Circling Back for the Diagnosis

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1 The new england journal of medicine Clinical Problem-Solving Caren G. Solomon, M.D., M.P.H., Editor Circling Back for the Diagnosis Joseph Rencic, M.D., Mengyu Zhou, M.D., Gerald Hsu, M.D., Ph.D., and Gurpreet Dhaliwal, M.D. In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors commentary follows. From the Department of Medicine, Tufts Medical Center, Boston (J.R., M.Z.); and the Department of Medicine, University of California, San Francisco, and the Medical Service, San Francisco Veterans Affairs Medical Center both in San Francisco (G.H., G.D.). Address reprint requests to Dr. Rencic at 800 Washington St., Box 398, Boston, MA 02111, or at jrencic@ tuftsmedicalcenter. org. N Engl J Med 2017;377: DOI: /NEJMcps Copyright 2017 Massachusetts Medical Society. A 28-year-old man presented to the emergency department with abdominal pain, nausea, and vomiting. The patient reported that he had had intermittent pain in the right upper and right lower quadrants of the abdomen for 6 weeks. The pain worsened when he ate food and usually abated within 1 to 2 hours after he took antacids. On this occasion, the pain was severe and had lasted for 8 hours. Intake of food had worsened the pain and was followed by an episode of nonbloody, nonbilious emesis. He did not have fever or chills. Recurrent, limited bouts of pain on the right side of the abdomen after meals are characteristic of biliary colic and peptic ulcer disease. The increased severity and persistence of the pain at the time of the patient s current presentation could represent evolution into acute cholecystitis or ulcer perforation. Other causes of pain on the right side of the abdomen include appendicitis, hepatitis, colitis, nephrolithiasis, and renal infarction, although these disorders seem to be unlikely on the basis of the recurrent and previously limited nature of the pain. The patient had received a diagnosis of Gilbert s syndrome 2 years earlier when his primary care physician noted that he had isolated indirect hyperbilirubinemia. He was obese (body-mass index [the weight in kilograms divided by the square of the height in meters], 33) and had nonalcoholic fatty liver disease. He reported that he had never used tobacco or recreational drugs and that he seldom drank alcohol. On physical examination, the temperature was 37.1 C, the heart rate 84 beats per minute, the blood pressure 145/90 mm Hg, the respiratory rate 18 breaths per minute, and the oxygen saturation 100% while he was breathing ambient air. He appeared to be uncomfortable because of the abdominal pain. Scleral icterus was present. Cardiac and pulmonary examinations were normal. There was mild tenderness in the right upper and right lower quadrants of the abdomen, with no rebound or guarding. There were no stigmata of chronic liver disease. The most common causes of isolated indirect hyperbilirubinemia in an adult are Gilbert s syndrome and hemolysis. Nonalcoholic fatty liver disease may be associated with dull discomfort in the right upper quadrant but does not cause severe pain. Obesity and hemolysis predispose patients to the formation of gallstones (cholesterol and pigment gallstones, respectively). The patient s jaundice and the tenderness on the right side of the abdomen suggest a hepatobiliary disorder such as hepatitis, hepatic infiltration, hepatic congestion, cholecystitis, or choledocholithiasis. The white-cell count was 19,800 per cubic millimeter (86% neutrophils, 5% lymphocytes, 8% monocytes, and zero bands), the hemoglobin level 16.0 g per deciliter, and 1778

