a complex cause of pleuritic chest painrigld.sbmu.ac.ir/uploads/070.pdfing a serum d-dimer level,...

clinical problem-solving

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

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.

n engl j med 367;18 nejm.org november 1, 20121742

From the Clinical Pathological Conference Series, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School — both in Boston. Ad-dress reprint requests to Dr. Levy at Brigham and Women’s Hospital, Harvard Institutes of Medicine Bldg., 77 Ave. Louis Pasteur (HIM855), Boston, MA 02115, or at [email protected].

An Interactive Medical Case involving the patient described in this Clinical Problem-Solving article is available at NEJM.org.

N Engl J Med 2012;367:1742-8.

DOI: 10.1056/NEJMcps1208614Copyright © 2012 Massachusetts Medical Society.

A 33-year-old man presented to the emergency department with pain in the right side of his chest that started 5 days earlier. It originated near his right shoulder blade and radiated throughout his right chest. The pain was worse with deep inspiration and when he was lying down. He also noted mild swelling of his lower legs during the past several weeks. He reported no cough, hemoptysis, sore throat, fever, chills, shortness of breath, abdominal pain, nausea, diarrhea, rashes, joint pains, or recent travel, including travel by air. He also reported that both his children had contracted strepto-coccal pharyngitis 1 month earlier.

The clinical evaluation should initially determine whether there is a potentially life-threatening cause of chest pain, including pulmonary embolus, acute coronary syn-drome, aortic dissection, or tension pneumothorax. The patient’s chest pain wors-ens with deep inspiration and recumbency, which suggests either a pleuritic cause, such as pulmonary embolus, pneumonia, pneumothorax, or viral pleurisy, or a mus-culoskeletal cause, such as costochondritis. Other pulmonary, cardiac, gastrointes-tinal, or musculoskeletal causes are also possible.

The patient had a history of ulcerative colitis, which had been diagnosed 4 years ear-lier when he presented to his primary care physician with chronic diarrhea, weight loss, and iron-deficiency anemia. Biopsy specimens of the small bowel obtained by means of upper gastrointestinal endoscopy were normal. A colonoscopy revealed dif-fuse colonic inflammation, and biopsy specimens of the colon showed chronic active colitis. The patient was treated with mesalamine, and he stopped taking the medica-tion after several months, when his symptoms had completely resolved. He had not seen his primary care physician since that time. On presentation, he was not taking any medications. He had never smoked tobacco and did not use alcohol or recreation-al drugs. He was in a monogamous relationship with his wife. There was no family history of colitis, lung disease, early coronary disease, or venous thromboembolism.

Active inflammatory bowel disease (IBD) is a known risk factor for pulmonary embolism; consequently, this patient’s history raises suspicion for this condition, especially given his description of pleuritic chest pain and edema of the lower legs. He does not have a history of typical cardiovascular risk factors, such as hypertension, hyperlipidemia, tobacco use, or a family history of early coronary artery disease.

On physical examination, the patient’s temperature was 36.9°C, his pulse 110 beats per minute, his blood pressure 141/82 mm Hg, his respiratory rate 16 breaths per minute, and his oxygen saturation 98% while he was breathing ambient air. He ap-peared well and was in no acute distress. He had no cervical, axillary, supraclavicular,

A Complex Cause of Pleuritic Chest PainLindsay Y. King, M.D., J. Kevin Tucker, M.D., Linda S. Lee, M.D.,

Bruce D. Levy, M.D., and Joseph Loscalzo, M.D., Ph.D.

An Interactive Medical Case

related to this article is available

at NEJM.org

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Copyright © 2012 Massachusetts Medical Society. All rights reserved.


n engl j med 367;18 nejm.org november 1, 2012 1743

or inguinal lymphadenopathy. No oropharyngeal erythema or exudate was present. Both lungs were clear to auscultation. No tenderness was detected on examination of the chest wall. A cardiac exami-nation revealed a regular rate and rhythm, with no murmurs, rubs, or gallops. His abdomen was soft and nontender to palpation, with normoactive bowel sounds and no hepatosplenomegaly. Rectal examination revealed guaiac-negative brown stool. The patient’s arms and legs were symmet-ric, with 1+ bilateral edema to the level of the mid-calves. Examination revealed no deformity, ery-thema, warmth, swelling, or tenderness in any joints. The skin examination was unremarkable.

The patient’s general appearance and vital signs are not suggestive of an acute, life-threatening condition. He has mild tachycardia and hyper-tension, which may be related to pain or anxiety, although tachycardia can be a sign of pulmonary embolism. The hypertension could be related to undiagnosed chronic hypertension or a new pro-cess. The examination is not suggestive of heart failure, valvular disease, pneumonia, a large pleu-ral effusion, pneumothorax, or a gastrointestinal cause of the chest pain. An electrocardiogram (ECG) and chest radiograph should be obtained.

