45-Year-Old Man With Abdominal Pain and Splenomegaly

A 45-year-old man presented to the emergency department at an outside facility with severe right upper quadrant abdominal pain, radiating to his back with deep inspiration. The pain had started the evening before, and the patient described it as dull and aching with intermittent episodes of sharp, stabbing discomfort. The pain was not associated with fever, nausea, vomiting, or diarrhea. He had no recent travel history. His medical history was notable for hypertension, type 2 diabetes mellitus, and gastroesophageal reflux disease. His family history was negative for liver disease or hematologic disorders.

His vital signs included the following: temperature, 36.8°C; heart rate, 74 beats/min; respiratory rate, 18 breaths/min; and blood pressure, 183/70 mm Hg. Physical examination was notable for a positive Murphy sign. Laboratory work-up revealed the following (reference ranges provided parenthetically): leukocyte count, 3.8 × 10⁹/L (3.4-9.6 × 10⁹/L); hemoglobin, 10.3 g/dL (13.2-16.6 g/dL); and platelet count, 84 × 10⁹/L (135-317 × 10⁹/L). Hepatic enzymes were within normal limits aside from an elevated total bilirubin level of 2.3 mg/dL (≤1.2 mg/dL). Lipase and amylase levels were normal.

• 1.
  Which one of the following imaging modalities would be most appropriate to perform next?

  • a.
    Transabdominal ultrasonography
  • b.
    Computed tomography
  • c.
    Magnetic resonance cholangiopancreatography
  • d.
    Endoscopic retrograde cholangiopancreatography
  • e.
    Endoscopic ultrasonography

The use of multiple imaging modalities may be appropriate if biliary tract disease is suspected, but the initial test of choice in a patient who presents with right upper quadrant abdominal pain is transabdominal ultrasonography. Ultrasonography is a sensitive test for detecting gallstones and is noninvasive, readily available, and cost-effective. Computed tomography exposes a patient to radiation and is less sensitive in the detection of gallstones because many gallstones are not radiopaque. Magnetic resonance cholangiopancreatography is a noninvasive test that uses magnetic resonance imaging to visualize the bile ducts and the pancreatic ducts. This is a useful test to assess for common bile duct stones but should not be performed initially. Endoscopic retrograde cholangiopancreatography is an invasive procedure that can be used to remove common bile duct stones and is indicated when suspicion for choledocholithiasis is high. Endoscopic ultrasonography is a minimally invasive procedure that can be utilized to assess for biliary stones, but it is not the initial test of choice.

Ultrasonography of the right upper quadrant revealed a dilated sludge-filled gallbladder without calculi or gallbladder wall thickening. Marked splenomegaly was also noted. The patient was admitted to the hospital for further work-up. Laboratory values were rechecked the following morning, at which point his total bilirubin level had increased to 4.3 mg/dL.

Because of concern for biliary obstruction, magnetic resonance cholangiopancreatography was obtained and revealed a markedly dilated gallbladder with sludge and several small stones near the neck of the gallbladder. A small amount of pericholecystic fluid was present. No stones or lesions were present in the common bile duct. Again, marked splenomegaly was noted at 25 cm (upper limit of normal, 11-14 cm) in the craniocaudal dimension. Abnormal signal intensity of the liver and spleen was observed and thought to be consistent with hemochromatosis, as well as numerous small focal dephasing artifacts concerning for portal hypertension.

Intravenous fluids and antibiotics were administered because of concern for acute cholecystitis. Repeated hemoglobin measurement the next morning revealed a decrease to 7.4 g/dL, and the patient was given a transfusion 1 U of packed red blood cells. Because of continued symptoms, the complexity of his case, and potential need for surgical intervention, he was transferred to our facility. On arrival, vital signs were stable. Physical examination was notable for a palpable spleen, palpable gallbladder, and right upper quadrant tenderness with palpation. Laboratory values at this time were as follows: hemoglobin, 9.1 g/dL; mean corpuscular volume, 77.9 fL (78.2-97.9 fL); mean corpuscular hemoglobin concentration, 33.1 g/dL (32-36 g/dL); red blood cell distribution width, 21% (11.8%-14.5%); platelet count, 106 × 10⁹/L; leukocyte count, 3.0 × 10⁹/L with a normal differential; reticulocyte percentage, 6.06% (0.60%-2.71%); absolute reticulocyte count, 213.9 × 10⁹/L (30.4-110.9 × 10⁹/L); haptoglobin, 29 mg/dL (30-200 mg/dL); lactate dehydrogenase, 247 U/L (122-222 U/L); and ferritin, 485 μg/L (24-336 μg/L). Vitamin B₁₂ and folate levels were within normal limits. His peripheral blood smear revealed spherocytes. Hepatic enzyme levels remained within normal limits, the total bilirubin concentration was elevated at 4.6 mg/dL, and direct bilirubin level was 0.9 mg/dL (0.0-0.3 md/dL).

