CLINICAL REVIEW
Abdominal Pain in Children With Sickle Cell Disease Melissa M. Rhodes, MD,*w David Gregory Bates, MD,*w Tina Andrews, RN, BSN,* Laura Adkins, RN, BSN,* Jennifer Thornton, APN,*w and Jolanda M. Denham, MD*w
Abstract: The differential diagnosis of abdominal pain is broad in any child, and further complicated in children with sickle cell disease (SCD). Acute causes of abdominal pain may require emergent surgery, such as for appendicitis or obstruction caused by a bezoar. Rapid intervention is necessary and life-saving in children with SCD and acute splenic or hepatic sequestration. The majority of children with SCD presenting to the physician’s office or emergency department will have subacute reasons for their abdominal pain, including but not limited to constipation, urinary tract infection, peptic ulcer disease, and cholecystitis. Vaso-occlusive pain often presents in children as abdominal pain, but is a diagnosis of exclusion. The case of a 10-year-old girl with intermittent abdominal pain is used as a starting point to review the pathophysiology, diagnosis, and treatment of the most acute and common causes of abdominal pain in children with SCD. Key Words: sickle cell disease, abdominal pain, splenic sequestration, peptic ulcer disease
(J Clin Gastroenterol 2014;48:99–105)
CASE REPORT A 10-year-old African American girl with homozygous sickle cell anemia [hemoglobin SS disease (Hb SS disease)] experienced recurrent episodes of abdominal pain. Her first episode of abdominal pain was at 7 years of age, described as burning, with the child pointing to her epigastric area. She was noted to have belching after meals. A clinical diagnosis of gastritis was made and she was started on ranitidine with resolution of her symptoms. Three months later, despite continuing ranitidine, she had generalized abdominal pain, particularly after meals. An abdominal ultrasound showed cholelithiasis (Fig. 1). Laparoscopic cholecystectomy was performed and revealed many pigmented gallstones. One year later, the child was again complaining of frequent abdominal pain that was peri-umbilical. She was referred to Gastroenterology, where she was diagnosed with chronic constipation, and started on polyethylene glycol. She did relatively well for the next 18 months, although she had recurrent episodes of pain that were treated as vaso-occlusive crisis (VOC) with ibuprofen and hydrocodone-acetaminophen elixir. Her abdominal pain became more frequent again and her weight gain was poor, so she was referred back to Gastroenterology. She was screened for Helicobacter pylori with stool antigen testing and started on a (PPI) for suspected peptic ulcer disease (PUD). One month later, the child was admitted to the hospital for acute chest syndrome (ACS). As she recovered from ACS, she began to vomit after every meal. She was noted to have significant abdominal distention before vomiting. An upper gastrointestinal (GI) series demonstrated a markedly enlarged stomach with good peristalsis, but no emptying of the stomach, consistent with gastric outlet obstruction (Fig. 2). Upper endoscopy revealed an enlarged but otherwise normal-appearing stomach with severe pyloric From the *Nationwide Children’s Hospital; and wDepartment of Pediatrics, The Ohio State University, Columbus, OH. The authors declare that they have nothing to disclose. Reprints: Melissa M. Rhodes, MD, Hematology/Oncology/BMT, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43235 (e-mail: [email protected]). Copyright r 2013 by Lippincott Williams & Wilkins
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stenosis. Biopsies were unremarkable, without eosinophilic infiltration, and immunohistochemical staining for H. pylori was negative. The scope was not able to pass through the pylorus. Computed tomography (CT) scan was reassuring that there was no extrinsic mass compressing the gastric outlet (Fig. 3). The child was maintained on total parenteral nutrition and naso-jejunal tube feedings while she underwent serial balloon dilations of the pylorus over 2 months (Fig. 4). When a small scope was able to pass through the pylorus, inflammation was visible and thought to be reactive from healing ulceration. No active ulcer was seen, but the amount of inflammation made resolution with balloon dilation alone unlikely. She required definitive treatment with surgical pyloromyotomy, at which time healing peptic ulceration of the proximal duodenum was noted, and thought to be secondary to nonsteroidal anti-inflammatory drug (NSAID) use. Since surgery, the child has done well, with no further abdominal pain, steady weight gain, and improved linear growth.
DIFFERENTIAL DIAGNOSIS OF ABDOMINAL PAIN IN A CHILD WITH SICKLE CELL DISEASE (SCD) Abdominal pain can be difficult to figure out in any child, and sickle cell disease (SCD) adds to the list of possible causes (Table 1). The most urgent cause particular to SCD that must be evaluated is acute splenic sequestration, the second leading cause of death in children under 10 years of age in this population.1 Like other children, those with SCD can also have appendicitis or other causes of an acute surgical abdomen. Rarely, bezoars can lead to life-threatening abdominal symptoms. Less emergent, but particular to children with SCD, are cholelithiasis, hepatic sequestration, renal infarcts, and VOC. Children with SCD have a higher incidence of urinary tract infection (UTI) and pyelonephritis compared with other children, and are also at risk for constipation, PUD, and vaso-occlusive abdominal pain. This article will review pathophysiology, diagnosis, and treatment of the most urgent and common causes of abdominal pain in children with SCD: splenic sequestration, hepatic sequestration, bezoar, cholelithiasis, renal infarction, UTI/pyelonephritis, constipation, PUD, and vaso-occlusive abdominal pain.
SPLENIC SEQUESTRATION Splenic sequestration is defined as a decrease in hemoglobin Z2 g/dL below the patient’s baseline with an associated acute increase in spleen size and evidence of increased erythropoiesis as measured by an elevated reticulocyte count.2,3 Thrombocytopenia may also be present but is not necessary to make the diagnosis. Splenic sequestration is caused by intrasplenic trapping of red blood cells (RBCs), which can result in hypovolemic shock within a matter of hours due to the majority of the patient’s blood volume being trapped in the spleen and not available in systemic circulation. Splenic sequestration has been described in all sickle genotypes but is most commonly reported in individuals with www.jcge.com |
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FIGURE 1. Cholelithiasis. A longitudinal sonographic view of the gallbladder demonstrates numerous echogenic foci (arrows) layering dependently within the gallbladder lumen.
Hb SS disease, among whom it affects 12.6% of children.4 The first episode of splenic sequestration typically occurs between 6 months and 6 years of age and is rare past 8 years of age because of infarction of splenic tissue. Individuals with Hb SC disease and sickle b-thalassemia maintain a portion of splenic function past the early school age years. Therefore, splenic sequestration may be seen in these individuals during
FIGURE 3. Gastric outlet obstruction. A coronal reconstructed view of the abdomen from an abdominal computed tomography scan shows a markedly distended fluid-filled stomach occupying most of the upper abdomen. There is no gastric wall thickening or space occupying mass at the level of the gastric outlet (arrow).
the older school age and adolescent years and even into adulthood.5 The first episode of splenic sequestration is often associated with a viral or bacterial infection.4 Common symptoms of splenic sequestration include: abdominal pain, abdominal fullness, pallor, and lethargy. Physical examination reveals splenomegaly, pallor, tachycardia, and possibly signs of hypovolemia, which are ominous when present. Acute transfusion with packed RBCs (PRBCs) should be performed immediately to stop progression of sequestration and restore blood volume. Transfusion is usually started with 5 mL/kg PRBCs because this can lead to autotransfusion of trapped RBCs out of the spleen and back into the circulation, and a >2 g/dL increase in hemoglobin can be seen. Approximately 50% to 67% of children who have had 1 episode of splenic sequestration will have subsequent episodes.4 Recurrence of splenic sequestration has been documented in individuals who have been treated conservatively with observation, as well as those who have been treated more aggressively with transfusion therapy, once transfusions are stopped.3 Splenectomy may be necessary to prevent recurrent and/or life-threatening episodes of splenic sequestration, but increases the risk of sepsis from encapsulated organisms. Chronic transfusion of 10 to 15 mL/kg PRBCs monthly is often used in children less than 2 years of age to prevent recurrence of splenic sequestration until the child can be immunized adequately against encapsulated organisms. FIGURE 2. Gastric outlet obstruction. A frontal radiograph of the abdomen obtained during upper gastrointestinal series shows a markedly enlarged barium-filled stomach. Despite active peristalsis, no contrast was observed to pass through the region of the pyloric channel adjacent to the level of the cholecystectomy surgical clips (arrow).