Wells’ criteria are helpful in predicting the risk of pulmonary embolus. According to these crite-ria, in the absence of an active malignant condi-tion, a history of deep venous thrombosis, recent immobilization or surgery, or hemoptysis, the pa-tient’s tachycardia and clinical symptoms suggest an intermediate probability of acute pulmonary embolus. Given his hemodynamic stability, obtain-ing a serum d-dimer level, which has a high negative predictive value, can be helpful in deter-mining whether there should be further investi-gation for pulmonary embolism.

An ECG revealed sinus tachycardia with nonspe-cific T-wave changes (Fig. 1). A chest radiograph showed a small right pleural effusion, with a right lower-lobe infiltrate. Results of laboratory evalua-tion included normal levels of electrolytes and glu-cose. The blood urea nitrogen level was 12 mg per deciliter (4.3 mmol per liter), and the creatinine level was 0.97 mg per deciliter (85.7 μmol per liter). The alanine aminotransferase level was 24 U per liter (reference range, 7 to 52), the aspartate ami-notransferase level 23 U per liter (reference range, 9 to 30), the alkaline phosphatase level 410 U per

liter (reference range, 36 to 118), total bilirubin level 0.2 mg per deciliter (3.4 μmol per liter; refer-ence range, 0.2 to 1.2 mg per deciliter [3.4 to 20.5 μmol per liter]), the albumin level 2.1 g per deci-liter (reference range, 3.7 to 5.4), and the total protein level 6.3 g per deciliter (reference range, 6.0 to 8.0). The white-cell count was 6290 per cu-bic millimeter, with 52% neutrophils, 33% lym-phocytes, 6% monocytes, 8% eosinophils, and 1% basophils. The hematocrit was 35.7%, with a mean corpuscular volume of 81.5 fl, and the plate-let count was 426,000 per cubic millimeter. The d-dimer level was 3418 ng per milliliter (reference range, <500). The prothrombin time, partial-thromboplastin time, and the international nor-malized ratio (INR) for prothrombin time were normal.

An infiltrate was seen in the right lower lobe on the chest radiograph, but pneumonia is unlikely given the absence of cough, shortness of breath, fever, and leukocytosis. The elevated d-dimer level is nonspecific but in this case supports a decision to conduct further evaluation for pul-monary embolism. At this point, empirical anti-coagulation therapy should be started and con-tinued until the results of more definitive testing are available. There is no evidence of an acute coronary syndrome on the patient’s ECG. Other notable abnormalities in the laboratory-test re-sults are a low level of albumin and an increased level of alkaline phosphatase. The decreased al-bumin level could be the result of urinary loss, of gastrointestinal loss or malabsorption, or of he-patic synthetic dysfunction; however, the normal INR argues against a hepatic cause of the patient’s condition. A urinalysis should be obtained. An el-evated alkaline phosphatase level most frequently arises from abnormalities in the hepatobiliary sys-tem or in bone; the level of γ-glutamyltransferase should be obtained to distinguish between these possibilities.

The patient was started on low-molecular-weight heparin. Pulmonary computed tomographic (CT) angiography revealed multiple subsegmental and segmental pulmonary emboli in both lungs, with a consolidated opacity in the right lower lobe that was consistent with an evolving pulmonary infarc-tion. A small right pleural effusion was present (Fig. 2). Urinalysis revealed 3+ protein and 2+ blood. There was no glucosuria. Microscopical examina-





tion of the sediment showed 5 to 10 white cells and 4 to 10 nondysmorphic red cells per high-power field. Hyaline casts but no cellular casts were pres-ent. A 24-hour urine collection obtained to inves-tigate the proteinuria contained 10,975 mg of protein. The patient’s total cholesterol level was 273 mg per deciliter (7.1 mmol per liter), and his level of low-density lipoprotein cholesterol was 207 mg per deciliter (5.4 mmol per liter).