2 the platelet count 196,000 per cubic millimeter. The levels of electrolytes, blood urea nitrogen, creatinine, and glucose were normal. The total bilirubin level was 6.7 mg per deciliter (115 μmol per liter; reference range, 0.2 to 1.1 mg per deciliter [3 to 19 μmol per liter]), and the direct bilirubin level was 2.6 mg per deciliter (44 μmol per liter; reference range, 0.0 to 0.3 mg per deciliter [0 to 5 μmol per liter]). The alanine aminotransferase level was 185 U per liter (normal value, <54), the aspartate aminotransferase level 157 U per liter (normal range, 10 to 42), and the alkaline phosphatase level 101 U per liter (normal range, 40 to 130). The albumin level was 4.7 g per deciliter. The international normalized ratio was 1.1. The lipase level was normal. Computed tomography (CT) of the abdomen revealed a normal-sized liver with mild steatosis and splenomegaly (16 cm in the sagittal diameter) but no gallstones, biliaryduct dilatation, or evidence of cholecystitis. The appendix was not visualized. The patient was admitted to the hospital, and intravenous administration of meropenem was initiated. The predominantly indirect hyperbilirubinemia suggests that Gilbert s syndrome or hemolysis may be accompanying the acute illness. However, pain on the right side of the abdomen, leukocytosis, and an elevated direct bilirubin level (proportional to the other liver biochemical values) arouse concern about cholecystitis or choledocholithiasis. The CT results suggest neither condition, but ultrasonography is more sensitive for the detection of gallstones within the gallbladder, and magnetic resonance cholangiography would detect or rule out choledocholithiasis more definitively. Although physiologic stress and dehydration may contribute to leukocytosis, ruling out cholangitis is essential. Hemolysis sometimes causes a modest elevation of aminotransferase levels (particularly the aspartate aminotransferase level) in addition to indirect hyperbilirubinemia. The normal hemoglobin level does not support a diagnosis of hemolysis, but the patient may have hemoconcentration or fully compensated hemolysis. A peripheralblood smear and reticulocyte count should be obtained. On the second hospital day, the abdominal pain abated and the white-cell count decreased to 14,200 per cubic millimeter, but the values on the liver biochemical tests increased. The total bilirubin level was 19.5 mg per deciliter (334 μmol per liter), and the direct bilirubin level 11.2 mg per deciliter (192 μmol per liter). The alanine aminotransferase level was 519 U per liter, the aspartate aminotransferase level 188 U per liter, and the alkaline phosphatase level 171 U per liter. Testing for hepatitis B surface antibody was positive. Hepatitis B surface antigen and antibodies to hepatitis A (IgM), hepatitis C, and hepatitis B core antigen were not detected. The ceruloplasmin level was normal. Testing for antinuclear and antimitochondrial antibodies was negative. Ultrasonography of the abdomen revealed a sludgefilled gallbladder with wall thickening and pericholecystic fluid, findings that are consistent with acute cholecystitis (Fig. 1A). There was no hepatic or common bile-duct dilatation or choledocholithiasis. Magnetic resonance cholangiopan- A B ** Figure 1. Ultrasonographic and Magnetic Resonance Cholangiopancreatography of the Gallbladder. An ultrasonographic image of the abdomen (Panel A) shows a gallbladder filled with sludge (arrow), with gallbladder-wall thickening (asterisks) and a small amount of pericholecystic fluid (arrowheads). A T 2 - weighted magnetic resonance image with fat suppression (Panel B) shows gallbladder-wall thickening and irregularity with associated pericholecystic fluid (arrowheads) and a moderate amount of dependent sludge in the gallbladder (arrow). 1779

3 The new england journal of medicine creatography (MRCP) confirmed these findings (Fig. 1B). Fatty infiltration of the liver and splenomegaly were noted on both studies. The portal and hepatic veins were patent, and normal flow was observed on ultrasonography. The acute rise in the direct bilirubin level can be explained by acute cholecystitis and transient biliary-duct obstruction superimposed on the patient s chronic liver disease (i.e., nonalcoholic fatty liver disease). The ultrasonographic and MRCP findings are consistent with acute cholecystitis, which can cause mild jaundice even in the absence of common bile-duct obstruction. Concomitant choledocholithiasis causes more substantial jaundice, although the direct bilirubin level is typically less than 10 mg per deciliter. It is possible that sludge or a gallstone transiently obstructed the common bile duct before the more sensitive imaging methods for the detection of choledocholithiasis were performed on the second hospital day; the reduction in pain would support that hypothesis. The