Case Report

1. Radiological Category: Thoracic Chest Principal Modality : CT Case Report Submitted by: Ashley Roberts, MS4 Faculty reviewer: Sandra Oldham, M.D Date accepted: 25 August 2010

2. Case History HPI: 74yo white female presented to an OSH with sudden onset bradycardia, dizziness, chest pain and SOB after a several week history of dry cough. She was transferred to MHH at the request of the family after developing altered mental status. Denies sick contacts or a previous history of respiratory difficulties. PMH: HTN, HLD, multiple TIAs, Afib for 1.5yrs, lung contusion many years ago. Home meds: Plavix, Coumadin, Amiodarone, Nifedipine, Nexium, Gabapentin, Toprol PSH: tonsillectomy, glaucoma Allergies: PCN, Demerol FH: Positive for CVAs and CAD.

3. Case History SH: Denies T/A/D. Previously held jobs include work in a rug factory and as a hospital aid. She has lived near both coal refineries and sugar factories, as well as in Pasadena. Currently works at Wal-Mart. ROS: negative except for HPI. Relevant PE: BP: 121/56, P 62-66, RR 20-33, SpO2: 94-98% on 4-5L NC Gen: Well-nourished, NAD CV: S1,S2, RRR. No murmur Pulm: Bilateral diffuse dry crackles, particularly in the lower lobes. Mild expiratory wheezing. Abd: WNL Extr: No clubbing/cyanosis, edema.

4. Radiological Presentations PA Chest X-rays show blunting of the left costophrenic angle. Lateral Shows clear evidence of effusion with possible bilateral involvement. No previous studies were available for comparison

5. Radiological Presentations CT Chest without contrast, lung window, coronal and axial sections

6. Radiological Presentations CT Chest without contrast, mediastinal window, axial sections

7. Radiological Presentations CT Chest without contrast, axial sections

8. Radiological Presentations CT Chest without contrast, coronal sections

9. Test Your Diagnosis Which one of the following is your choice for the appropriate diagnosis? After your selection, go to next page. • Amyloidosis • Pneumoconiosis • Amiodaronetoxicity • Calcified Pulmonary Metastases • Hemachromatosis

10. 2 view Chest X-ray shows bilateral effusions. Unenhanced CT scan shows scattered areas of ground glass opacitiies, and focal areas of dense lung consolidations containing air bronchograms in the basilar segments of the bilateral lower lobes. Adjacent to these consolidations are moderate bilateral pleural effusions. High attenuation is also noted in the liver parenchyma. Findings and Differentials Findings: Differentials: Each of these diagnoses present patterns of high attenuation on CT • Amyloidosis • Pneumoconiosis • Amiodarone toxicity • Calcified Pulmonary Metastases • Hemachromatosis

11. 2 view Chest X-ray shows bilateral effusions. Unenhanced CT scan shows focal areas of dense lung consolidations containing air bronchograms in the basilar segments of the bilateral lower lobes. Adjacent to these consolidations are moderate bilateral pleural effusions. High attenuation is also noted in the liver parenchyma. Findings and Differentials Findings: Differentials: • Amyloidosis • Pneumoconiosis • Calcified Pulmonary Metastases • Hemochromatosis • Amiodarone toxicity - Rarely occurs in the lungs, and liver findings will be hypodense • (coal) CT appearance is of multiple hyperdense nodules • No liver involvement • Have an appearance of focal calcification • within a pulmonary nodule rather • than a generally hyperattenuated appearance -Liver will be hyperattenuated, but no lung involvement - Bingo!

12. Given the unique radiological presentation, and the patient’s history of atrial fibrillation, her images are consistent with Amiodarone-induced pulmonary toxicity (AIPT). Amiodarone is one of the most widely prescribed anti-arrhythmic in the US due to it’s multiple clinical applications and it’s cardiovascular efficacy. Indications include both ventricular and supraventricular arrhythmias. It does not exacerbate CHF, nor is it pro-arrhythmic. The patients that benefit the most from the use of amiodarone are those with: Afib, LV dysfunction, acute sustained arrhythmias, and those with ICDs and symptomatic shocks. However, amiodarone use must be closely monitored.… Discussion