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HEPATIC SEQUESTRATION Young adults with SCD have hepatic involvement in 10% of admissions for pain,6 which usually presents with right upper quadrant pain, tender hepatomegaly, fever, elevated white blood cells, and mild elevations in r
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FIGURE 4. Pyloric channel dilation. Two views of the abdomen obtained during fluoroscopic balloon dilation of the pyloric channel. A, An endoscope is present within the stomach (thick arrow). A balloon catheter is placed at the site of stricture and is partially inflated. A waist in the balloon identifies the stricture location (white arrow). B, Progressive inflation of the balloon shows disappearance of the waist indicating successful dilation of the stricture (white arrow).
transaminases and bilirubin. Hepatic sequestration can occur, and is differentiated from vaso-occlusive pain by a significant drop in hemoglobin (> 2 g/dL from baseline) with an appropriate increase in reticulocytosis. Sickled RBCs become trapped in hepatic sinusoids and cause a process similar to splenic sequestration, with the potential for severe anemia and hypovolemic shock. This typically occurs in teenagers or adults rather than young children, but has been reported in children as young as 5 years of age.7 A rare but potentially fatal complication of SCD is intrahepatic cholestasis, the most severe form of hepatic sequestration. This entity is accompanied by extremely high bilirubin levels, with over half of the bilirubin conjugated, and the additional problem of coagulopathy. Patients often die of fulminant hepatic failure. Treatment with emergent exchange transfusion and transfusion of plasma may decrease the high fatality rate of this complication.8
BEZOAR Children with SCD have an increased incidence of pica, the mouthing or eating of nonfood items.9 The incidence of pica decreases with age, but it is as high as 50% in preschoolaged children with SCD.9 Although rare, gastric or intestinal bezoars resulting from ingestion of hair or foam can be lifethreatening.10–12 While taking the history of a child with SCD and abdominal pain, one must remember to ask about eating nonfood items. If the response is positive, consider imaging of the abdomen. Although CT with oral contrast is the most sensitive imaging technique, plain films and ultrasound can also be diagnostic.10 If present, gastric or intestinal bezoars may require emergency surgery, but may be ameliorated by endoscopy. r
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CHOLELITHIASIS A hallmark of SCD is hemolytic anemia, which is more severe in patients with Hb SS/Hb S b0 thalassemia than in those with Hb SC disease or Hb S b + thalassemia. Hemolyzed RBCs leak bilirubin, which remains unconjugated, and can form pigmented gallstones. As part of normal physiology, the gallbladder contracts after a fatty meal. If gallstones are present, the stones are forced up against the cystic duct, leading to pressure and to pain. The pain typically localizes to the right upper quadrant, or it can radiate to the right shoulder blade or to the chest. Patients often report the pain as dull but constant for 1 to 2 hours at a time. Although typical symptoms present 1 to 2 hours after a fatty meal, patients do not always report such an association. Patients with SCD reporting episodic abdominal pain should be investigated for cholelithiasis, which is present in 50% by 18 years of age.13–15 Abdominal ultrasound can usually diagnose cholelithiasis in patients with SCD, with nuclear hepatobiliary scans rarely being necessary. Children with symptomatic cholelithiasis should have scheduled cholecystectomy, both to prevent further pain episodes and to eliminate the risk for acute cholecystitis or associated pancreatitis. Scheduled cholecystectomy is typically laparoscopic rather than open, which has been shown to reduce the length of hospitalization without increasing intraoperative risks.16 Therapeutic management of children with SCD incidentally found to have cholelithiasis by ultrasound for another reason, but who are asymptomatic, remains unclear. Some advocate cholecystectomy before complications,17 but others would wait, as complications from asymptomatic cholelithiasis are rare.18 Common bile duct obstruction can www.jcge.com |
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TABLE 1. Causes of Abdominal Pain in Children With Sickle Cell Disease Common, Emergent Splenic sequestration Hepatic sequestration Cholecystitis Pyelonephritis Renal infarction Common, nonemergent Constipation Vaso-occlusive pain Gastroenteritis Urinary tract infection Cholelithiasis/choledocholithiasis Peptic ulcer disease Functional abdominal pain Uncommon, emergent Appendicitis Gut malrotation/intussusceptions Bezoar Pancreatitis Pelvic inflammatory disease Bowel necrosis Obstruction Incarcerated hernia Tumor (renal medullary carcinoma) Uncommon, nonemergent Inflammatory bowel disease Lactose intolerance Nephrolithiasis Celiac disease
occur at the time of initial presentation, or years after cholecystectomy, and has a higher incidence in patients with SCD than the general population (30% to 50% vs. 10% to 15%).19 Clinicians should have a low threshold for performing endoscopic retrograde cholangiopancreatography in children with symptoms of biliary disease, even after cholecystectomy.19,20
RENAL INFARCTION The pathophysiology of renal injury is mostly from the process of chronic sickling of the erythrocytes in the renal microvasculature. The arterial side of the renal microvasculature normally has low oxygen tension, hypertonicity, and a low pH. In the renal medulla, these factors promote further formation of sickled hemoglobin polymers in the RBCs. This event results in an increase of blood viscosity, functional venous engorgement, and interstitial edema, predisposing the renal microcirculation to ischemia and infarction. Obliteration of the medullary vasculature initially results in segmental scarring and interstitial fibrosis, and progresses to infarction and necrosis, such as papillary necrosis. It is thought that, because of the destruction in the medulla, renal cortical blood flow and glomerular filtration rate are increased by the secretion of vasodilator prostaglandins.21 The most common glomerular changes, namely glomerulomegaly with hypercellularity, and focal and segmental glomerulosclerosis, occur in more than half of individuals with SCD but are not associated with pain.22 Papillary necrosis often presents as painful gross hematuria, whereas the glomerular lesion presents with various degrees of painless hematuria and proteinuria. Hematuria is a common problem in SCD and can develop at any age. It is thought to be caused by infarction
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of the microvessels of the medulla and renal papillae. Patients with sickle cell trait are prone to episodes of painless gross hematuria as well. Treatment consists of bed rest and hydration, but transfusions may be necessary for excessive blood loss. Other causes of hematuria need to be excluded, such as nephrolithiasis, coagulopathy, and tumors involving the bladder, ureter, or kidneys. Renal medullary carcinoma is a highly aggressive kidney tumor predominantly affecting patients with sickle cell trait or Hb SC disease, occurring both in children and adults. Patients usually present with flank pain and hematuria, which can be a common complex in SCD, posing a delay in diagnosis of this highly malignant tumor.23 Ultrasound of the kidneys and bladder can identify the location of bleeding either from a stone or a tumor. Increased echogenicity of the renal pyramids or calcyceal clubbing by urography may suggest sickle cell nephropathy.21
UTI/PYELONEPHRITIS Children with SCD are more susceptible to UTI and pyelonephritis. Splenic infarcts lead to a reduced humoral immune response, which predisposes patients with SCD to encapsulated bacterial infections, including UTI.24 As in children without SCD, there is a greater prevalence for UTI among girls and predominance in gram-negative organisms.22 There is also an association between symptomatic UTI and sickle cell pain episodes, bacteremia, and pneumonia.25 Consideration for UTI should be taken when a child with SCD presents with abdominal pain. Diagnosis is completed by obtaining a clean catch urinalysis with a reflex culture, which is a relatively simple and inexpensive test, followed by treatment with the appropriate antibiotic.