• 2.
  Which one of the following diagnoses is the most likely cause of this patient's hyperbilirubinemia?

  • a.
    Choledocholithiasis
  • b.
    Nonalcoholic steatohepatitis
  • c.
    Dubin-Johnson syndrome
  • d.
    Sepsis
  • e.
    Hemolysis

The fractionation of elevated bilirubin into 2 distinct categories, conjugated and unconjugated, is useful for establishing a differential diagnosis for hyperbilirubinemia. An elevated conjugated bilirubin level is often caused by biliary obstruction, liver disease, or inherited disorders that affect the excretion of bilirubin. Elevated unconjugated bilirubin is the result of increased production of bilirubin, reduced uptake of bilirubin by the liver, or ineffective bilirubin conjugation. Choledocholithiasis results in elevated conjugated bilirubin levels as the pathway for excretion is obstructed by stones in the common bile duct. Nonalcoholic steatohepatitis can cause elevated conjugated bilirubin levels due to hepatocellular injury. Dubin-Johnson syndrome is an inherited disorder resulting from inherited mutations in genes responsible for bilirubin transport that results in a primarily conjugated hyperbilirubinemia. Although sepsis can cause an increase in production of bilirubin and result in elevated unconjugated bilirubin levels, this patient has remained afebrile with normal vital signs. The patient's anemia, decreased haptoglobin concentration, and increased absolute reticulocyte count indicate that he likely has hemolysis resulting in increased unconjugated bilirubin due to the destruction of red blood cells.

Because of concern for portal hypertension on the earlier ultrasound study, Doppler imaging was obtained. The results were notable for mild hepatic steatosis, splenomegaly, and gallbladder distention, this time with gallbladder wall thickening. Splenic, portal, and hepatic veins as well as the main hepatic artery were patent with antegrade flow. The general surgery service recommended further evaluation with a hepatobiliary iminodiacetic acid scan to determine whether the patient had acute cholecystitis. The hepatobiliary scan showed no gallbladder filling at 4 hours, consistent with acute cholecystitis, and a percutaneous cholecystostomy tube was placed for interim management until elective cholecystectomy. The patient continued to have anemia, and his hemoglobin level decreased again to 7.4 g/dL. On further questioning, the patient recalled an episode from 10 years previously when his eyes became yellowed. He was evaluated by his primary care physician, but no diagnosis was made. He also recalled a liver biopsy performed at another facility many years previously but could not recall a diagnosis being made and he did not have records of the results.

• 3.
  To further evaluate for the etiology of this patient's anemia, which one of the following should be performed next?

  • a.
    Direct antiglobulin testing
  • b.
    Bone marrow biopsy
  • c.
    Hemoglobin electrophoresis
  • d.
    Transthoracic echocardiography
  • e.
    Thick and thin blood smears

Laboratory investigations thus far are suggestive of hemolytic anemia. Hemolytic anemia can have a wide variety of underlying etiologies, and applying a systematic approach can aid considerably in establishing a diagnosis. An important distinction to narrow the differential diagnosis of hemolytic anemia is whether the process is immune mediated, an evaluation best done using the direct antiglobulin test. Although the patient has evidence of pancytopenia, a bone marrow biopsy is not indicated at this time because his bone marrow demonstrates an appropriate response to his anemia, as evidenced by the brisk reticulocytosis. Hemoglobin electrophoresis would be indicated as a possible next step if the patient was found to have a non–immune-mediated hemolytic process to assess for hemoglobinopathies such as thalassemia, sickle cell anemia, and related disorders. β-Thalassemia major is diagnosed early in life because of the severity of anemia and the need for ongoing red blood cell transfusion support, and patients with sickle cell anemia present with anemia and painful vaso-occlusive crises. Patients with thalassemia minor (trait) are often asymptomatic or may have a mild hypochromic microcytic anemia with an increase in the red blood cell count and a normal red blood cell distribution width. Although mechanical hemolysis can occur in individuals who have improperly functioning prosthetic heart valves, this patient has no history of cardiac valve replacement, and hence echocardiography would not be indicated. Parasitic infections such as malaria and babesiosis can cause hemolytic anemia, and thick and thin blood smears would be useful if these were suspected. However, in the absence of travel to malaria-endemic regions and the lack of a history of tick bites and fevers, these are unlikely as causes of his ongoing hemolysis.

The patient's direct antiglobulin test (Coombs test) result was negative. Additional testing was performed including urine hemosiderin, which was negative, and plasma free hemoglobin, which was normal. His laboratory investigations thus far were notable for non–immune-mediated hemolytic anemia of unclear etiology.

• 4.
  Based on the clinical scenario, which one of the following diagnoses is most likely?