indirect bilirubin level remains high, but hemolysis or Gilbert s syndrome rarely elevates the indirect bilirubin level to more than 5 mg per deciliter (86 μmol per liter). The combination of liver disease and hemolysis in a young patient should prompt the consideration of Wilson s disease. However, he does not have the disproportionate elevation of the aspartate aminotransferase level to the alanine aminotransferase level that is typical of Wilson s disease, and the ceruloplasmin level is normal. Given the elevated aminotransferase levels, it is important to consider viral, toxic, vascular, and autoimmune causes of hepatitis. The standard panel for viral hepatitis was negative, although false negatives can occur. Polymerase-chainreaction testing can supplement the typical hepatitis panel when suspicion for viral infection (e.g., acute hepatitis C virus infection) is high. Tests for viruses that occasionally infect the liver such as cytomegalovirus, Epstein Barr virus, and herpes simplex virus also need to be considered. It would be helpful to ask the patient about the use of acetaminophen, other over-the-counter medications, and nutritional supplements that might cause hepatotoxic effects. There was no antecedent hypotension or hepatic-vein obstruction observed on ultrasonography to suggest a vascular cause of hepatic injury. The splenomegaly is unlikely to be attributable to portal hypertension, given the normal albumin level, international normalized ratio, and platelet count. Splenomegaly could arise from infiltration (e.g., infection or cancer) or the accumulation of abnormal red cells in the context of hemolysis. On the third hospital day, the abdominal pain resolved, and the patient remained afebrile. The total bilirubin level was 5.7 mg per deciliter (97 μmol per liter), and the direct bilirubin level 2.5 mg per deciliter (43 μmol per liter). The alanine aminotransferase level was 292 U per liter, the aspartate aminotransferase level 89 U per liter, and the alkaline phosphatase level 174 U per liter. Meropenem was discontinued. The patient was discharged home, referred to surgery for an elective cholecystectomy, and scheduled for an appointment in the general medicine clinic the next day. The clinical picture is consistent with acute cholecystitis and superimposed transient biliary obstruction (e.g., passed sludge or gallstone). The rapid resolution is more typical of sludge or gallstone passage than viral or toxic hepatitis. In the clinic, a physician who had not met the patient previously reviewed his test results from 2 years earlier. Along with an indirect bilirubin level of 1.9 mg per deciliter (32 μmol per liter), the patient had had an elevated lactate dehydrogenase level of 320 U per liter (normal range, 120 to 220) and a haptoglobin level of less than 8 mg per deciliter (normal range, 26 to 240). His levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were normal at that time. The hemoglobin level was 15.0 g per deciliter, and the mean corpuscular volume was 83.6 fl, with a mean corpuscular hemoglobin concentration of 37 g per deciliter (normal range, 32 to 36) and a red-cell distribution width of 15.7% (normal range, 11.5 to 14.5). Review of the ultrasonographic report from 2 years earlier revealed hepatomegaly with fatty liver infiltration and splenomegaly (16 cm in the sagittal diameter). There were no gallstones. Sustained indirect hyperbilirubinemia, an elevated lactate dehydrogenase level, an undetectable haptoglobin level, and splenomegaly with a normal hemoglobin level suggest compensated hemolysis. Hemolytic anemia may be caused by im- 1780