CONSTIPATION Constipation is one of the most common gastrointestinal problems in children of all ages, but reports of the exact prevalence are highly variable. A systematic review in 2006 found a prevalence ranging from 0.7% to 29.6%, with a median of 8.9% of all children.26 Constipation is the most common cause of abdominal pain in children presenting both to the emergency department and to primary care.27–29 The pathophysiology of constipation is complex, with genetic predisposition, low fiber intake, poor fluid intake, sedentary lifestyle, and a history of painful stooling leading to a cycle of stool retention all playing a part in the problem.26,30 Diagnosis of constipation is made mostly by history taking, using Rome III criteria from 2006.31 Constipation is best treated with education and judicious use of polyethylene glycol for initial bowel cleanout, followed by a maintenance regimen of polyethylene glycol and/or other osmotic or stimulant laxatives for 6 to 24 months.30,32 Of particular importance to children with SCD is to remember that opioid medications all have in common the side effect of constipation. Children who do not normally suffer from constipation should be placed on stool softeners at a minimum, and potentially on osmotic or stimulant laxatives, with the use of opioids.33
PUD An adult population-based study estimated the prevalence of PUD at 5% to 15%.34 On the basis of 353 adult SCD patients, a Jamaican study estimated the prevalence of duodenal ulcer (DU) at 7.7%.35 Despite the lack of large population-based pediatric studies, rates of PUD in r
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childhood appear to be low. Large pediatric centers anecdotally report an incidence of 5 to 7 children with gastric or DUs per 2500 hospital admissions each year.36 A few case reports of PUD in pediatric SCD patients exist,37,38 but population-based prevalence studies of PUD in pediatric SCD patients are absent. In a 2009 adult study, the majority of 154 Hb SS and Hb SC patients localized abdominal pain to the epigastrium (36% and 50%, respectively).39 In the same study, PUD/gastritis occurred more frequently than abdominal VOC, hepatopathy, enteritis, and cholelithiasis among all patients.39 The pathogenesis of peptic ulcers in the general population includes acid hypersecretion, decreased mucosal resistance, or a combination of the 2. Rao et al37 and Julka et al40 proposed sickling-induced arterial occlusion resulting in a primary mucosal infarctive lesion, ultimately causing duodenal ulceration (DU). This hypothesis is supported by work from Serjeant et al,35 who reported that DU was more common in individuals with elevated irreversible sickle cell counts, and Lee et al,41 who reported that total and fetal hemoglobin levels were significantly lower in SCD-DU patients. Rao et al37 suggest a common pathophysiology of arterial occlusion with compromised blood supply in both leg and DU formation, and that suppression of sickle hemoglobin production with RBC transfusions may promote DU healing, similar to the healing observed with leg ulcers.42 Owing to the minimal role of acid hypersecretion and the substantial effects of sickling-induced mucosal damage in the creation of DU in SCD patients, acid blockade should be considered adjunctive therapy. Definitive endoscopic and surgical interventions should be considered early to minimize the risk of morbidity, including intestinal perforation, GI bleeds, and gastric outlet obstruction. Contrast radiography of the upper GI tract, also referred to as a barium meal or an upper GI series, can often demonstrate peptic ulcer, as well as ulcer-related gastric outlet obstruction (as in this case patient).43 Air contrast, also known as double-contrast studies, more accurately identifies DUs compared with single-contrast studies.44 The accuracy of upper GI series, however, may be limited by poor visualization of shallow or small (< 0.5 cm) ulcers, very large ulcers, and the performing radiologist’s lack of experience or expertise.45 Capsule endoscopy can detect ulcers when used in evaluation of obscure GI bleeding.46,47 Although it is more invasive and may require anesthesia, routine upper endoscopy more accurately diagnoses ulcers compared with singlecontrast and double-contrast studies.48 In addition, upper endoscopy is preferable over other techniques as biopsies can be obtained to make definitive diagnoses and to evaluate for malignancy. Endoscopy allows for better assessment of impending medical emergencies (eg, deep ulcers with adherent clots, active bleeding) and performing of therapeutic maneuvers, if warranted.49 Stool occult blood may be helpful in assessing bleeding from a peptic ulcer. Elevated serum gastrin and subnormal gastric pH levels suggest gastrinomas and Zollinger-Ellison syndrome. H. pylori are gram-negative bacteria that, owing to their ability to produce urease, can withstand the acidic environment of gastric mucosa.50 H. pylori infection is a common cause of DUs and gastritis in both adults and children.51 H. pylori infection does not appear to be more common in SCD patients as supported by a recent study of 72 SCD patients with recurrent abdominal pain, in which 70% were H. pylori IgG positive, similar to the rates among the nonr
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SCD cohort.52 As H. pylori may require iron for growth, the authors also propose that iron overload may contribute to the high prevalence of H. pylori infection among SCD patients, younger than 5 years of age in particular.52 H. pylori infection may also increase the risk of NSAID-induced ulcers.53 In children, stool antigen assays are more sensitive, whereas serum IgG and polymerase chain reaction from oral mucosa have higher specificity for H. pylori infection.54 In a meta-analysis of pediatric studies of H. pylori therapies in developed nations, 2 to 6 weeks of nitroimidazole and amoxicillin, 1 to 2 weeks of clarithromycin, amoxicillin, and a PPI, and 2 weeks of a macrolide, a nitroimidazole, and a PPI or bismuth, amoxicillin, and metronidazole were the most efficacious therapeutic regimens.55 There are 2 additional risk factors for PUD particular to children with SCD about which providers should be aware. Children with SCD who have received multiple blood transfusions may be treated with iron chelators. Deferasirox is an oral iron chelator that has gastric ulcer listed in its product information as an infrequent adverse event. Gastric protection is not routinely recommended with deferasirox, but PUD should be considered in children who experience abdominal pain with this medication.56 Secondly, like the child described in our case, many children with SCD take frequent NSAIDs as part of their treatment for vaso-occlusive pain. Gastric protection with oral NSAIDs is not routinely recommended in children, although the literature supports high-dose histamine 2 receptor antagonists or PPIs for patients at high risk for PUD.57–59 Further, various NSAIDs have different safety profiles related to PUD, with selective Cox-2 inhibitors being safer than ibuprofen, which is generally safer than ketorolac or naproxen.60,61 Our program, like many others, uses ibuprofen alone in most patients, and either ibuprofen or a selective Cox-2 inhibitor along with a PPI in patients with known or suspected PUD.
VASO-OCCLUSIVE PAIN Vaso-occlusive pain in SCD can be obvious when there is visible swelling, no history of injury or fever, and no overlying erythema, such as in dactylitis. Although more often than not, it is a clinical diagnosis based on patient history of severe pain in a typical location for that patient, precipitated by change in the weather, dehydration, stress, overuse, or exposure to cold, and improved with hydration, rest, and pain medications. It is caused by irreversible sickling leading to sickled polymers that obstruct blood flow and prevent oxygenation to tissues.2 Abdominal vasoocclusive pain is difficult to differentiate from other organic causes of abdominal pain, including many of those described above, as well as functional abdominal pain of childhood, in which no pathologic mechanism can be found to explain the pain. Thorough history of the onset, location, type of pain, exacerbating and relieving factors including food, defecation, and acid reducers can be helpful. Physical examination should rule out an acute surgical abdomen, splenomegaly, hepatomegaly, or mass. Lack of bowel sounds or metabolic acidosis should be considered signs concerning for ischemic colitis. The child should have complete bowel rest and imaging performed with ultrasound or CT scan. Only once other causes have been considered and effectively ruled out, we advocate treating for vaso-occlusive pain with both an NSAID and opioid scheduled around the clock for 24 to 48 hours, increasing www.jcge.com |
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oral hydration, and adding medications for constipation. If there is any concern for gastritis or NSAID use is prolonged, a high-dose acid blocker should also be used.