This patient meets all the diagnostic criteria for the nephrotic syndrome — namely, proteinuria (>3.5 g in 24 hours), hypoalbuminemia, periph-eral edema, and hyperlipidemia. Most cases of the nephrotic syndrome, other than those caused by diabetic nephropathy, are caused by a primary glomerular disease, such as membranous ne-phropathy, focal segmental glomerulosclerosis, minimal-change disease, or membranoprolifera-tive glomerular disease. Secondary causes of the nephrotic syndrome include systemic diseases (e.g., diabetes mellitus, systemic lupus erythema-tosus, and amyloidosis), cancer, medications (e.g., nonsteroidal antiinflammatory drugs), and infections (e.g., the human immunodeficiency virus [HIV], hepatitis B and C, and syphilis). The urinalysis narrows the differential diagnosis; the absence of cellular casts decreases the likelihood of membranoproliferative disease. The patient was taking no medications, and there were no

symptoms or signs of systemic illness; his nor-mal glucose level on admission argues against diabetes mellitus. Although risk factors for sexu-ally transmitted diseases and viral hepatitis are not apparent, the patient should still be tested for HIV, syphilis, and viral hepatitis, because patient his-tories are often incomplete. Ultimately, a renal-biopsy specimen will probably be needed for a definitive diagnosis. Regardless of the cause, the nephrotic syndrome increases the risk of venous thromboembolism.

The results of HIV antibody testing were negative. The antineutrophil cytoplasmic antibody (ANCA) titer was 1:640, with an atypical staining pattern. Cryoglobulins, antitreponemal IgG antibody, hep-atitis B virus core antibody and surface antigen, and hepatitis C virus antibody were not detected. The level of γ-glutamyltransferase was elevated at 418 U per liter (normal range, 14 to 62).

In anticipation of a renal biopsy, low-molecular-weight heparin was replaced with unfractionated heparin, which was then briefly discontinued for the procedure. Kidney-biopsy specimens showed membranous nephropathy, stage II to III (Fig. 3). Light microscopy revealed glomeruli with nor-mal cellularity and without signs of inflamma-tion, fibrosis, or sclerosis, and the peripheral capillary walls were outlined by thickened base-ment membranes (Fig. 3A). Electron microscopy

I aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

II

III

VI

Figure 1. Findings on Electrocardiography.

A 12-lead electrocardiogram reveals sinus tachycardia with nonspecific T-wave abnormalities in leads III and aVF.





revealed a thickened glomerular basement mem-brane and subepithelial deposits separated by ex-tensions of the glomerular basement membrane (Fig. 3B). Immunofluorescence microscopy re-vealed diffuse granular deposition of IgG along the peripheral capillary walls (Fig. 3C).

Membranous nephropathy is among the two most common causes of the nephrotic syndrome in adults (focal segmental glomerulosclerosis is the other). Membranous nephropathy can be idio-pathic or may result from a systemic disorder. The absence of serologic evidence of an underly-ing systemic cause of membranous nephropathy suggests that the cause may be idiopathic. Despite the presence of ANCA, the atypical staining pat-tern is characteristically associated with IBD and not systemic vasculitis. The patient’s pulmonary embolism is probably related to the membranous nephropathy, IBD, or both. The elevated levels of alkaline phosphatase and γ-glutamyltransferase remain unexplained. The patient’s history of coli-

A

B

Figure 2. Findings on Pulmonary CT Angiography.

Images from pulmonary CT angiography show multiple subsegmental pulmonary emboli (Panel A, arrows), an evolving pulmonary infarct in the right lower lobe (Panel B, arrow), and a small right pleural effusion (Panel B, arrowhead).

A

B

C

Figure 3. Examination of Renal-Biopsy Specimens.

A renal-biopsy specimen examined by means of light microscopy shows a glomerulus with capillaries outlined by thickened basement membranes (Panel A, arrows; periodic acid–Schiff). Another specimen, examined with electron microscopy, shows a glomerular capillary with a thickened glomerular basement membrane (Panel B, double-headed arrow) and subepithelial deposits (arrows) separated by extensions (or spikes) of the glomerular basement membrane (arrowheads). Immunofluorescence microscopy shows a glomerulus with diffuse granular deposition of IgG (Panel C, arrow; fluorescein isothiocyanate-labeled anti-IgG) along the peripheral capillary walls.





tis increases the possibility of primary sclerosing cholangitis. The diagnosis of primary sclerosing cholangitis can be evaluated either radiologically with magnetic resonance cholangiopancreatog-raphy (MRCP) or endoscopically with endoscopic retrograde cholangiopancreatography (ERCP).

Abdominal ultrasonography revealed a contracted gallbladder. The common bile duct was dilated to 10.1 mm. ERCP revealed diffuse irregularity and beading of the intrahepatic bile ducts. There was smooth tapering at the distal end of the extrahe-patic bile duct, with no apparent stricture (Fig. 4). A colonoscopy revealed moderate inflammation throughout the colon, including the rectum. Biopsy specimens revealed mild-to-moderate chronic ac-tive pancolitis.