13. Pharmacokinetics: Amiodarone is highly lipid-soluble and contains an iodinated component. It is the iodinated component that is responsible for the high attenuation appearance on CT It tends to accumulate in adipose tissue and highly perfused organs such as the liver, lungs, and spleen. It is metabolized in the liver via the cytochrome p450 system and has a half-life of approximately 6 months. Of note, neither amiodarone nor it’s metabolite are able to be removed by dialysis. Discussion

14. Amiodarone is well-known to have adverse effects involving multiple organs. Among them are: Corneal deposits Thyroid dysfunction (both hyper- and hypo-) Bone marrow suppression Abnormal liver function tests Coagulopathies Drug-drug interactions The most serious and clinically limiting side effect, however, is AIPT. Discussion

15. Pulmonary toxicity occurs both by direct cytotoxic effects through the generation of free radicals, and by a cell-mediated immune reaction. High concentrations of the drug accumulate within macrophages and type II pneumocytes. Lung biopsy of patients with AIPT show diffuse interstitial pneumonitis, hyperplasia of type II pneumocytes, thickening of alveolar septae with inflammatory infiltrate, and varying degrees of fibrosis. Discussion Microstructural exam shows characteristic lamellated myelin bodies, and foamy macrophages. These findings are present even in the absence of toxicity. Image borrowed from the Veterans Affairs National Department of Electron Microscopy

16. Clinical presentation Incidence of AIPT varies from 2-15% depending on the prescribed dose. The most common presentation is one of a subacute pneumonia after months to years of amiodarone use: Non-productive cough, progressive shortness of breath, fever, and malaise +/- pleuritic chest pain PFTs will demonstrate a restrictive pattern In severe cases it can also present as a rapidly progressive pneumonitis with development of ARDS Particularly in patients receiving contrast for pulmonary angiography and Patients undergoing cardiac or pulmonary surgery Discussion

17. Risk factors for the development of AIPT: Dose-dependent effect, particularly with respect to the total cumulative dose Patients most at risk are those receiving >/= 400mg daily for >2 months OR those receiving 200mg daily for >2 years That said, AIPT can occur at any time during treatment Other risk factors include: Male sex Age Pre-existing lung disease Potentially race (higher incidence in a Japanese population in one study) Exposure to supplemental oxygen Discussion

18. Radiographic presentation: CXR: will reveal patchy or diffuse infiltrates, often bilaterally, and sometimes with a ground glass appearance. HRCT: Lung: Ground glass opactities; in early disease, these may be peripheral Infiltrates: interstitial, alveolar, or both. Usually bilateral Areas of high attenuation due to amiodarone accumulation Peripheral lung nodules or masses Dense bibasilar reticular opacities, which suggest fibrosis Pleural thickening and effusions Abdomen: High attenuation in the liver and spleen Discussion

19. Diagnosis and Treatment: AIPT should be suspected in any patient on amiodarone therapy with new onset or worsening pulmonary symptoms or changes on CXR CXR, and PFTs should be obtained at baseline, and a CXR should be obtained yearly so that toxicity can be closely monitored. Have a low threshold for getting new CXR and PFTs if clinically indicated. If diagnosis is confirmed, discontinue the drug and begin systemic steroids The long half-life of amiodarone may mean that things will get worse before they get better. Steroids should be given for 6 months to a year. Cases of relapse have been documented with early steroid withdrawal, particularly in patients with a large amount of adipose tissue. Discussion

20. Amiodarone-induced lung toxicity Diagnosis

21. Marchiori E, et al. Diffuse High-Attenuation Pulmonary Abnormalities: A Pattern-Oriented Diagnostic Approach on High resolution CT. American Journal of Roentgenology 2005; 184: 273-282Wolkove N, Baltzan M. Amiodarone Pulmonary Toxicity. Canadian Respiratory Journal 2009; 16(2): 43-48Georgiades CS, et al. Amyloidosis: Review and CT Manifestations. Radiographics, March 2004; 24(2): 405-416Merck Manual’s Online Medical Library: Coal Worker’s Pneumoconiosis. http://www.merck.com/mmhe/sec04/ch049/ch049f.htmlBeo SB, et al. Atypical Pulmonary Metastases: Spectrum of Radiographic Findings. Radiographics, March 2001; 21:403-417Vassallo P, Trohman G. Prescribing Amiodarone: An Evidence-Based Review of Clinical Indications. JAMA 2007; 298(11): 1312-1322 References