RECOMMENDATIONS FOR EVALUATION Each child with SCD presenting with abdominal pain obviously requires a careful history taking and physical examination. While history taking, attention should be given to eating habits, including whether or not the child eats nonfood items (pica), hydration, and fiber content that would raise suspicion for constipation, and whether or not pain is associated with dairy products. Timing of pain in relation to eating is helpful in raising or lowering suspicion of cholelithiasis. A thorough history of bowel habits is essential to determine the role of constipation in the child’s pain, and bathroom hygiene for possibility of UTI. Blood in the urine or changes in the appearance or odor of the urine may lead to concerns for pyelonephritis or renal infarction. Vomiting without diarrhea raises concern for appendicitis or for obstruction, whereas vomiting and diarrhea together are more typical of gastroenteritis. Medication used, including dosages and frequency, may give clues for opioid-induced constipation or risk for PUD from NSAIDs. If pain is relieved by oral analgesics, this pain is typical of a child’s VOC, and no other red flags are raised, further VOC management is in order. Of course, location and characterization of the pain may point to PUD, appendicitis, splenic sequestration, or hepatic sequestration. Physical examination should focus on any peritoneal signs that may indicate an acute surgical abdomen, splenomegaly, hepatomegaly, or mass. Simple lab tests include a CBC and reticulocyte count (decreased hemoglobin and platelets in either splenic or hepatic sequestration), transaminases and bilirubin (very high in hepatic sequestration, hyperbilirubinemia alone in choledocholithiasis), lipase and amylase if pancreatitis is suspected, and urinalysis for UTI (leukocyte esterase, nitrates) or renal infarct (RBCs in the urine). Abdominal ultrasound is helpful for suspected cholelithiasis, appendicitis, pyelonephritis, or mass.
THE CASE In returning to our patient, by 10 years of age she experienced a significant amount of abdominal pain, from various pathologic causes described above. She was treated clinically for gastritis, constipation, and vaso-occlusive pain, and surgically for symptomatic cholelithiasis. She has not had any evidence of renal disease, other than hyposthenuria. She has not had splenic or hepatic sequestration and does not have pica. Before developing gastric outlet obstruction, she had been treated for pain on and off for months, with episodic use of ibuprofen. This NSAID use, along with severe SCD as manifested by ACS and low baseline hemoglobin, may have contributed to development of peptic ulceration of her duodenum, complicated by formation of a stricture, and pyloric outlet obstruction. REFERENCES 1. Lee A, Thomas P, Cupidore L, et al. Improved survival in homozygous sickle cell disease: lessons from a cohort study. BMJ. 1995;311:1600–1602. 2. Lenfant C. The Management of Sickle Cell Disease. Bethesda, MD: NIH/NHLBI Publication 02-2117; 2002:119–121. 3. Kinney TR, Ware RE, Schultz WH, et al. Long-term management of splenic sequestration in children with sickle cell disease. J Pediatr. 1990;117:194–199.
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4. Brousse V, Elie C, Benkerrou M, et al. Acute splenic sequestration crisis in sickle cell disease: cohort study of 190 paediatric patients. Br J Haematol. 2012;156:643–648. 5. Solanki DL, Kletter GG, Castro O. Acute splenic sequestration crises in adults with sickle cell disease. Am J Med. 1986; 80:985–990. 6. Johnson CS, Omata M, Tong MJ. Liver involvement in sickle cell disease. Medicine (Baltimore). 1985;64:349–356. 7. Ahmed N, Chizhevsky V. Acute hepatic sequestration associated with pneumococcal infection in a 5 year old boy with sickle beta 0 thalassemia. J Pediatr Hematol Oncol. 2007;29: 720–724. 8. Shao SH, Orringer EP. Sickle cell intrahepatic cholestasis: approach to a difficult problem. Am J Gastroenterol. 1995; 90:2048–2050. 9. Lemanek KL, Brown RT, Armstrong FD, et al. Dysfunctional eating patterns and symptoms of pica in children and adolescents with sickle cell disease. Clin Pediatr. 2002;41: 493–500. 10. Malhotra A, Jones L, Drugas G. Simultaneous gastric and small intestinal trichobezoars. Pediatr Emerg Care. 2008;24: 774–776. 11. Aletepeter T, Annes J, Meller J. Foam bezoar: resection of perforated terminal ileum in a 17 year old with sickle beta + thalassemia and pica. J Pediatr Surg. 2011;46:E31–E32. 12. Sciaretta JD, Bond SJ. Gastric trichobezoar: abdominal mass in a child with sickle cell disease. Pediatr Emerg Care. 2011;27:1014–1015. 13. Walker TM, Hambleton IR, Serjeant GR. Gallstones in sickle cell disease: observations from the Jamaican Cohort Study. J Pediatr. 2000;136:80–85. 14. Gumiero AP, Bellomo-Brandao MA, Costa-Pinto EA. Gallstones in children with sickle cell disease followed up at a Brazilian hematology center. Arq Gastroenterol. 2008;45: 313–318. 15. Balci A, Karazincir S, Sangun O, et al. Prevalence of abdominal ultrasonographic abnormalities in patients with sickle cell disease. Diagn Interv Radiol. 2008;14:133–137. 16. Goers T, Panepinto J, DeBaun M, et al. Laparoscopic versus open abdominal surgery in children with sickle cell disease is associated with a shorter hospital stay. Pediatr Blood Cancer. 2008;50:603–606. 17. Suell MN, Horton TM, Dishop MK, et al. Outcomes for children with gallbladder abnormalities and sickle cell disease. J Pediatr. 2004;145:617–621. 18. Bogue CO, Murphey AJ, Gerstle JT, et al. Risk factors, complications, and outcomes of gallstones in children: a singlecenter review. J Pediatr Gastroenterol Nutr. 2010;50:303–308. 19. Amoako MO, Casella JF, Strouse JJ. High rates of recurrent biliary tract obstruction in children with sickle cell disease. Pediatr Blood Cancer. 2013;60:650–652. 20. Issa H, Al-Salem AH. Role of ERCP in the era of laparoscopic cholecystectomy for the evaluation of choledocholithiasis in sickle cell anemia. World J Gastroenterol. 2011;17:1844–1847. 21. Saborio P, Scheinman JI. Sickle cell nephropathy. J Am Soc Nephrol. 1999;10:187–192. 22. Bruno D, Wigfall DR, Zimmerman SA, et al. Genitourinary complications of sickle cell disease. J Urol. 2001;166:803–811. 23. Davis CJ, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma. The seventh sickle cell nephropathy. Am J Surg Pathol. 1995;19:1–11. 24. Lopez Revuelta RK, Ricard Andres MP. Kidney abnormalities in sickle cell disease. Nefrologia. 2011;31:591–601. 25. Cumming V, Ali S, Forrester T, et al. Asymptomatic bacteriuria in sickle cell disease: a cross sectional study. BMC Infect Dis. 2006;6:46–51. 26. Van den Berg MM, Benninga MA, DiLorenzo C. Epidemiology of childhood constipation: a systematic review. Am J Gastroenterol. 2006;101:2401–2409. 27. Loening-Baucke V, Swidsinski A. Constipation a cause of acute abdominal pain in children. J Pediatr. 2007;151: 666–669. r
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28. Diamanti A, Bracci F, Reale A, et al. Incidence, clinical presentation, and management on constipation in a pediatric ED. Am J Emerg Med. 2010;28:189–194. 29. Gijsbers CFM, Kneepkens CMF, Schweizer JJ, et al. Recurrent abdominal pain in 200 children: somatic causes and diagnostic criteria. Acta Paediatr. 2011;100:208–214. 30. Rajindrajith S, Devanarayana NM. Constipation in children: novel insight into epidemiology, pathophysiology, and management. J Neurogastroenterol Motil. 2011;17:35–47. 31. Rasquin A, DiLorenzo C, Forbes D, et al. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology. 2006;130:1527–1537. 32. Nurko S, Youssef NN, Sabri M, et al. PEG3350 in the treatment of childhood constipation: a multicenter, doubleblinded, placebo-controlled trial. J Pediatr. 2008;153:254–261. 33. O’Brien SH, Fan L, Kelleher KJ. Inpatient use of laxatives during opioid administration in children with sickle cell disease. Pediatr Blood Cancer. 2010;54:559–562. 34. Aro P, Storskrubb T, Ronkainen J, et al. Peptic ulcer disease in a general adult population: the Kalixanda study: a random population-based study. Am J Epidemiol. 2006;163:1025–1034. 35. Serjeant GR, May H, Patrick A, et al. Duodenal ulceration in sickle cell anemia. Trans R Soc Trop Med Hyg. 1973;67:59–63. 36. Kliegman RM. Nelson Textbook of Pediatrics. Philadelphia: Elsevier Inc.; 2011. 37. Rao S, Royal JE, Conrad HA Jr, et al. Duodenal ulcer in sickle cell anemia. J Pediatr Gastroenterol Nutr. 1990;10:117–120. 38. Hein GE, McCalla RL, Thorne GW. Sickle cell anemia: with report of a case with autopsy. Am J Med Sci. 1927;173:763–772. 39. Akinola NO, Bolarinwa RA, Faponle AF. The import of abdominal pain in adults with sickle cell disorder. West Afr J Med. 2009;28:83–86. 40. Julka RN, Aduli F, Lamps LW, et al. Ischemic duodenal ulcer, an unusual presentation of sickle cell disease. J Natl Med Assoc. 2008;100:339–341. 41. Lee MG, Thirumalai CH, Terri SI, et al. Endoscopic and gastric acid studies in homozygous sickle cell disease and upper abdominal pain. Gut. 1989;30:569–572. 42. Chernoff AI, Shapleigh JB, Moore CV. Therapy of chronic ulceration of the legs associated with sickle cell anemia. JAMA. 1954;155:1487–1491. 43. Feldman M. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 9th ed. Philadephia: Elsevier; 2010. 44. Levine MS. Role of the double-contrast upper gastrointestinal series in the 1990s. Gastroenterol Clin North Am. 1995;24:289–308. 45. Mettler F. Essentials of Radiology. 2nd ed. Philadephia: Elsevier; 2005.