The findings on colonoscopy and biopsy are con-sistent with a diagnosis of ulcerative colitis, and the results of ERCP suggest primary sclerosing cholangitis. Ulcerative colitis is the most common form of IBD and is associated with many extrain-testinal manifestations, including primary scle-rosing cholangitis. Primary sclerosing cholangi-tis is characterized by progressive inflammation, fibrosis, and destruction of the intrahepatic and extrahepatic bile ducts.

Diagnoses of pulmonary emboli and the nephrot-ic syndrome were made, with the latter a result of idiopathic membranous nephropathy. IBD with associated primary sclerosing cholangitis was also diagnosed. The patient was discharged from the hospital with prescriptions for warfarin for the pulmonary emboli, lisinopril for the protein-uria, and mesalamine for the ulcerative colitis. He did not want to receive immunosuppressive thera-py for the membranous nephropathy and contin-ues to have marked proteinuria.

Commen ta r y

This patient’s presentation was notable for a com-plex series of clinical problems that at first glance were not clearly related. Why should pulmonary embolism develop in a young man with mild ul-cerative colitis? Might gastrointestinal loss or mal-absorption due to the ulcerative colitis explain the hypoalbuminemia? Is there a link to the ele-vated level of alkaline phosphatase? Careful clin-ical problem-solving led to the diagnosis of four interconnected illnesses: venous thromboembo-lism, membranous nephropathy, primary scle-rosing cholangitis, and IBD.

There is an increased risk of venous thrombo-embolism in patients with IBD and the nephrot-ic syndrome. As compared with matched controls, patients with IBD have a higher risk of venous thromboembolism; the relative risk is reported to be higher by a factor of 3 to 4 in patients with IBD, with an absolute risk of 2.6 per 1000 person-years.1 During a flare, the risk is even greater.1 Thrombosis in patients with the nephrotic syn-drome can arise as a result of increased platelet activation and aggregation, loss of anticoagulant proteins, decreased activity of the fibrinolytic sys-tem, and associated conditions, such as the anti-phospholipid syndrome.2 In cohort studies of patients with the nephrotic syndrome, the an-nual incidence of venous thromboembolism is approximately 1%.3,4 The risk is more closely linked to hypoalbuminemia than to proteinuria3; the risk of venous thromboembolism increases by a factor of approximately 2 for each decrease of 1 g per deciliter in the albumin level.3 Current evidence does not conclusively support the use of anticoagulation as prophylaxis for venous throm-boembolism in patients with IBD or membranous nephropathy. This patient’s untreated membranous nephropathy and associated hypoalbuminemia

Figure 4. Findings on Endoscopy.

On endoscopic retrograde cholangiopancreatography, the intrahepatic ducts have a beaded appearance (ar-rows), and diffuse irregularities can be seen (arrow-head). No dominant stricture is seen.





suggest that the anticoagulation treatment initi-ated for the pulmonary emboli should continue indefinitely.

Idiopathic membranous nephropathy results from antibodies directed at podocyte antigens. The majority of patients with idiopathic mem-branous nephropathy have IgG4 antibodies against an epitope in the M-type phospholipase A2 receptor, indicating that the receptor is a major antigen involved in this disease.5 Sponta-neous remission occurs in 20 to 33% of patients.6 Inhibition of the renin–angiotensin system is recommended, and this patient was treated with lisinopril. This patient decided against immuno-suppressive therapy, but immunosuppressive agents — including glucocorticoids, cyclophos-phamide, and rituximab — have been used with varying degrees of success in the treatment of idiopathic membranous nephropathy.6

Primary sclerosing cholangitis develops in up to 7% of patients with IBD, and approximately 70 to 80% of patients with primary sclerosing cholangitis have IBD.7 Primary sclerosing chol-angitis is more prevalent in patients with ulcer-ative colitis than in those with Crohn’s disease. It is also associated with an increased risk of co-lonic dysplasia, colorectal carcinoma, cholangio-carcinoma, and pancreatic cancer.7 Patients with both ulcerative colitis and primary sclerosing cholangitis have a risk of colon cancer that is four times as high as that among patients with ulcer-ative colitis only.8 As in this case, patients are often asymptomatic at diagnosis. Typical symptoms in-clude fatigue, jaundice, pruritus, and weight loss. The diagnosis is based on characteristic changes in the biliary tree seen on MRCP, ERCP, or both. A liver biopsy is not necessary for diagnosis. For pa-tients with a new diagnosis of primary sclerosing cholangitis, the 2010 guidelines from the Amer-ican Association for the Study of Liver Diseases (AASLD) recommend colonoscopy with random biopsies,9 followed by surveillance colonoscopies every 1 to 2 years in those with IBD.9 Current gas-trointestinal society guidelines for patients with IBD without primary sclerosing cholangitis recom-mend beginning surveillance colonoscopy between 8 and 10 years after the diagnosis of pancolitis and continuing every 1 to 3 years thereafter.10