4 mune, microangiopathic, or infectious processes or may result from congenital abnormalities of the erythrocyte membrane, enzymes, or hemoglobin, such as hereditary spherocytosis, glucose- 6-phosphate dehydrogenase deficiency, sickle cell disease, and thalassemia. The elevated mean corpuscular hemoglobin concentration is particularly characteristic of hereditary spherocytosis. Laboratory studies from the clinic visit after discharge revealed a reticulocyte percentage of 3.2% (normal range, 0.5 to 2.2) and an absolute reticulocyte count of 172,100 per cubic millimeter (normal range, 31,500 to 108,800). Peripheral-blood smears obtained at that appointment and on the first hospital day were reviewed by a hematopathologist and showed Pappenheimer bodies (iron-containing granules) but no spur cells, schistocytes, or spherocytes. At that appointment, the patient s mother recalled that the patient s father had undergone a cholecystectomy for gallstones at 27 years of age. The sustained reticulocytosis in this patient is a compensatory response to ongoing hemolysis. His father s history of gallstones at a young age suggests a heritable hemolytic anemia with pigment gallstones. Sickle cell disease, thalassemias, and hereditary spherocytosis cause premature cholelithiasis, but the peripheral-blood smear does not show evidence of these conditions. Furthermore, thalassemias are characterized by microcytosis, and symptomatic thalassemia and sickle cell disease typically manifest in childhood and are associated with anemia. The patient probably had transient hepatic injury from obstructing sludge or a gallstone arising from a chronic hereditary hemolytic state. The atypical features of transient biliary obstruction in this patient are the absence of common bile-duct dilatation on multiple imaging studies and marked hyperbilirubinemia, although the latter was probably multifactorial. The family history, elevated mean corpuscular hemoglobin concentration, and chronic compensated hemolysis with a predisposition toward gallstone formation favor a diagnosis of hereditary spherocytosis. Spherocytes are nearly universal in hereditary spherocytosis but may not be seen on the peripheral-blood smear in mild cases in which the number of deformed red cells is low. Figure 2. Peripheral-Blood Smear. A peripheral-blood smear (Wright s stain) shows spherocytes (selectively indicated by arrows). Four weeks later, the patient underwent a laparoscopic cholecystectomy, which revealed multiple pigment gallstones, with the largest one measuring 1.0 cm by 0.6 cm by 0.6 cm. A perioperative peripheral-blood smear that was reviewed by a second hematopathologist showed occasional spherocytes. One month after the cholecystectomy, the patient saw a hematologist. Laboratory values from that visit showed a normalization of the aminotransferase levels and a return to his baseline levels of total bilirubin (3.3 mg per deciliter [56 μmol per liter]) and direct bilirubin (0.9 mg per deciliter [15 μmol per liter]). An osmotic fragility test revealed increased erythrocyte fragility, and flow-cytometric determination of eosin-5- maleimide (EMA) labeled red cells showed decreased fluorescence, which confirmed the diagnosis of hereditary spherocytosis. A direct antiglobulin test was not performed. A peripheralblood smear that was obtained 7 months later showed multiple spherocytes (Fig. 2). To evaluate concomitant Gilbert s syndrome, uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) genotyping was performed. The result showed heterozygosity for the TA7 polymorphism. Although bilirubin levels may be slightly increased in heterozygous states, homozygosity is typically required in order to diagnose Gilbert s syndrome definitively. The chronic indirect hyperbilirubinemia that was observed in this patient was attributed to hereditary spherocytosis. Seven months later, he felt well, with no recurrence of his abdominal pain. Commentary An acute exacerbation of intermittent pain on the right side of the abdomen that was associated with hyperbilirubinemia and elevated amino- 1781

5 The new england journal of medicine transferase levels suggested a common event: acute cholecystitis with transient biliary obstruction from sludge or gallstones. However, latent clues in the medical record, including laboratory evidence of hemolysis, a high mean corpuscular hemoglobin concentration, and splenomegaly, suggested an uncommon cause: hereditary spherocytosis. Hereditary spherocytosis is the most common hemolytic anemia that is caused by a defect in red-cell membranes, with an incidence of 1 case per 2000 persons of northern European ancestry. 