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46. Rondonotti E, Soncini M, Girelli C, et al. Small bowel capsule endoscopy in clinical practice: a multicenter 7-year survey. Eur J Gastroenterol Hepatol. 2010;22:1380–1386. 47. Liao Z, Gao R, Xu C, et al. Gastrointest Endosc. 2010;71: 280–286. 48. Talley NJ, Silverstein MD, Agre´us L, et al. AGA technical review. Evaluation of dyspepsia. Gastroenterology. 1998;114: 582–589. 49. Bope ET, Kellerman RD. Conn’s Current Therapy 2012. 1st ed. Philadephia: Elsevier; 2011. 50. Owen RJ. Bacteriology of Helicobacter pylori. Baillieres Clin Gastroenterol. 1995;9:415–440. 51. Hassall E, Dimmick JE. Unique features of Helicobacter pylori disease in children. Dig Dis Sci. 1991;36417–36423. 52. Senbanjo IS, Akinsegun A, Diaku-Akinwumi I, et al. Helicobacter pylori infection among a pediatric population with sickle cell disease. J Natl Med Assoc. 2010;102:1095–1099. 53. Woods KF, Onuoha A, Schade RR, et al. Helicobacter pylori infection in sickle cell disease. J Natl Med Assoc. 2000;92: 361–365. 54. Bonamico M, Strappini PM, Bonci E, et al. Evaluation of stool antigen test, PCR on ORAL samples and serology for the noninvasive detection of Helicobacter pylori infection in children. Helicobacter. 2004;9:69–76. 55. Khurana R, Fischbach L, Chiba N, et al. Meta-analysis: Helicobacter pylori eradication treatment efficacy in children. Aliment Pharmacol Ther. 2007;25:523–536. 56. Bauters T, Mondelaers V, Robays H, et al. Gastric ulcer in a child treated with deferasirox. Pharm World Sci. 2010;32: 112–113. 57. Chan FKL. Single-tablet ibuprofen/double-dose famotidine for reduction of gastric and duodenal ulcers (REDUCE Trials): what can be reduced? Am J Gastroenterol. 2012;107:387–388. 58. Laine L, Kivitz AJ, Bello AE, et al. Double-blind randomized trials of single-tablet ibuprofen/high-dose famotidine vs. ibuprofen alone for reduction of gastric and duodenal ulcers. Am J Gastroenterol. 2012;107:379–386. 59. Rostom A, Dube C, Wells G, et al. Prevention of NSAIDinduced gastroduodenal ulcers. Cochrane Database Syst Rev. 2002;4:CD002296. 60. Gonzalez ELM, Patrignani P, Tacconelli S, et al. Variability among nonsteroidal anti-inflammatory drugs in risk of upper gastrointestinal bleeding. Arthritis Rheum. 2010;62:1592–1601. 61. Chang CH, Chen HC, Lin JW, et al. Risk of hospitalization for upper gastrointestinal adverse events associated with nonsteroidal anti-inflammatory drugs: a nationwide case-crossover study in Taiwan. Pharmacoepidemiol Drug Saf. 2011;20: 763–771.
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Abdominal Pain in Children With Sickle Cell Disease Melissa M. Rhodes, MD,*w David Gregory Bates, MD,*w Tina Andrews, RN, BSN,* Laura Adkins, RN, BSN,* Jennifer Thornton, APN,*w and Jolanda M. Denham, MD*w
Abstract: The differential diagnosis of abdominal pain is broad in any child, and further complicated in children with sickle cell disease (SCD). Acute causes of abdominal pain may require emergent surgery, such as for appendicitis or obstruction caused by a bezoar. Rapid intervention is necessary and life-saving in children with SCD and acute splenic or hepatic sequestration. The majority of children with SCD presenting to the physician’s office or emergency department will have subacute reasons for their abdominal pain, including but not limited to constipation, urinary tract infection, peptic ulcer disease, and cholecystitis. Vaso-occlusive pain often presents in children as abdominal pain, but is a diagnosis of exclusion. The case of a 10-year-old girl with intermittent abdominal pain is used as a starting point to review the pathophysiology, diagnosis, and treatment of the most acute and common causes of abdominal pain in children with SCD. Key Words: sickle cell disease, abdominal pain, splenic sequestration, peptic ulcer disease
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CASE REPORT A 10-year-old African American girl with homozygous sickle cell anemia [hemoglobin SS disease (Hb SS disease)] experienced recurrent episodes of abdominal pain. Her first episode of abdominal pain was at 7 years of age, described as burning, with the child pointing to her epigastric area. She was noted to have belching after meals. A clinical diagnosis of gastritis was made and she was started on ranitidine with resolution of her symptoms. Three months later, despite continuing ranitidine, she had generalized abdominal pain, particularly after meals. An abdominal ultrasound showed cholelithiasis (Fig. 1). Laparoscopic cholecystectomy was performed and revealed many pigmented gallstones. One year later, the child was again complaining of frequent abdominal pain that was peri-umbilical. She was referred to Gastroenterology, where she was diagnosed with chronic constipation, and started on polyethylene glycol. She did relatively well for the next 18 months, although she had recurrent episodes of pain that were treated as vaso-occlusive crisis (VOC) with ibuprofen and hydrocodone-acetaminophen elixir. Her abdominal pain became more frequent again and her weight gain was poor, so she was referred back to Gastroenterology. She was screened for Helicobacter pylori with stool antigen testing and started on a (PPI) for suspected peptic ulcer disease (PUD). One month later, the child was admitted to the hospital for acute chest syndrome (ACS). As she recovered from ACS, she began to vomit after every meal. She was noted to have significant abdominal distention before vomiting. An upper gastrointestinal (GI) series demonstrated a markedly enlarged stomach with good peristalsis, but no emptying of the stomach, consistent with gastric outlet obstruction (Fig. 2). Upper endoscopy revealed an enlarged but otherwise normal-appearing stomach with severe pyloric From the *Nationwide Children’s Hospital; and wDepartment of Pediatrics, The Ohio State University, Columbus, OH. The authors declare that they have nothing to disclose. Reprints: Melissa M. Rhodes, MD, Hematology/Oncology/BMT, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43235 (e-mail: [email protected]). Copyright r 2013 by Lippincott Williams & Wilkins
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stenosis. Biopsies were unremarkable, without eosinophilic infiltration, and immunohistochemical staining for H. pylori was negative. The scope was not able to pass through the pylorus. Computed tomography (CT) scan was reassuring that there was no extrinsic mass compressing the gastric outlet (Fig. 3). The child was maintained on total parenteral nutrition and naso-jejunal tube feedings while she underwent serial balloon dilations of the pylorus over 2 months (Fig. 4). When a small scope was able to pass through the pylorus, inflammation was visible and thought to be reactive from healing ulceration. No active ulcer was seen, but the amount of inflammation made resolution with balloon dilation alone unlikely. She required definitive treatment with surgical pyloromyotomy, at which time healing peptic ulceration of the proximal duodenum was noted, and thought to be secondary to nonsteroidal anti-inflammatory drug (NSAID) use. Since surgery, the child has done well, with no further abdominal pain, steady weight gain, and improved linear growth.
