became progressively more severe with advancing years, also increased in frequency, from three or four attacks per year during her adolescence and early adult years to an average of twice per month since the age of 28 years. Abdominal crises in the form of abdominal pain with mild to moderate distention were much less frequent during her late 20s, occurring on an average twice annually. Most of her abdominal crises were associated with skeletal pain, although some occurred independently. Her steady-state hematologic values averaged as follows: hemoglobin, 7.5 g/dl; hematocrit, 0.23; red blood cell (RBC) count, 3.34 X [10.sup.12]/L; mean corpuscular volume (MCV), 72.4 fl; mean corpuscular hemoglobin (MCH), 22.7 pg; reticulocyte count, 10%, white blood cell (WBC) count, 8.0 X [10.sup.9]/L with normal differential count; platelet count, 310 X [10.sup.9]/L; hemoglobin S (HbS), 85.5%; hemoglobin F (HbF), 7.8%; and hemoglobin [A.sub.2] ([HbA.sub.2]), 6.7%. The diagnosis of sickle cell-[[beta].sup.o]-thalassemia was confirmed by performing DNA analysis, with the [[beta].sup.s] gene being of the severe [[beta].sup.s]20 Bantu haplotype. Medical history showed that the patient had undergone cholecystectomy at age 17 years. Family history revealed that she was 1 of 11 siblings, with one brother who also had sickle cell disease.

In December 1991, while recovering from acute chest syndrome in the hospital, she developed severe, generalized abdominal pain with repeated vomiting and constipation. Examination revealed an afebrile, mildly jaundiced woman with generalized abdominal distention and tenderness, absent bowel sounds, but no liver or splenic enlargement. Plain radiographs of the abdomen revealed gaseous distention of the colon but no air/fluid levels were observed. Conventional management, including nasogastric aspiration, flatus tube insertion, and nil by mouth orders, plus exchange blood transfusion, resulted in slight improvement in her condition. A barium meal with follow-through examination 36 hours later revealed only dilated 1oops of bowel with pooling of contrast medium. During the ensuing 3 days, her abdominal symptoms and signs did not improve. Therefore, surgical intervention was reluctantly considered to be obligatory, because coincidental acute organic intestinal obstruction could not be ruled out.

At laparotomy, the small bowel appeared macroscopically normal, but dilated loops of large bowel above a redundant sigmoid colon and a collapsed distal loop of the sigmoid colon and rectum without obvious organic obstruction were noted. These features were suggestive of a volvulus of the sigmoid colon (a relatively common condition in the Middle East) (1) that might have corrected itself spontaneously. The sigmoid colon was resected. Histologic sections of the resected sigmoid colon and of various biopsies of mesenteric lymph nodes and the jejunum were essentially normal. Ganglion cells, intramural nerves, and blood vessels also appeared normal on light and electron microscopy of numerous sections of the bowel wall.

Postoperative recovery was uneventful and was accompanied by modest clinical improvement. She was discharged pain-free on the 10th postoperative day, but with moderate abdominal distention and infrequent, slightly audible bowel sounds. During the ensuing 3 months, chronic intractable constipation with moderate abdominal distention and discomfort dominated her clinical picture. Her monthly admissions for painful skeletal crises continued; these attacks of bone pain were usually associated with acute exacerbations of her chronic abdominal distention and were always accompanied by very weak, infrequent bowel sounds. Anorectal manometry performed a year after her laparotomy showed no evidence of anorectal dysmotility. Acute exacerbation of her chronic intestinal obstruction responded consistently to conservative management, including oral cisapride therapy.