1 In hereditary spherocytosis, deficiencies in membrane or associated cytoskeletal proteins from inherited gene mutations result in weakened interactions between the membrane and cytoskeleton (Fig. 3). This leads to membrane degradation by means of vesiculation and pro- A Normal erythrocyte Glycophorin C Band 4.2 Ankyrin α-spectrin Band 4.1 Actin In hereditary spherocytosis deficiencies in membrane or cytoskeletal proteins lead to membrane loss Membrane-associated proteins anchor the lipid bilayer to the spectrin cytoskeleton HEALTHY ERYTHROCYTE β-spectrin Microvesicle Glycophorin C Spherocyte Band 4.2 Ankyrin α-spectrin Band 4.1 Actin One or more proteins are deficient, causing detachment from the spectrin cytoskeleton β-spectrin SPHEROCYTE B Spherocyte SPLENIC CORD Erythrocyte entering splenic sinusoid SPLENIC SINUSOID Splenic macrophage Spherocytes undergoing hemolysis Endothelial cell To systemic circulation Figure 3. Hemolysis in Hereditary Spherocytosis. Panel A shows the structure of a normal red cell and a spherocyte; insets show interactions between the membrane and cytoskeleton mediated by the proteins band 3,, band 4.2, and ankyrin; glycophorin C, band 3,, band 4.1, and actin; and α-spectrin and β-spectrin. Gene mutations of any of the shaded proteins can lead to deficiencies that cause hereditary spherocytosis. Disruption of the connection between the lipid bilayer and cytoskeleton results in microvesiculation, membrane loss, and spherocyte formation. Panel B shows the red pulp of the spleen in which red cells transit from the cords to the sinusoids through tight spaces between endothelial cells. Spherocytes are less deformable owing to a reduced surface-to-volume ratio and are selectively retained in the cords, where further destruction or hemolysis occurs. 1782

6 gressive membrane loss as red cells pass through the splenic cords. The resultant spherical shape leads to decreased deformability and the characteristic appearance on the peripheral-blood smear. These spherocytes have difficulty passing through the narrow fenestrations of venous sinusoids and are destroyed by macrophages within the spleen. 1 Patients with hereditary spherocytosis typically present with hemolytic anemia with jaundice, splenomegaly, an elevated mean corpuscular hemoglobin concentration, and spherocytosis. Mild hereditary spherocytosis, which this patient had, is distinguished from moderate and severe hereditary spherocytosis by the degree of anemia (hemoglobin level, usually 11 to 15 g per deciliter), reticulocytosis (reticulocyte percentage, usually 3% to 6%), bilirubinemia (bilirubin level, usually 1 to 2 mg per deciliter [17 to 34 μmol per liter]), and spherocytosis (usually 2 to 3 spherocytes per high-power field). 1 Traditionally, the measurement of hemolysis in a hypotonic solution (the osmotic fragility test) has been used to confirm the diagnosis in patients in whom standard laboratory features are insufficient. However, test results are normal in 10 to 20% of patients with hereditary spherocytosis and can be abnormal in patients with other causes of spherocytosis, such as autoimmune hemolytic anemia. 2 The EMA binding test is a flow-cytometric assay that detects decreased binding of the dye EMA to the band 3 protein; deficiency of this protein is a central pathophysiological feature in hereditary spherocytosis. The EMA binding test, which has a sensitivity of 90% and specificity of 95%, is now the preferred diagnostic test in equivocal cases. 3 Splenectomy is the treatment for symptomatic moderate or severe hereditary spherocytosis. 2 Splenectomy does not alter erythrocyte cytoskeletal abnormalities, but it eliminates the primary location of hemolysis. Current consensus discourages splenectomy in mild hereditary spherocytosis because the risks associated with resultant immunocompromise outweigh the risk of hemolytic complications. 2 In patients with moderate or severe hereditary spherocytosis, this risk benefit ratio is inverted because splenectomy substantially diminishes hemolysis and the incidence of pigment gallstones. The incidence of cholelithiasis among children and young adults with hereditary spherocytosis is approximately 40%. 