DIFFERENTIAL DIAGNOSIS OF ABDOMINAL PAIN IN A CHILD WITH SICKLE CELL DISEASE (SCD) Abdominal pain can be difficult to figure out in any child, and sickle cell disease (SCD) adds to the list of possible causes (Table 1). The most urgent cause particular to SCD that must be evaluated is acute splenic sequestration, the second leading cause of death in children under 10 years of age in this population.1 Like other children, those with SCD can also have appendicitis or other causes of an acute surgical abdomen. Rarely, bezoars can lead to life-threatening abdominal symptoms. Less emergent, but particular to children with SCD, are cholelithiasis, hepatic sequestration, renal infarcts, and VOC. Children with SCD have a higher incidence of urinary tract infection (UTI) and pyelonephritis compared with other children, and are also at risk for constipation, PUD, and vaso-occlusive abdominal pain. This article will review pathophysiology, diagnosis, and treatment of the most urgent and common causes of abdominal pain in children with SCD: splenic sequestration, hepatic sequestration, bezoar, cholelithiasis, renal infarction, UTI/pyelonephritis, constipation, PUD, and vaso-occlusive abdominal pain.
SPLENIC SEQUESTRATION Splenic sequestration is defined as a decrease in hemoglobin Z2 g/dL below the patient’s baseline with an associated acute increase in spleen size and evidence of increased erythropoiesis as measured by an elevated reticulocyte count.2,3 Thrombocytopenia may also be present but is not necessary to make the diagnosis. Splenic sequestration is caused by intrasplenic trapping of red blood cells (RBCs), which can result in hypovolemic shock within a matter of hours due to the majority of the patient’s blood volume being trapped in the spleen and not available in systemic circulation. Splenic sequestration has been described in all sickle genotypes but is most commonly reported in individuals with www.jcge.com |
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FIGURE 1. Cholelithiasis. A longitudinal sonographic view of the gallbladder demonstrates numerous echogenic foci (arrows) layering dependently within the gallbladder lumen.
Hb SS disease, among whom it affects 12.6% of children.4 The first episode of splenic sequestration typically occurs between 6 months and 6 years of age and is rare past 8 years of age because of infarction of splenic tissue. Individuals with Hb SC disease and sickle b-thalassemia maintain a portion of splenic function past the early school age years. Therefore, splenic sequestration may be seen in these individuals during
FIGURE 3. Gastric outlet obstruction. A coronal reconstructed view of the abdomen from an abdominal computed tomography scan shows a markedly distended fluid-filled stomach occupying most of the upper abdomen. There is no gastric wall thickening or space occupying mass at the level of the gastric outlet (arrow).
the older school age and adolescent years and even into adulthood.5 The first episode of splenic sequestration is often associated with a viral or bacterial infection.4 Common symptoms of splenic sequestration include: abdominal pain, abdominal fullness, pallor, and lethargy. Physical examination reveals splenomegaly, pallor, tachycardia, and possibly signs of hypovolemia, which are ominous when present. Acute transfusion with packed RBCs (PRBCs) should be performed immediately to stop progression of sequestration and restore blood volume. Transfusion is usually started with 5 mL/kg PRBCs because this can lead to autotransfusion of trapped RBCs out of the spleen and back into the circulation, and a >2 g/dL increase in hemoglobin can be seen. Approximately 50% to 67% of children who have had 1 episode of splenic sequestration will have subsequent episodes.4 Recurrence of splenic sequestration has been documented in individuals who have been treated conservatively with observation, as well as those who have been treated more aggressively with transfusion therapy, once transfusions are stopped.3 Splenectomy may be necessary to prevent recurrent and/or life-threatening episodes of splenic sequestration, but increases the risk of sepsis from encapsulated organisms. Chronic transfusion of 10 to 15 mL/kg PRBCs monthly is often used in children less than 2 years of age to prevent recurrence of splenic sequestration until the child can be immunized adequately against encapsulated organisms. FIGURE 2. Gastric outlet obstruction. A frontal radiograph of the abdomen obtained during upper gastrointestinal series shows a markedly enlarged barium-filled stomach. Despite active peristalsis, no contrast was observed to pass through the region of the pyloric channel adjacent to the level of the cholecystectomy surgical clips (arrow).
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HEPATIC SEQUESTRATION Young adults with SCD have hepatic involvement in 10% of admissions for pain,6 which usually presents with right upper quadrant pain, tender hepatomegaly, fever, elevated white blood cells, and mild elevations in r
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FIGURE 4. Pyloric channel dilation. Two views of the abdomen obtained during fluoroscopic balloon dilation of the pyloric channel. A, An endoscope is present within the stomach (thick arrow). A balloon catheter is placed at the site of stricture and is partially inflated. A waist in the balloon identifies the stricture location (white arrow). B, Progressive inflation of the balloon shows disappearance of the waist indicating successful dilation of the stricture (white arrow).