In August 1995, at the age of 33 years, she was readmitted with another severe attack of acute intestinal obstruction, similar to the 1991 episode. This time her condition did not respond to the usual conservative management. Partial relief of her abdominal symptoms occurred only after the institution of magnesium sulfate (30 g/d) and pyridostigmine (60 mg every 4 h) therapy. Introduction of a long-term regimen of partial red blood cell exchange transfusion and simple transfusion (which increased total hemoglobin to a steady-state level of 10 g/dl, and decreased HbF to 3.5% and HbS to <30%), combined with daily treatment with magnesium sulfate, appeared to considerably ameliorate her abdominal symptoms; her admissions for painful skeletal crises also decreased. Unfortunately, her serum ferritin level increased to 4,039 [micro]g/L with regular red blood cell transfusion. Therefore, hydroxyurea therapy was instituted, initially at a dose of 20 mg/kg/d, then increasing to 30 mg/kg/d after 3 months. While taking the higher dose of hydroxyurea, the severity of her chronic abdominal condition abated considerably, and admissions for acute abdominal exacerbation with or without concomitant painful skeletal crises were significantly reduced from once or twice per month to once in 8 to 10 weeks. In 1997, 5 years after her laparotomy for acute intestinal obstruction, barium studies revealed a radiologically normal small bowel but a sluggish, moderately dilated colon free of any obstructive lesions but consistent with chronic colonic pseudo-obstruction. A mesenteric angiogram obtained at that time was also normal. Her current average steady-state hematologic values are as follows: hemoglobin, 8.0 g/dl; hematocrit, 0.258; RBC count, 3.79 X [10.sup.12]/L; MCV, 73.2 fl; MCH, 22.8 pg; reticulocyte count, 7.6%; WBC count, 8.09 X [10.sup.9]/L; platelet count, 276 X [10.sup.9]/L; HbF, 11.2%; [HbA.sub.2], 6.5%; and HbS, 82.3%.

Patient 2

A 22-year-old Omani University student had been diagnosed with sickle cell disease at another hospital when he was a child. He was first referred to Sultan Qaboos University Hospital (SQUH) in October 1996, when he was found to be slightly pale and icteric, with an enlarged, nontender spleen that was palpable 4 cm below the left costal margin. His previous steady-state blood counts were as follows: hemoglobin, 10.8 g/dl; hematocrit, 0.31; RBC count, 4.6 X [10.sup.12]/L; MCV, 63.8 fi; MCH, 20.9 pg; mean corpuscular hemoglobin concentration (MCHC), 32.8 g/dl; red blood cell distribution width index (RDW), 21.6%; and reticulocyte count, 1.6%. Hemoglobin analysis showed the following distribution: HbF, 10.7%; Hb[A.sub.2], 4.7%; and HbS, 84.6%. DNA studies confirmed the [[beta].sup.S]/[[beta].sup.S] genotype (ie, homozygous sickle cell disease [sickle cell anemia]). Since coming to SQUH, the course of his illness had been marked by frequent visits to the emergency department, several admissions annually for painfu l skeletal vaso-occlusive events, and an episode of acute chest syndrome.

In July 1999, he was admitted to the hospital with a 4-day history of severe lower abdominal pain and constipation, without vomiting or urinary symptoms. He was afebrile, pale, and icteric, with marked generalized abdominal distention and tenderness, tympanic abdominal percussion note, and absent bowel sounds; there was no significant change in his blood cell counts. A plain abdominal x-ray film showed a dilated colon full of feces. On the basis of previous experience, a diagnosis of acute colonic pseudo-obstruction was made. Conservative management, comprising intravenous hydration, opioid analgesia, oral magnesium sulfate therapy, retention enema, and partial exchange transfusion resulted in gradual reestablishment of bowel activity, which became normal after 72 hours. He was discharged after 7 days, after the resolution of all signs and symptoms. Since then, he has had several painful skeletal and visceral crises but no further episodes of intestinal pseudo-obstruction.

Discussion

The course of illness in these two sickle cell disease patients was complicated by bouts of acute colonic pseudo-obstruction (Ogilivie's syndrome). (2) In the second patient, complete recovery ensued, without any recurrence so far. His bowel disorder possibly represented an extreme form of gut hypotonia, which sometimes occurs simultaneously with bladder atony and is frequently encountered as a manifestation of "sterile" abdominal crises of sickle cell disease. (3) Such abdominal crises may simulate the acute surgical abdomen. (4,5) In our first patient, the attack of acute colonic pseudo-obstruction did not resolve completely, despite aggressive management, but developed into a chronic pseudo-obstruction, which not infrequently has been punctuated by acute exacerbation.

