Clifford D. Packer

Cushing's Syndrome Due to Antiretroviral-Budesonide Interaction

TO THE EDITOR: Oral budesonide is a generally well-tolerated treatment for inflammatory bowel disease due to its extensive first-pass metabolism through hepatic CYP3A4, which minimizes systemic adverse effects. However, protease inhibitors such as ritonavir and atazanavir inhibit CYP3A4, thus decreasing the biotransformation and inactivation of glucocorticoids.1,2 Case Report. A 75-year-old man with a history of HIV for 27 years, hepatitis C, hypothyroidism, recurrent deep venous thrombosis, hypertension, and chronic kidney disease was admitted for treatment of worsening chronic diarrhea and bright red blood per rectum. His medications were atazanavir 300 mg daily, atenolol 12.5 mg twice daily, atropine/diphenoxylate 4 times daily as needed, calcitriol 0.25 μg daily, cholecalciferol 400 units daily, subcutaneous fondaparinux 7.5 mg daily, lamivudine 150 mg daily, levothyroxine 0.112 mg daily, lisinopril 10 mg daily, loperamide 2 mg as needed, nevirapine 300 mg twice daily, ranitidine 300 mg daily, ritonavir 100 mg daily, testosterone patch 5 mg/24 hours, trazodone 50 mg at bedtime, and vardenafil 20 mg as needed. Blood pressure was 125/75 mm Hg and weight was 77.1 kg. Initial laboratory testing showed serum creatinine 1.6 mg/dL, potassium 4.2 mEq/L, bicarbonate 20 mEq/L, and normal liver function. Colonoscopy showed lymphocytic colitis at multiple biopsy sites. Oral budesonide 3 mg 3 times a day was started for treatment of lymphocytic colitis. The patient’s diarrhea improved, but he was admitted 12 days later with 10.4-kg weight gain, severe leg and facial swelling, and uncontrolled hypertension. Physical examination was notable for blood pressure 177/102 mm Hg, cushingoid facies, and 2+ pedal and pretibial edema to the knees. Lungs were clear, S3 heart sound was not present, and jugular venous pressure was normal at 5 cm. Laboratory testing revealed serum creatinine 1.3 mg/dL, potassium 2.8 mEq/L, bicarbonate 32 mg/dL, albumin 3.1 g/dL, urinalysis negative for protein, brain natriuretic peptide 292 pg/mL, thyroid-stimulating hormone 7.5 mIU/L, free thyroxine 1.07 ng/dL, and serum cortisol 0.8 μg/dL. Echocardiogram showed normal left and right ventricular function. Because the colitis had improved dramatically with budesonide therapy, the plan was to continue it for a full 6-week treatment course, if possible. Amlodipine, hydralazine, and furosemide were added to control the hypertension and edema, but budesonide was discontinued after 3 weeks because of persistent severe edema that was refractory to furosemide. The diarrhea was eventually controlled by alternating loperamide and atropine/diphenoxylate treatment. The edema had resolved 15 days after discontinuation of budesonide, at which time laboratory testing showed serum potassium 4.6 mEq/L and bicarbonate 23 mg/dL. Discussion. Budesonide is inactivated through extensive first-pass metabolism by hepatic CYP3A4. The P-glycoprotein (PGP) export pump also limits budesonide serum concentrations by promoting the gastrointestinal excretion of CYP3A4 substrates. By inhibiting CYP3A4 and PGP, protease inhibitors such as ritonavir and atazanavir limit both the first-pass metabolism and gastrointestinal excretion of CYP3A4 substrates and result in increased serum concentrations of steroids.1,2 As the most potent CYP3A4 inhibitor among HIV protease inhibitors, ritonavir has been most closely tied to adverse interactions with steroids.1 Our patient developed edema, weight gain, uncontrolled hypertension, cushingoid facies, hypokalemia, and metabolic alkalosis shortly after initiation of budenoside, with resolution of all symptoms soon after it was stopped. Congestive heart failure, liver disease, and nephrotic syndrome were ruled out as causes of the edema, which supported the diagnosis of iatrogenic Cushing’s syndrome. Although budesonide concentrations were not measured, the very low serum cortisol level (0.8 μg/dL) in a clinical setting of hypercortisolism provides strong indirect evidence that levels of an exogenous corticosteroid (ie, budesonide) were high. Adrenal suppression has been described in a number of cases of iatrogenic Cushing’s disease due to ritonavir-steroid interactions.3 The Naranjo probability scale and Horn Drug Interaction Probability Scale score characterized this as a probable drug interaction.4,5 There are 28 reported cases of Cushing’s syndrome resulting from an interaction between ritonavir and fluticasone.3 In theory, ritonavir can also increase serum concentrations of budesonide and result in systemic glucocorticoid complications.3 De Wachter et al. described 2 patients with cystic fibrosis who developed budesonide-induced Cushing’s syndrome while being treated with cytochrome P450 inhibitors (1 with itraconazole and 1 with clarithromycin).6 Recently, Kedem et al. reported a case of iatrogenic Cushing’s syndrome due to coadministration of ritonavir and inhaled budesonide in a patient with asthma and HIV infection.7 To our knowledge, ours is the first published report of oral budesonide causing iatrogenic Cushing’s syndrome in a patient on an antiretroviral regimen containing ritonavir. Foisy et al. have suggested that the combination of fluticasone and ritonavir should be avoided but that budesonide might be a safer option.3 There is now evidence, however, that both inhaled and oral budesonide can cause iatrogenic Cushing’s syndrome in patients taking ritanovir. Based on these case reports, it seems unlikely that budesonide offers any safety advantage over traditional corticosteroids. Clinicians must carefully consider the risks and benefits of any corticosteroid treatment in HIV-infected patients who are taking antiretroviral drugs.