  • a.
    Thrombotic thrombocytopenic purpura
  • b.
    Hemolytic uremic syndrome
  • c.
    Paroxysmal nocturnal hemoglobinuria
  • d.
    Glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • e.
    Hereditary spherocytosis (HS)

Another important distinction that can aid in identifying the etiology of hemolytic anemia is to determine whether the hemolysis is intravascular or extravascular. This patient had negative results on a urine hemosiderin test and normal results on plasma free hemoglobin testing, both of which would be expected with extravascular hemolysis. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are both classified as microangiopathic hemolytic anemias that occur as a result of mechanical disruption of the red blood cell membrane within the intravascular space and typically present with schistocytes on peripheral smear. Paroxysmal nocturnal hemoglobinuria is an acquired stem cell disorder that predisposes red blood cells to lysis by activation of the complement system, resulting in intravascular hemolysis. The G6PD deficiency is an inherited enzyme deficiency that predisposes individuals to oxidative damage and can cause intravascular hemolysis at times of increased oxidative stress, such as with infection or drug exposure. The oxidative damage in G6PD deficiency results in inclusion bodies in red blood cells called Heinz bodies. These inclusion bodies are later removed by the spleen and can ultimately result in the appearance of bite cells on peripheral smear. This patient presented with anemia, jaundice, and splenomegaly in addition to spherocytes on peripheral smear, and a diagnosis of HS must be considered.

To further evaluate for HS, an osmotic fragility test was performed. The osmotic fragility test determines the degree of hemolysis of red blood cells when exposed to varying degrees of hypotonic salt solutions. Alterations in the red blood cell membrane in HS make cells more prone to hemolysis, although results of this test can be positive with any cause of increased membrane fragility. The patient's osmotic fragility test results were positive, and further testing was performed including the eosin-5-maleimide binding test (band 3 testing). This test utilizes flow cytometry to assess for the eosin-5-maleimide dye binding to the band 3 protein, which is reduced in patients with HS. The results of the binding test were equivocal. Despite this result, the suspicion for HS remained high based on the clinical picture and laboratory findings. The decision was made to pursue next-generation sequencing for the genes involved in the proteins ankyrin and spectrin, which are instrumental in maintaining the integrity of the red blood cell membrane.

The patient continued to follow up with the general surgery department, which recommended cholecystectomy approximately 6 to 8 weeks after percutaneous cholecystostomy tube placement. If it was determined that his hypersplenism also required treatment, the plan was to pursue laparoscopic splenectomy at the same time as cholecystectomy.

• 5.
  In the context of this patient's potential upcoming procedure, which one of the following is recommended?

  • a.
    Pneumococcal, meningococcal, and Haemophilus influenzae vaccinations
  • b.
    Tetanus-diphtheria-acellular pertussis, measles-mumps-rubella, and herpes zoster vaccinations
  • c.
    Lifelong daily antibiotic prophylaxis with amoxicillin following splenectomy
  • d.
    Avoidance of all live attenuated vaccines following splenectomy
  • e.
    Administration of extended thromboprophylaxis following splenectomy

The spleen is an important organ that protects against infection from encapsulated organisms. Before elective splenectomy, it is important for individuals to receive vaccinations against these organisms, which include Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B. Asplenic individuals are not at increased risk for infection with tetanus, measles, mumps, rubella, or herpes zoster because these are not encapsulated organisms. Although the use of daily antibiotic prophylaxis is recommended in young children, the need for and effectiveness of daily antibiotic prophylaxis following splenectomy in adults is uncertain. When inactivated versions of vaccines are not available, it is recommended that asplenic individuals continue to receive live attenuated vaccines as recommended for the general population. Although splenectomy is often followed by a reactive thrombocytosis, patients do not require prophylactic anticoagulation beyond usual care for surgery.

Unfortunately, the patient became acutely ill approximately 6 weeks after initial presentation with fevers and decreased cholecystostomy tube drainage. He was admitted to the hospital for recurrent acute cholecystitis, received intravenous antibiotics, and underwent urgent laparoscopic cholecystectomy. A decision was made not to pursue splenectomy at the same time because the patient was acutely ill and next-generation sequencing test results were still pending. Pathologic examination of the gallbladder revealed severe acute purulent cholecystitis with the presence of 5 pigmented stones ranging in size from 0.2 to 0.5 cm.

Genetic analysis revealed variations in the ankyrin 1 (ANK1 c.3630-8C>G) and spectrin alpha 1 (SPTA1 c.4453C>T, SPTA1 c.6531-12C>T) genes, which were of undetermined significance. Mutations in these genes are heterogeneous and many of them are private mutations (restricted to small populations or single families), and therefore changes in these genes must be interpreted within the clinical picture. In light of this patient's clinical and laboratory findings, it is still suspected that he has a form of HS. Given the milder phenotype, he is currently being observed and will be reevaluated for the need for splenectomy in the future depending on the degree of ongoing hemolysis and his recovery from the current cholecystitis.