Abdominal complications in sickle cell disease rarely involve the colon. Reports of colonic abnormalities include acute necrotizing colitis in an adult, (6) pseudomembranous colitis in a child, (7) ischemic colitis, (8) and nonspecific ulcerative proctocolitis. (9) The pathogenesis of these inflammatory complications seems to be due to sicklemic microvascular occlusion. The pathogenesis of colonic pseudo-obstruction is unclear, however, for not only were various disorders such as collagen vascular diseases, visceral myopathies, and neuropathies reportedly associated with intestinal pseudo-obstruction (10) excluded, but no evidence of microvascular occlusion was found on light or electron microscopy of various sections of the bowel wall. Moreover, mesenteric angiography did not reveal any macrovascular occlusion. Thus, the pathogenesis of colonic pseudo-obstruction is unclear in these two patients. The improvement in the abdominal condition and in the frequency of painful skeletal crises after the institution of hydroxyurea therapy, however, strongly suggests that the colonic disorder is a complication of sickle cell disease (although rare) rather than a coincidental development. Moreover, these two cases demonstrate that a patient with sickle cell disease may recover rapidly from an acute pseudo-obstruction, or the pseudo-obstruction may become chronic. A systematic investigation, including studies of gut transit times, intestinal manometry, and the possible use of appropriate animal models, could provide useful information regarding disorders of colonic motility in the sickling hemoglobinopathies.

Conclusion

Acute colonic pseudo-obstruction developed in two patients with severe sickle cell disease. In the first patient, the abdominal condition became chronic but improved with hydroxyurea treatment, while in the second case, the acute attack resolved completely and never recurred. Although the pathogenesis of this colonic pseudo-obstruction is uncertain, the pattern of the illness indicates a strong etiologic association with the sickling hemoglobinopathy rather than a coincidental occurrence.

Accepted January 14, 2002.

References

(1.) Ballantyne GH. Revicw of sigmoid volvulus: Clinical patterns and pathogenesis. Dis Colon Rectum 1982;25:823-830.

(2.) Rex DK. Acute colonic pseudo-obstruction (Ogilvie's syndrome). Gastroenterologist 1994;2:233-238.

(3.) Serjeant GR, Cculaer CD, Lethbridge R, et al. The painful crisis of homozygous sickle cell disease: Clinical features. Br J Haematol 1994;87:586-591.

(4.) Serjeant GR. The gut and abdomen, in Serjeant GR: Sickle Cell Disease. Oxford, Oxford University Press, 1992, ed 2, pp 167-169.

(5.) Anchord JL. Gastroenterologic and hepatobiliary manifestations, in Embury SH, Hebbel RP, Mohandas N (eds): Sickle Cell Disease: Basic Principles and Clinical Practice, New York, Raven Press, 1994, pp 663-672.

(6.) van der Neut FW, Statius van Eps LW, van Enk A, van de Sandt MM. Maternal death due to acute necrotizing colitis in homozygous sickle cell disease. Neth J Med 1993;42:132-133.

(7.) Baruchel S, Delifer JC, Sigalet D, et al. Pseudomembranous colitis in sickle cell disease responding to exchange transfusion. J Pediatr 1992;121:915-917.

(8.) Gage TP, Gagnier JM. Ischemic colitis complicating sickle cell crisis. Gastroenterology 1983;84:171-174.

(9.) Terry SI, Rajendran A, Hanchard B, Serjeant GR. Ulcerative colitis in sickle cell disease. J Clin Gastroenterol 1987;9:55-57.

(10.) Russel JC, Welch JP. Motility disorders, in Welch JP: Bowel Obstruction: Differential Diagnosis and Clinical Management. Philadelphia, W.B. Saunders Co., 1990, pp 166-193.

RELATED ARTICLE: Key Points

* The development of pseudo-obstruction of the colon as a complication of sickle cell disease is reported for the first time.

* Acute colonic pseudo-obstruction became chronic in one patient but was followed by full recovery in the second patient.

* Transfusion of red blood cells or treatment with hydroxyurea ameliorated the chronic manifestations of the large bowel pseudo-obstruction and reduced the frequency of recurrent acute exacerbation.

* Disorders known to cause abnormalities of colonic motility were excluded.

* Pathogenesis of colonic pseudo-obstruction in these two patients is unclear because evidence of microvascular or macrovascular occlusion is lacking.

From the Departments of Haematology and Surgery, College of Medicine, Sultan Qaboos University and Sultan Qaboos University Hospital, AlKhod, Sultanate of Oman.

+ Deceased.

Reprint requests to Huxley Knox-Macaulay, MD, 7, The Green, Stanstead, Sudbury, Suffolk CO10 9AS, United Kingdom.

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