Gastrointestinal Manifestations Of Sickle Cell Disease

Timothy A. Woodward, M.D.
Timothy A. Woodward, M.D. is a Consultant in the
Department of Gastroenterology at the Mayo Clinic, Jacksonville.

Introduction

Sickle cell disease (SCD) is an inherited disorder caused by the abnormal properties conveyed to sickle red blood cells by the mutant sickle hemoglobin, Hb S. At the sixth position of the hemoglobin beta-chain, a valine is substituted for glutamic acid. This abnormality leads to polymerization of the hemoglobin when the oxygen saturation is lowered, resulting in red blood cell deformity, vaso-occlusion, ischemia, and infarction. Chronic hemolysis is also a consequence of the sickling phenomenon, particularly with homozygous HbS disease. Gastrointestinal complications are myriad and include conditions such as cholelithiasis, biliary sludge, colitis, and pancreatitis. These and other gastrointestinal-related conditions will be examined, particularly within the context of current biological insights.

Cholelithiasis and Hepato-biliary Disease

Pigmented gallstones are the result of the chronic hemolysis of the sickle cell disease. Studies reveal that close to 70% of patients develop gallstones, though the incidence is much lower in patients with HbSC and HbS-beta thalasemmia.1 In the pediatric population, gallstones may serve as a nidus for infection.2 In order to avoid the subsequent confusion of acute cholecystitis pain and acute painful sickling episodes, laparoscopic cholecystectomy has become a feasible approach in the management of assymptomatic gallstones.3-4 However, one study has recommended caution with regards to laparoscopic cholecystectomy due to perioperative complications in the context of sickle cell disease, advocating open cholecystectomy instead.5 Regarding choledocholithiasis, Gholson, et al have found an increased incidence of common duct stones in SCD in the setting of hyperbilirubinemia and cholelithiasis.6

Hepatic crisis in sickle cell disease is characterized by right upper quadrant abdominal pain, jaundice, hepatomegaly, and fever. As noted above, this constellation of findings is strongly suggestive of acute cholecystitis thus making diagnosis difficult. It has been estimated that 7 to 10 percent of hospitalizations for sickle cell anemia were complicated by hepatic crises,7 with the most marked biochemical abnormality being an elevation in serum bilirubin. Total bilirubin is usually less than 15 mg/dL although extreme levels of greater than 50 mg/dL may occur. As much as 50 percent of this bilirubin is the direct fraction. Serum aminotransferases are abnormal. Massive hepatic sickling leading to sequestration of red blood cells in the liver has been postulated as a cause of acute hepatic failure with hepatomegaly.8 Deaths related to fulminant hepatic failure in the absence of any other demonstrable cause in SCD patients have been reported.9

Acute and chronic intrahepatic cholestasis also have been associated with SCD. Treatment includes apheresis as well correction of any underlying coagulopathy.10 Hepatitis B and C has been shown to be at an increased incidence in SCD. This has been demonstrated to be directly related to the number of transfusions received.11-12

Pancreatic Disease

Pancreatitis is a rarely sited cause of abdominal pain in SCD. In a review of pancreatitis of childhood, six patients with SCD displayed evidence of pancreatitis.13 Five of the children underwent cholecystectomy with no further episodes. As of this publication, only two case reports have demonstrated pancreatitis during a sickle cell crisis. One involved a 51 year-old man who subsequently went on to develop a pancreatic pseudocyst that was treated conservatively with gradual resolution.14 The other case was that of a three-year-old girl with no evidence of biliary tract disease or other etiologic factors.15 Proposed mechanisms of disease activity include endothelial damage leading to microthrombi and ischemia, with subsequent triggering of pancreatic autodigestion.

Duodenal Ulcer Disease

There is no substantial evidence to support the hypothesis that gastric and duodenal ulcers (DU) occur more frequently in SCD.16-17 Reports on gastric acid production in SCD patients are conflicting. Early authors reported hypochlorhydria in this disorder,18 though later authors have demonstrated normal gastric acid secretion.19 The incidence of Helicobacter pylori in SCD has not been established. It has been suggested, though, that healing may be delayed in patients with SCD and duodenal ulcer disease due to vaso-occlusion.20 Regardless, DU should be considered in the differential diagnosis in SCD patients with right upper quadrant and epigastric pain. Diagnostic studies should include endoscopy early in the course of pain. Repeat endoscopy should be done in 4 to 6 weeks to monitor response to therapy. In those cases with poor healing, surgical management should be considered much earlier than in non-SCD individuals. As an alternative to surgery, a short-term periodic red blood cell transfusion should be considered.20

Helicobacter pylori has been associated with chronic gastritis in children.21-22 A case report describes a patient with SCD, recurrent abdominal pain and hematemesis in which Helicobacter pylori gastritis was documented. Treatment with Helicobacter pylori eradication therapy led to resolution of symptoms.23

Appendicitis and Colitis

The incidence of acute appendicitis does not appear to be increased in the SCD population, 24 with one study suggesting that the likelihood of developing appendicitis in SCD patients is less than one third of that of the population at large.25 However, it is suggested that when acute appendicitis develops, it has a rapid course with a high incidence of gangrene and perforation. Al-Salem et al.26 reported a 66.7% increase in gangrene and perforation in patients with acute appendicitis and SCD versus 5% of the remaining population. It is thus recommended that patient with SCD and abdominal pain should be evaluated carefully and frequently, and when acute appendicitis appears probable they should be operated upon early.

Ischemic colitis is relatively rare in patients with SCD. This is felt in part to be due to the low degree of oxygen extracted by the bowel (15-20% of oxygen delivered) and rapid flow due to arteriovenous shunting in the bowel wall. Even though uncommon, ischemic injury of the colon should be considered in those patients in crisis who develop severe intestinal colic, rectal bleeding, or signs of peritonitis. Diagnostic studies should include flexible sigmoidoscopy, abdominal plain films and computed tomography (CT) of the abdomen.

Pseudomembranous colitis not associated with Clostridium difficile infection has been demonstrated in a patient with SCD.27 It has been suggested by one study that the prevalence of ulcerative colitis may be greater in patients with SCD than the general population.28

Summary

In differentiating sickle cell disease patients with abdominal crises from those with potentially surgical abnormalities, history and physical examination are the primary factors distinguishing specific disorders. Specifically, localized abdominal pain, similarity to prior crises, lack of a precipitating event, and lack of pain relief with hydration and oxygen are hallmarks of potentially surgically correctable lesions in these patients. Laboratory tests are of lesser utility in distinguishing between two different processes. Ultrasound and or computer tomography should be early modalities in the diagnostic algorithm.

REFERENCES

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Jacksonville Medicine / June, 2000

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