Fatal hemolytic anemia associated with metformin: A case report

IntroductionMetformin is a widely prescribed biguanide antidiabetic drug that has been implicated as a cause of hemolytic anemia in three previous case reports. We report a case of rapidly fatal hemolysis that was temporally associated with the initiation of metformin treatment for diabetes. Clinicians need to be aware of this rare but potentially serious side effect of metformin.Case presentationA 56-year-old Caucasian man with type 2 diabetes mellitus was started on metformin to improve glycemic control. Shortly afterwards, he developed progressive fatigue, exertional dyspnea, cranberry-colored urine and jaundice. Laboratory studies showed severe hemolysis, with a drop in hemoglobin from 14.7 to 6.6 g/dl over 4 days, markedly elevated lactate dehydrogenase, bilirubin and reticulocyte counts, and a low haptoglobin level. A peripheral blood smear showed no schistocytes, and a direct Coombs test was positive for anti-IgG and negative for anti-C3. Despite corticosteroid treatment and transfusion of packed red blood cells, the patient developed increasing dyspnea, hypotension, further decline in hemoglobin to 3.3 g/dl, and fatal cardiorespiratory arrest 12 hours after admission.ConclusionThe serologic findings in this case suggest an autoimmune hemolytic anemia, caused either by a drug-induced autoantibody or a warm autoantibody. Based on the temporal association with metformin and the lack of other clear precipitating causes, we propose that metformin-induced hemolysis with a drug-induced autoantibody is a strong possibility. This mechanism differs from a previously described case with a possible antibody to the erythrocyte-drug complex. It has been shown, however, that hemolysis may occur via multiple mechanisms from the same drug. Clinicians should consider the possibility of metformin-associated immune hemolytic anemia in patients with otherwise unexplained hemolysis.

Cannabinoid Hyperemesis Syndrome: A Case Report and Review of Pathophysiology

Cannabis is the most widely used illicit drug in the United States, with lifetime prevalence of use estimated at 42% to 46%. The antiemetic properties of cannabis are well-known by the medical community and the general public; however, less well-recognized is the paradoxical potential for certain chronic users to develop hyperemesis. We describe in this case a patient with prior extensive work-up for nausea and vomiting and previous diagnosis of cyclic vomiting syndrome who presented with characteristic features of cannabinoid hyperemesis syndrome. We review the current literature for this condition and highlight potential mechanisms for its pathogenesis.

SOAP-V: Introducing a method to empower medical students to be change agents in bending the cost curve.

Medical students must learn how to practice high-value, cost-conscious care. By modifying the traditional SOAP (Subjective-Objective-Assessment-Plan) presentation to include a discussion of value (SOAP-V), we developed a cognitive forcing function designed to promote discussion of high-value, cost-conscious care during patient delivery. The SOAP-V model prompts the student to consider (1) the evidence that supports a test or treatment, (2) the patients preferences and values, and (3) the financial cost of a test or treatment compared to alternatives. Students report their findings to their teams during patient care rounds. This tool has been successfully used at 3 medical schools. Preliminary results find that students who have been trained in SOAP-V feel more empowered to address the economic healthcare crisis, are more comfortable in initiating discussions about value, and are more likely to consider potential costs to the healthcare system.