transaminases and bilirubin. Hepatic sequestration can occur, and is differentiated from vaso-occlusive pain by a significant drop in hemoglobin (> 2 g/dL from baseline) with an appropriate increase in reticulocytosis. Sickled RBCs become trapped in hepatic sinusoids and cause a process similar to splenic sequestration, with the potential for severe anemia and hypovolemic shock. This typically occurs in teenagers or adults rather than young children, but has been reported in children as young as 5 years of age.7 A rare but potentially fatal complication of SCD is intrahepatic cholestasis, the most severe form of hepatic sequestration. This entity is accompanied by extremely high bilirubin levels, with over half of the bilirubin conjugated, and the additional problem of coagulopathy. Patients often die of fulminant hepatic failure. Treatment with emergent exchange transfusion and transfusion of plasma may decrease the high fatality rate of this complication.8
BEZOAR Children with SCD have an increased incidence of pica, the mouthing or eating of nonfood items.9 The incidence of pica decreases with age, but it is as high as 50% in preschoolaged children with SCD.9 Although rare, gastric or intestinal bezoars resulting from ingestion of hair or foam can be lifethreatening.10–12 While taking the history of a child with SCD and abdominal pain, one must remember to ask about eating nonfood items. If the response is positive, consider imaging of the abdomen. Although CT with oral contrast is the most sensitive imaging technique, plain films and ultrasound can also be diagnostic.10 If present, gastric or intestinal bezoars may require emergency surgery, but may be ameliorated by endoscopy. r
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CHOLELITHIASIS A hallmark of SCD is hemolytic anemia, which is more severe in patients with Hb SS/Hb S b0 thalassemia than in those with Hb SC disease or Hb S b + thalassemia. Hemolyzed RBCs leak bilirubin, which remains unconjugated, and can form pigmented gallstones. As part of normal physiology, the gallbladder contracts after a fatty meal. If gallstones are present, the stones are forced up against the cystic duct, leading to pressure and to pain. The pain typically localizes to the right upper quadrant, or it can radiate to the right shoulder blade or to the chest. Patients often report the pain as dull but constant for 1 to 2 hours at a time. Although typical symptoms present 1 to 2 hours after a fatty meal, patients do not always report such an association. Patients with SCD reporting episodic abdominal pain should be investigated for cholelithiasis, which is present in 50% by 18 years of age.13–15 Abdominal ultrasound can usually diagnose cholelithiasis in patients with SCD, with nuclear hepatobiliary scans rarely being necessary. Children with symptomatic cholelithiasis should have scheduled cholecystectomy, both to prevent further pain episodes and to eliminate the risk for acute cholecystitis or associated pancreatitis. Scheduled cholecystectomy is typically laparoscopic rather than open, which has been shown to reduce the length of hospitalization without increasing intraoperative risks.16 Therapeutic management of children with SCD incidentally found to have cholelithiasis by ultrasound for another reason, but who are asymptomatic, remains unclear. Some advocate cholecystectomy before complications,17 but others would wait, as complications from asymptomatic cholelithiasis are rare.18 Common bile duct obstruction can www.jcge.com |
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TABLE 1. Causes of Abdominal Pain in Children With Sickle Cell Disease Common, Emergent Splenic sequestration Hepatic sequestration Cholecystitis Pyelonephritis Renal infarction Common, nonemergent Constipation Vaso-occlusive pain Gastroenteritis Urinary tract infection Cholelithiasis/choledocholithiasis Peptic ulcer disease Functional abdominal pain Uncommon, emergent Appendicitis Gut malrotation/intussusceptions Bezoar Pancreatitis Pelvic inflammatory disease Bowel necrosis Obstruction Incarcerated hernia Tumor (renal medullary carcinoma) Uncommon, nonemergent Inflammatory bowel disease Lactose intolerance Nephrolithiasis Celiac disease
occur at the time of initial presentation, or years after cholecystectomy, and has a higher incidence in patients with SCD than the general population (30% to 50% vs. 10% to 15%).19 Clinicians should have a low threshold for performing endoscopic retrograde cholangiopancreatography in children with symptoms of biliary disease, even after cholecystectomy.19,20
RENAL INFARCTION The pathophysiology of renal injury is mostly from the process of chronic sickling of the erythrocytes in the renal microvasculature. The arterial side of the renal microvasculature normally has low oxygen tension, hypertonicity, and a low pH. In the renal medulla, these factors promote further formation of sickled hemoglobin polymers in the RBCs. This event results in an increase of blood viscosity, functional venous engorgement, and interstitial edema, predisposing the renal microcirculation to ischemia and infarction. Obliteration of the medullary vasculature initially results in segmental scarring and interstitial fibrosis, and progresses to infarction and necrosis, such as papillary necrosis. It is thought that, because of the destruction in the medulla, renal cortical blood flow and glomerular filtration rate are increased by the secretion of vasodilator prostaglandins.21 The most common glomerular changes, namely glomerulomegaly with hypercellularity, and focal and segmental glomerulosclerosis, occur in more than half of individuals with SCD but are not associated with pain.22 Papillary necrosis often presents as painful gross hematuria, whereas the glomerular lesion presents with various degrees of painless hematuria and proteinuria. Hematuria is a common problem in SCD and can develop at any age. It is thought to be caused by infarction
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of the microvessels of the medulla and renal papillae. Patients with sickle cell trait are prone to episodes of painless gross hematuria as well. Treatment consists of bed rest and hydration, but transfusions may be necessary for excessive blood loss. Other causes of hematuria need to be excluded, such as nephrolithiasis, coagulopathy, and tumors involving the bladder, ureter, or kidneys. Renal medullary carcinoma is a highly aggressive kidney tumor predominantly affecting patients with sickle cell trait or Hb SC disease, occurring both in children and adults. Patients usually present with flank pain and hematuria, which can be a common complex in SCD, posing a delay in diagnosis of this highly malignant tumor.23 Ultrasound of the kidneys and bladder can identify the location of bleeding either from a stone or a tumor. Increased echogenicity of the renal pyramids or calcyceal clubbing by urography may suggest sickle cell nephropathy.21
UTI/PYELONEPHRITIS Children with SCD are more susceptible to UTI and pyelonephritis. Splenic infarcts lead to a reduced humoral immune response, which predisposes patients with SCD to encapsulated bacterial infections, including UTI.24 As in children without SCD, there is a greater prevalence for UTI among girls and predominance in gram-negative organisms.22 There is also an association between symptomatic UTI and sickle cell pain episodes, bacteremia, and pneumonia.25 Consideration for UTI should be taken when a child with SCD presents with abdominal pain. Diagnosis is completed by obtaining a clean catch urinalysis with a reflex culture, which is a relatively simple and inexpensive test, followed by treatment with the appropriate antibiotic.
CONSTIPATION Constipation is one of the most common gastrointestinal problems in children of all ages, but reports of the exact prevalence are highly variable. A systematic review in 2006 found a prevalence ranging from 0.7% to 29.6%, with a median of 8.9% of all children.26 Constipation is the most common cause of abdominal pain in children presenting both to the emergency department and to primary care.27–29 The pathophysiology of constipation is complex, with genetic predisposition, low fiber intake, poor fluid intake, sedentary lifestyle, and a history of painful stooling leading to a cycle of stool retention all playing a part in the problem.26,30 Diagnosis of constipation is made mostly by history taking, using Rome III criteria from 2006.31 Constipation is best treated with education and judicious use of polyethylene glycol for initial bowel cleanout, followed by a maintenance regimen of polyethylene glycol and/or other osmotic or stimulant laxatives for 6 to 24 months.30,32 Of particular importance to children with SCD is to remember that opioid medications all have in common the side effect of constipation. Children who do not normally suffer from constipation should be placed on stool softeners at a minimum, and potentially on osmotic or stimulant laxatives, with the use of opioids.33
PUD An adult population-based study estimated the prevalence of PUD at 5% to 15%.34 On the basis of 353 adult SCD patients, a Jamaican study estimated the prevalence of duodenal ulcer (DU) at 7.7%.35 Despite the lack of large population-based pediatric studies, rates of PUD in r
