Case 1: Normal D-dimer levels in a patient with multiple pulmonary emboli
Devika Nair, MD
A 39-year-old man presented to the ED with a 1-day history of left lower quadrant abdominal pain consistent with previous episodes of diverticulitis. His only symptom was abdominal pain, and his physical exam was significant only for tenderness to deep palpation in the left lower quadrant. The patient's vital signs were unremarkable, including an oxygen saturation of 100% on room air. Results of admission testing are shown in Table 1.
This patient was incidentally demonstrated to have asymptomatic and likely chronic bilateral pulmonary emboli. D-dimer testing was performed for strictly educational purposes and was done after the CT results were known. Contrary to expectation, the patient had a normal D-dimer level despite multiple confirmed pulmonary emboli.
D-dimer testing has been used to predict venous thromboembolic disease in low-risk patients. In hemodynamically stable patients with a low pretest probability, guidelines suggest that a normal D-dimer level effectively rules out pulmonary embolism due to the test's strong negative predictive value.
However, the utility of the D-dimer may be limited in certain instances. Numerous trials have demonstrated falsely elevated D-dimers in patients who are pregnant, elderly, or hospitalized. Large-scale trials evaluating false-negative D-dimers are lacking, but smaller studies have shown that D-dimer testing is less sensitive in patients who have recently experienced trauma or who have had symptoms for at least 2 weeks. Our case suggests that patients with chronic, asymptomatic pulmonary emboli may have falsely negative results on D-dimer tests.
More recently, D-dimers have been used to determine the risk for recurrent disease in patients who have already completed anticoagulation. One systematic review found that patients with normal D-dimers 1 month after anticoagulation had a 3.5% risk of recurrent thromboembolism, while patients with elevated values had a risk of 8.9%. Clinicians can use this information to assist in the risk-benefit analysis of ongoing anticoagulation in certain cases of venous thromboembolism.
- D-dimers may be falsely positive in certain patient groups (elderly, pregnant, or hospitalized patients) and falsely decreased in others (patients who have had recent trauma or longer symptom duration).
- D-dimers may be useful in measuring the chance of recurrent thromboembolism following anticoagulation and can thus be used to guide treatment decisions regarding the length of anticoagulant treatment.
Case 2: Vitamin B12 deficiency presenting with altered mental status and thrombocytopenia
Ashley Ellison, MD, ACP Resident/Fellow Member
An 80-year-old woman with unknown medical history was found wandering alone in a local pharmacy disoriented to person, place, and time. She was guarded and would not answer any questions regarding medical history, review of systems, substance use, or past medications. Given her inability to state her name, no collateral information could be gathered. Vital signs were normal. Aside from confusion, disorientation, and thin body habitus, there were no abnormalities on physical exam and neurological exam was normal. Results of admission testing are shown in Table 2.
This patient's diagnosis is vitamin B12 deficiency. B12 deficiency typically presents with pallor, macrocytic anemia, and paresthesias and/or peripheral neuropathy. Up to 25% of patients with B12 and/or folate deficiency have normal mean corpuscular volume. Gastrointestinal symptoms can also be present, including glossitis, decreased appetite, and diarrhea. Psychiatric symptoms are less common, but B12 deficiency has been linked to dementia, irritability, depression, and, in rare cases, psychosis. Thrombocytopenia is found in approximately 20% of patients with B12 deficiency and is generally mild (100,000-150,000 cells/mUL), but severe cases (<100,000 cells/UL) can occur. B12 deficiency appears to contribute to ineffective thrombopoiesis, but a more detailed mechanism is unknown.
Diagnosis involves a B12 level; when the result is less than 200 pg/mL (95%-100% specific), no further testing is required. Intermediate B12 levels (200-300 pg/mL) should be followed by measurement of methylmalonic acid (MMA) and homocysteine. Elevation of both MMA and homocysteine confirm a diagnosis of B12 deficiency with a sensitivity and specificity of 94% and 99%, respectively. If MMA is normal and homocysteine is elevated, folate deficiency is the more likely diagnosis, with a sensitivity and specificity of 86% and 99%, respectively.