Severe Romiplostim-Induced Rebound Thrombocytopenia After Splenectomy for Refractory ITP:

Objective: To report a case of severe rebound thrombocytopenia after temporary discontinuation of romiplostim during splenectomy in the context of refractory immune (idiopathic) thrombocytopenic purpura (ITP). Case Summary: A 65-year-old man with a history of severe refractory ITP failing multiple treatments was considered for romiplostim therapy. He was initiated on 1 µg/kg and titrated upward to 4 µg/kg to elevate and stabilize his platelet levels prior to splenectomy. On day 74 of his clinical course, his platelets increased to 434 × 109/L, and his scheduled dose of romiplostim was withheld on day 75 for fear of romiplostim-induced postsplenectomy rebound thrombocytosis. On day 78, his platelets dropped precipitously to 9 × 109/L, and he experienced multiple episodes of epistaxis. He was reinitiated at 5 µg/kg and soon recovered. He later missed a scheduled dose of romiplostim, and his platelets fell to 23 × 109/L. After resuming romiplostim at 8 µg/kg, his platelets continued to recover. Discussion: Romiplostim, a thrombopoietin mimetic is directly regulated by megakaryocytes and existing circulating platelets via a negative feedback mechanism. This explains the theoretical risk of rapid clearance of romiplostim caused by an increased platelet pool. Clinically, alternative causes of his severe postoperative thrombocytopenia were considered and deemed unlikely. The rebound effect was observed after romiplostim was withdrawn on 2 occasions, and platelet counts improved after restarting romiplostim. The Naranjo Adverse Drug Reaction Probability Score of 7 suggests a probable adverse drug reaction. Conclusion: Physicians using romiplostim as a bridge to splenectomy should be cautious about withholding a scheduled dose around the time of surgery.

Lithium Toxicity Presenting as Transient Transcortical Motor Aphasia: A Case Report

Patients with chronic lithium toxicity typically present with symptoms of agitation, confusion, tremor, ataxia, and hyperreflexia. In rare cases, however, lithium toxicity can present with transient cognitive and language deficits. We report the case of a lithium-toxic patient who presented with transient transcortical motor aphasia, which resolved 2 days after discontinuation of lithium. This is the first report of focal transcortical motor aphasia in a patient with lithium toxicity. Given the narrow therapeutic range of lithium, clinicians should be aware of the possibility of focal aphasia as a rare manifestation of lithium toxicity.

How to Write a Traditional Case Report

The traditional case report consists of a title, abstract, introduction, case description, discussion, and conclusion with a teaching point. This chapter describes how to write a traditional case report, from title to conclusion, in a logical, concise, and publishable style. Key requirements for a successful case report include a straightforward and descriptive title; a focused case description with all essential elements; appropriate use of clinimetrics, including clinical biomarkers, laboratory tests, and reproducible indices; a graphical timeline; a discussion of the context of the case, with a comparison table if appropriate; an explanation of the events of the case, including cause and effect or relatedness of events, differential diagnosis, and a well-supported and logical hypothesis; speculation on the broader implications of the case; and a conclusion with a simple, clear, and memorable teaching point.

The Historical Tradition of Case Reporting

The case report as we know it today has evolved over almost 4000 years. From the medical writings of the ancient Egyptian physician-priests, who mixed practical observation with magical beliefs, and the detailed and objective case descriptions of Hippocrates’ Epidemics, this chapter traces the key stages in the development of the modern case report. The works of Hippocrates, Galen, Rhazes, Avicenna, Lusitanus, Wang Ji, John Warren, James Parkinson, and William Osler illustrate the changing forms and functions of the case report from ancient times through the Dark Ages, the Enlightenment, the Scientific Revolution, and the beginnings of modern medicine. The twentieth century saw a tremendous surge in the publication of case reports focusing on new diseases, drug side effects, etiology and mechanisms of disease, therapy, prognosis, and education. In the 1980s and 1990s, the rise of evidence-based medicine and the impact factor led to a temporary decline in case report publication; since then, case reports have rebounded with the development of electronic case report journals, along with an increasing appreciation for the evidence value of case reports.

The Future of the Case Report

In the future, case reports, n-of-1 trials, and individual biometric and genomic studies will play increasingly important roles in personalized medicine. Aggregated case reports will be mined for data, which will guide the care of patients with disease and treatment variables too complex to be addressed by randomized controlled trials. Physicians will use the database to make treatment decisions at the point of contact. Case reports capture novelty and innovation, and flourish at the cutting edge of new technologies. Two recent case reports hint at future directions: the innovative use of a smartphone activity tracker to guide arrhythmia management, and circulating tumor DNA to determine the specific mechanism of tumor resistance without a biopsy in a patient with metastatic nonsmall cell lung cancer.

It’s Published!

Authors of published case reports may be invited to participate in peer review, write editorials, and interact with news media. Participation in peer review stimulates academic growth, sharpens clinical insight, and helps to uphold the validity of the editorial process. Editorial writing gives authors a forum to discuss such topics as pathophysiology, mechanisms of disease, alternate hypotheses, and broader implications of the case findings. Most authors prefer to publish in PubMed-indexed journals, in the belief that their articles will receive more citations and the prestige of PubMed indexing will help with academic promotion. Initial citation rates for case reports are lower than that for other article types, such as meta-analyses and randomized trials, but case report citations tend to accrue steadily over time; long-term citation rates might be more appropriate for comparison. The social media response to case reports can be tracked both on journal websites and through publication analytics services such as Altmetric and ResearchGate.