4,5 Cholecystectomy is generally reserved for patients with symptomatic gallstone-related disease. Retrospective studies have shown that children with mild hereditary spherocytosis who undergo symptom-driven cholecystectomy infrequently have subsequent splenectomy 6,7 ; these findings suggest that splenectomy at the time of cholecystectomy is not indicated in these patients. Various barriers and missed opportunities delayed the diagnosis of hereditary spherocytosis in this patient. The first outpatient provider probably considered hemolysis on the basis of the testing of the lactate dehydrogenase and haptoglobin levels. However, the normal hemoglobin level may have provided false reassurance, leading to a diagnosis of Gilbert s syndrome (although the splenomegaly could not be explained by this diagnosis). The inpatient providers did not seek a rare unifying diagnosis because the patient s obesity provided a common explanation for his gallstones. Finally, when hemolysis was recognized on the postdischarge retrospective review of outpatient and inpatient data, the namesake finding of the underlying condition spherocytes was initially absent. Without the highly specialized knowledge that spherocytes are not visible in 2 to 3% of patients with mild hereditary spherocytosis, it would be difficult to justify pursuing this diagnosis. 8 A diagnosis of mild hereditary spherocytosis 2 years earlier would not have warranted a splenectomy, cholecystectomy, medications, or screening for cholelithiasis. However, had the patient known of his hereditary spherocytosis and its associated risk of gallstone disease, he might have presented to the health care system earlier in his 6-week course of episodic abdominal pain. Outpatient ultrasonography and an expedited cholecystectomy could have avoided the cost and complications associated with acute cholecystitis and transient common bile-duct obstruction, which entailed hospitalization, radiation exposure, and substantial discomfort. In retrospect, it is easy to see how scrutiny of the elevated mean corpuscular hemoglobin concentration or early inquiry about family history might have pointed to hereditary spherocytosis. Yet the challenges of recognizing hemolysis without anemia and recognizing hereditary spherocytosis without spherocytes would have remained. All clinicians aspire to discern diagnostic patterns 1783

7 when they first emerge, but sometimes we have to circle back to make the correct diagnosis. Dr. Dhaliwal reports receiving honoraria from ISMIE Mutual Insurance Company and Physicians Reciprocal Insurers. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Drs. Hoon Ji, Monika Pilichowska, and Julia Rissmiller, of Tufts Medical Center, for their interpretation of key aspects of the pathological and radiologic findings and Dr. W. Adam Janes for contribution to the treatment of this patient. References 1. Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis. Lancet 2008; 372: Bolton-Maggs PH, Langer JC, Iolascon A, Tittensor P, King MJ. Guidelines for the diagnosis and management of hereditary spherocytosis 2011 update. Br J Haematol 2012; 156: Bianchi P, Fermo E, Vercellati C, et al. Diagnostic power of laboratory tests for hereditary spherocytosis: a comparison study in 150 patients grouped according to molecular and clinical characteristics. Haematologica 2012; 97: Bates GC, Brown CH. Incidence of gallbladder disease in chronic hemolytic anemia (spherocytosis). Gastroenterology 1952; 21: Tamary H, Aviner S, Freud E, et al. High incidence of early cholelithiasis detected by ultrasonography in children and young adults with hereditary spherocytosis. J Pediatr Hematol Oncol 2003; 25: Ruparel RK, Bogert JN, Moir CR, et al. Synchronous splenectomy during cholecystectomy for hereditary spherocytosis: is it really necessary? J Pediatr Surg 2014; 49: Alizai NK, Richards EM, Stringer MD. Is cholecystectomy really an indication for concomitant splenectomy in mild hereditary spherocytosis? Arch Dis Child 2010; 95: Mariani M, Barcellini W, Vercellati C, et al. Clinical and hematologic features of 300 patients affected by hereditary spherocytosis grouped according to the type of the membrane protein defect. Haematologica 2008; 93: Copyright 2017 Massachusetts Medical Society. clinical problem-solving series The Journal welcomes submissions of manuscripts for the Clinical Problem-Solving series. This regular feature considers the step-by-step process of clinical decision making. For more information, please see authors.nejm.org. 1784