This patient was treated with B12 injections, 1,000 µg/d, for 1 week and was then discharged on daily oral B12 (1,000 µg). She was alert, oriented to person, place, and time, and cooperative upon discharge. Her thrombocytopenia and anemia also resolved before discharge. Anti-intrinsic factor antibodies were positive, and the cause of her B12 deficiency was thus identified as pernicious anemia.
- B12 deficiency typically presents with macrocytic anemia and peripheral neuropathy or paresthesias but can cause altered mental status and thrombocytopenia.
- Diagnostic testing is dependent on B12 levels; levels below 200 pg/mL require no confirmatory testing; intermediate levels (200-300 pg/mL) require MMA and homocysteine measurements.
Case 3: Secondary Evans syndrome
Farah Kaiksow, MD, MPP, ACP Resident/Fellow Member
A 27-year-old man presented with a 4-day history of shortness of breath, jaundice, and fever. He had no active medical issues and took no medications. His medical history was significant only for idiopathic thrombocytopenic purpura (ITP) at age 14, which was diagnosed and treated in Honduras. The patient used alcohol and tobacco occasionally, his last sexual activity was 3 months prior, and he used condoms regularly.
On physical examination, the patient was febrile and tachycardic. He had scleral icterus and hepatosplenomegaly, and his skin appeared moderately jaundiced with no petechiae or bruising. Complete blood count results were as follows: 3,100 white cells/mL with a normal differential, a platelet count on the low end of normal, severe anemia with a hemoglobin of 4.4 g/dL with an elevated mean corpuscular volume and red blood cell distribution width, and an elevated reticulocyte count. Lactate dehydrogenase and total bilirubin levels were also elevated, haptoglobin was significantly decreased, and direct Coombs test was positive. Hepatitis C antibody was positive, and hepatitis C virus RNA level was significant. Red blood cell transfusion was ordered, but administration was delayed because of autoantibodies in the patient's blood. Transfusion was completed the day after admission; the patient's hemoglobin responded appropriately, and his symptoms began to improve.
The patient was diagnosed with Evans syndrome, the combination of ITP and autoimmune hemolytic anemia (AIHA). In both conditions, autoantibodies attack a particular cell line, leading to thrombocytopenia and/or anemia. Some patients also have autoantibodies against neutrophils. Half of Evans syndrome patients have ITP and AIHA simultaneously, but in the other half the 2 conditions are separated in time, often by many years. While there have been reports of spontaneous and permanent remission, the more common clinical picture is a relapsing and remitting course that has a poor prognosis despite appropriate therapy. Steroids are first-line treatment, with IV immunoglobulin in instances of ITP. Many patients, however, require second-line therapy with other medicines such as rituximab or cyclophosphamide. Splenectomy is occasionally required.
Without an identifiable cause, these patients are diagnosed with primary Evans syndrome. Evolving research suggests an underlying disease leading to a systemic state of immune dysregulation, i.e., secondary Evans syndrome. In these patients, associated conditions include systemic lupus erythematosus, common variable immunodeficiency syndrome, and lymphoproliferative disorders, particularly lymphomas. Hepatitis C, as was present in this patient, is also implicated as a cause.
- Evans syndrome is the combination of simultaneous or sequential ITP and AIHA and can be primary or secondary.
- Physicians should rule out underlying diseases that may require further treatment before diagnosing primary Evans syndrome.
Case 4: Dextromethorphan and prescription medications
Irene Hurst, MS
A 30-year-old man presented with episodic presyncope, weakness, and blurred vision. He started having symptoms of an upper respiratory infection 1 day prior, which he treated with an over-the-counter medication that contained dextromethorphan. He took the medication approximately 20 to 30 minutes before onset of symptoms, which were characterized as dizziness, blurred vision, tingling in his extremities, and a clammy sensation. These resolved over 2 hours and did not recur. The patient's medical history was significant for supraventricular tachycardia, controlled with propafenone and atenolol. Workup for new cardiac, neurological, and vasovagal etiologies for this episode were negative. Electrocardiograms on admission and subsequently were normal, and a 24-hour Holter monitor demonstrated no arrhythmia.