The 2010 guidelines from the AASLD,9 which were published after the time of this patient’s evaluation, recommend checking serum IgG4 lev-els to identify autoimmune cholangitis, because

this condition cannot be distinguished from pri-mary sclerosing cholangitis with the use of chol-angiography alone.9 Serum IgG4 levels that are twice the upper limit of the normal range are sug-gestive of autoimmune cholangitis, which may be responsive to treatment with glucocorticoids. A finding of elevated serum IgG4 levels in this pa-tient would provide a potential molecular link to his membranous nephropathy with IgG deposi-tion, especially because a major ligand for the M-type phospholipase A2 receptor is group IB phospholipase A2, which is abundant in pancre-atic secretions.11

There is no standard medical therapy for pri-mary sclerosing cholangitis. Data from random-ized controlled trials indicate that ursodeoxycho-lic acid does not alter the natural progression of the disease, and one trial has reported that high doses may lead to an increase in adverse events, including death and the need for liver transplan-tation.12 Because immunosuppressive therapy has also failed to prove beneficial in patients with pri-mary sclerosing cholangitis, AASLD guidelines do not recommend glucocorticoids or other immu-nosuppressive therapies for this condition.9 En-doscopic intervention may be necessary for pa-tients with rapidly progressive disease, biliary obstruction, or cholangitis, both to treat the bili-ary condition and to evaluate the patient for the possibility of cholangiocarcinoma. The treatment of choice for end-stage primary sclerosing chol-angitis is orthotopic liver transplantation.

The patient was discharged while taking a 5-aminosalicylate, mesalamine, which is consid-ered first-line treatment for mild-to-moderate pan-colitis. A 5-aminosalicylate can be used for both induction and maintenance of remission. Gluco-corticoids and other immunosuppressive therapies are reserved for patients with moderate-to-severe disease. Surgical therapy is considered when the disease is refractory to medical therapy.

In summary, this patient’s apparently straight-forward presentation of localized pleuritic chest pain resulting from pulmonary emboli belied the presence of much more complex underlying systemic illnesses that predisposed him to an increased risk of venous thromboembolism. Ac-tive IBD, primary sclerosing cholangitis, and mem-branous nephropathy were unrecognized until the pulmonary emboli developed. This case empha-sizes the fact that even when the cause of present-ing symptoms seems readily apparent, there is still





a need for careful consideration of other poten-tially related diagnoses.

No 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. Helmut Rennke and Ibrahim Batal from the Department of Pathology at Brigham and Women’s Hospital for providing the renal pathology images and detailed interpreta-tions thereof, and Dr. Beatrice Trotman-Dickenson from the Department of Radiology at Brigham and Women’s Hospital for providing the CT images.

References

1. Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet 2010; 375:657-63.2. Singhal R, Brimble KS. Thromboem-bolic complications in the nephrotic syn-drome: pathophysiology and clinical management. Thromb Res 2006;118:397-407.3. Lionaki S, Derebail VK, Hogan SL, et al. Venous thromboembolism in patients with membranous nephropathy. Clin J Am Soc Nephrol 2012;7:43-51.4. Mahmoodi BK, ten Kate MK, Waanders F, et al. High absolute risks and predictors of venous and arterial throm-boembolic events in patients with nephrot-ic syndrome: results from a large retro-spective cohort study. Circulation 2008; 117:224-30.

5. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009;361:11-21.6. Lewis JB, Neilon EG. Glomerular dis-eases. In: Longo DL, Kasper DL, Jameson JL, Fauci AS, Hauser SL, Loscalzo J, eds. Harrison’s principles of internal medi-cine. 18th ed. New York: McGraw-Hill, 2012:2347-8.7. Venkatesh PG, Navaneethan U, Shen B. Hepatobiliary disorders and complica-tions of inflammatory bowel disease. J Dig Dis 2011;12:245-56.8. Soetikno RM, Lin OS, Heidenreich PA, Young HS, Blackstone MO. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastro-intest Endosc 2002;56:48-54.

9. Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010; 51:660-78.10. Itzkowitz SH, Present DH. Consensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease. Inflamm Bowel Dis 2005;11:314-21.11. Ishizaki J, Hanasaki K, Higashino K, et al. Molecular cloning of pancreatic group I phospholipase A2 receptor. J Biol Chem 1994;269:5897-904.12. Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing chol-angitis. Hepatology 2009;50:808-14.Copyright © 2012 Massachusetts Medical Society.

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