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childhood appear to be low. Large pediatric centers anecdotally report an incidence of 5 to 7 children with gastric or DUs per 2500 hospital admissions each year.36 A few case reports of PUD in pediatric SCD patients exist,37,38 but population-based prevalence studies of PUD in pediatric SCD patients are absent. In a 2009 adult study, the majority of 154 Hb SS and Hb SC patients localized abdominal pain to the epigastrium (36% and 50%, respectively).39 In the same study, PUD/gastritis occurred more frequently than abdominal VOC, hepatopathy, enteritis, and cholelithiasis among all patients.39 The pathogenesis of peptic ulcers in the general population includes acid hypersecretion, decreased mucosal resistance, or a combination of the 2. Rao et al37 and Julka et al40 proposed sickling-induced arterial occlusion resulting in a primary mucosal infarctive lesion, ultimately causing duodenal ulceration (DU). This hypothesis is supported by work from Serjeant et al,35 who reported that DU was more common in individuals with elevated irreversible sickle cell counts, and Lee et al,41 who reported that total and fetal hemoglobin levels were significantly lower in SCD-DU patients. Rao et al37 suggest a common pathophysiology of arterial occlusion with compromised blood supply in both leg and DU formation, and that suppression of sickle hemoglobin production with RBC transfusions may promote DU healing, similar to the healing observed with leg ulcers.42 Owing to the minimal role of acid hypersecretion and the substantial effects of sickling-induced mucosal damage in the creation of DU in SCD patients, acid blockade should be considered adjunctive therapy. Definitive endoscopic and surgical interventions should be considered early to minimize the risk of morbidity, including intestinal perforation, GI bleeds, and gastric outlet obstruction. Contrast radiography of the upper GI tract, also referred to as a barium meal or an upper GI series, can often demonstrate peptic ulcer, as well as ulcer-related gastric outlet obstruction (as in this case patient).43 Air contrast, also known as double-contrast studies, more accurately identifies DUs compared with single-contrast studies.44 The accuracy of upper GI series, however, may be limited by poor visualization of shallow or small (< 0.5 cm) ulcers, very large ulcers, and the performing radiologist’s lack of experience or expertise.45 Capsule endoscopy can detect ulcers when used in evaluation of obscure GI bleeding.46,47 Although it is more invasive and may require anesthesia, routine upper endoscopy more accurately diagnoses ulcers compared with singlecontrast and double-contrast studies.48 In addition, upper endoscopy is preferable over other techniques as biopsies can be obtained to make definitive diagnoses and to evaluate for malignancy. Endoscopy allows for better assessment of impending medical emergencies (eg, deep ulcers with adherent clots, active bleeding) and performing of therapeutic maneuvers, if warranted.49 Stool occult blood may be helpful in assessing bleeding from a peptic ulcer. Elevated serum gastrin and subnormal gastric pH levels suggest gastrinomas and Zollinger-Ellison syndrome. H. pylori are gram-negative bacteria that, owing to their ability to produce urease, can withstand the acidic environment of gastric mucosa.50 H. pylori infection is a common cause of DUs and gastritis in both adults and children.51 H. pylori infection does not appear to be more common in SCD patients as supported by a recent study of 72 SCD patients with recurrent abdominal pain, in which 70% were H. pylori IgG positive, similar to the rates among the nonr
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SCD cohort.52 As H. pylori may require iron for growth, the authors also propose that iron overload may contribute to the high prevalence of H. pylori infection among SCD patients, younger than 5 years of age in particular.52 H. pylori infection may also increase the risk of NSAID-induced ulcers.53 In children, stool antigen assays are more sensitive, whereas serum IgG and polymerase chain reaction from oral mucosa have higher specificity for H. pylori infection.54 In a meta-analysis of pediatric studies of H. pylori therapies in developed nations, 2 to 6 weeks of nitroimidazole and amoxicillin, 1 to 2 weeks of clarithromycin, amoxicillin, and a PPI, and 2 weeks of a macrolide, a nitroimidazole, and a PPI or bismuth, amoxicillin, and metronidazole were the most efficacious therapeutic regimens.55 There are 2 additional risk factors for PUD particular to children with SCD about which providers should be aware. Children with SCD who have received multiple blood transfusions may be treated with iron chelators. Deferasirox is an oral iron chelator that has gastric ulcer listed in its product information as an infrequent adverse event. Gastric protection is not routinely recommended with deferasirox, but PUD should be considered in children who experience abdominal pain with this medication.56 Secondly, like the child described in our case, many children with SCD take frequent NSAIDs as part of their treatment for vaso-occlusive pain. Gastric protection with oral NSAIDs is not routinely recommended in children, although the literature supports high-dose histamine 2 receptor antagonists or PPIs for patients at high risk for PUD.57–59 Further, various NSAIDs have different safety profiles related to PUD, with selective Cox-2 inhibitors being safer than ibuprofen, which is generally safer than ketorolac or naproxen.60,61 Our program, like many others, uses ibuprofen alone in most patients, and either ibuprofen or a selective Cox-2 inhibitor along with a PPI in patients with known or suspected PUD.
VASO-OCCLUSIVE PAIN Vaso-occlusive pain in SCD can be obvious when there is visible swelling, no history of injury or fever, and no overlying erythema, such as in dactylitis. Although more often than not, it is a clinical diagnosis based on patient history of severe pain in a typical location for that patient, precipitated by change in the weather, dehydration, stress, overuse, or exposure to cold, and improved with hydration, rest, and pain medications. It is caused by irreversible sickling leading to sickled polymers that obstruct blood flow and prevent oxygenation to tissues.2 Abdominal vasoocclusive pain is difficult to differentiate from other organic causes of abdominal pain, including many of those described above, as well as functional abdominal pain of childhood, in which no pathologic mechanism can be found to explain the pain. Thorough history of the onset, location, type of pain, exacerbating and relieving factors including food, defecation, and acid reducers can be helpful. Physical examination should rule out an acute surgical abdomen, splenomegaly, hepatomegaly, or mass. Lack of bowel sounds or metabolic acidosis should be considered signs concerning for ischemic colitis. The child should have complete bowel rest and imaging performed with ultrasound or CT scan. Only once other causes have been considered and effectively ruled out, we advocate treating for vaso-occlusive pain with both an NSAID and opioid scheduled around the clock for 24 to 48 hours, increasing www.jcge.com |
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oral hydration, and adding medications for constipation. If there is any concern for gastritis or NSAID use is prolonged, a high-dose acid blocker should also be used.
RECOMMENDATIONS FOR EVALUATION Each child with SCD presenting with abdominal pain obviously requires a careful history taking and physical examination. While history taking, attention should be given to eating habits, including whether or not the child eats nonfood items (pica), hydration, and fiber content that would raise suspicion for constipation, and whether or not pain is associated with dairy products. Timing of pain in relation to eating is helpful in raising or lowering suspicion of cholelithiasis. A thorough history of bowel habits is essential to determine the role of constipation in the child’s pain, and bathroom hygiene for possibility of UTI. Blood in the urine or changes in the appearance or odor of the urine may lead to concerns for pyelonephritis or renal infarction. Vomiting without diarrhea raises concern for appendicitis or for obstruction, whereas vomiting and diarrhea together are more typical of gastroenteritis. Medication used, including dosages and frequency, may give clues for opioid-induced constipation or risk for PUD from NSAIDs. If pain is relieved by oral analgesics, this pain is typical of a child’s VOC, and no other red flags are raised, further VOC management is in order. Of course, location and characterization of the pain may point to PUD, appendicitis, splenic sequestration, or hepatic sequestration. Physical examination should focus on any peritoneal signs that may indicate an acute surgical abdomen, splenomegaly, hepatomegaly, or mass. Simple lab tests include a CBC and reticulocyte count (decreased hemoglobin and platelets in either splenic or hepatic sequestration), transaminases and bilirubin (very high in hepatic sequestration, hyperbilirubinemia alone in choledocholithiasis), lipase and amylase if pancreatitis is suspected, and urinalysis for UTI (leukocyte esterase, nitrates) or renal infarct (RBCs in the urine). Abdominal ultrasound is helpful for suspected cholelithiasis, appendicitis, pyelonephritis, or mass.
THE CASE In returning to our patient, by 10 years of age she experienced a significant amount of abdominal pain, from various pathologic causes described above. She was treated clinically for gastritis, constipation, and vaso-occlusive pain, and surgically for symptomatic cholelithiasis. She has not had any evidence of renal disease, other than hyposthenuria. She has not had splenic or hepatic sequestration and does not have pica. Before developing gastric outlet obstruction, she had been treated for pain on and off for months, with episodic use of ibuprofen. This NSAID use, along with severe SCD as manifested by ACS and low baseline hemoglobin, may have contributed to development of peptic ulceration of her duodenum, complicated by formation of a stricture, and pyloric outlet obstruction. REFERENCES 1. Lee A, Thomas P, Cupidore L, et al. Improved survival in homozygous sickle cell disease: lessons from a cohort study. BMJ. 1995;311:1600–1602. 2. Lenfant C. The Management of Sickle Cell Disease. Bethesda, MD: NIH/NHLBI Publication 02-2117; 2002:119–121. 3. Kinney TR, Ware RE, Schultz WH, et al. Long-term management of splenic sequestration in children with sickle cell disease. J Pediatr. 1990;117:194–199.
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