It is presumed that this patient experienced recurrent episodes of supraventricular tachycardia, most likely due to a medication interaction between propafenone and dextromethorphan. A Medscape drug interaction search identified the possibility of this reaction; however, 4 commonly used pharmaceutical references did not.
Both drugs are metabolized by the CYP2D6 cytochrome P450 enzyme system. On its own, dextromethorphan has pro-arrhythmic effects, where it inhibits the human Ether-à-go-go Related Gene (hERG)-encoded potassium channel in the heart. This causes prolongation of the QT interval by inhibiting hERG-mediated repolarization of cardiac action potential and can lead to torsades de pointes. As a class 1C antiarrhythmic, propafenone has an inhibitory effect on early sodium channel current and mild β-blockade effects, making it useful for atrial fibrillation and other supraventricular tachycardias. When propafenone is unmetabolized by the CYP2D6 system, patients experience more central nervous system side effects, particularly dizziness, paresthesias, and blurred vision, as in this patient. Patients who are slow CYP2D6 metabolizers (often from Eastern countries, as was this patient) have consistently higher levels of propafenone in their blood, which increases the risk of toxicity. This patient's lack of symptoms or recurrent arrhythmia during inpatient hospitalization was attributed to withholding of dextromethorphan, and he was advised to avoid this medication in the future.
- Dextromethorphan, a ubiquitous ingredient in many over-the-counter preparations, may interact with prescription medications via a cytochrome-P450 mechanism.
- No single drug reference is all-inclusive, and the lack of a published drug interaction should not dissuade clinicians from considering one that appears clinically evident.
Case 5: Acute interstitial nephritis caused by zonisamide
Allie Abrams-Downey, MD, ACP Resident/Fellow Member
A 64-year-old man with a history of seizure disorder presented with increased seizure activity, despite adherence to his home regimen of phenytoin and phenobarbital. The patient's phenytoin and phenobarbital dosages had been recently decreased due to daytime oversedation. A neurology consultant recommended starting a new antiepileptic, zonisamide. Before the patient began taking the new medication, his creatinine was normal (0.86 mg/dL). Within 48 hours of zonisamide treatment, his creatinine increased to 4.6 mg/dL. Zonisamide was withdrawn, and he was admitted to the hospital for further evaluation.
Urinalysis revealed protein and eosinophils. He remained nonoliguric throughout admission. His creatinine continued to increase and peaked at 7.34 mg/dL. He was started on a short course of high-dose oral prednisone. At the time of discharge, approximately 4 days after withdrawal of zonisamide, his creatinine had decreased to 1.88 mg/dL. It ultimately returned to normal (0.73 mg/dL).
The patient was diagnosed with acute interstitial nephritis (AIN) secondary to zonisamide. Acute kidney injury secondary to AIN is a common diagnosis, particularly in the management of hospitalized patients. Unfortunately, the classic triad of fever, rash, and eosinophilia is fairly rare, occurring in only 5% to 10% of AIN cases. Often patients remain nonoliguric and only have an isolated laboratory finding of increased serum creatinine. Many medications are commonly associated with AIN, in particular NSAIDs and penicillin-based antibiotics, although other medications may cause AIN even if the effect is not well established.
Making the diagnosis involves keeping a high index of suspicion for AIN in the setting of a new medication. The gold standard for diagnosis is renal biopsy; however, this invasive test is often deferred and should only be performed in certain clinical situations. Noninvasive laboratory findings, such as peripheral eosinophilia, eosinophiluria, and pyuria, may suggest AIN but are not confirmatory. Eosinophiluria, once thought to be the gold standard, has a sensitivity of 40% to 67% and a specificity of 72% to 83%.
AIN is managed by immediately withdrawing the causative medication. The role of steroids in the management of drug-induced AIN remains controversial, although case series and anecdotal experience support their use in selected cases. Decisions regarding the use of steroids, which were given to this patient, can be made on a case-by-case basis and in conjunction with nephrology consultation.
- AIN is classically caused by NSAIDs and antibiotics but should be considered for any precipitous rise in creatinine after the administration of a new medication.
- In the appropriate clinical context, lack of eosinophiluria does not rule out AIN and renal biopsy may be necessary for kidney injury that continues to worsen.