The Brief Case is a bimonthly column comprising summaries of real-life inpatient cases. It is written by hospital physicians and edited by Christopher Sankey, MD, ACP Member, a hospitalist at Yale-New Haven Hospital in Connecticut. If you are interested in writing one or more summaries of cases from your hospital, please email us.
Case 1: Antiphospholipid antibody syndrome and adrenal hemorrhage
Renuka Naik, MD, PhD, Tim Poore, MD, and Sima Pendharkar, MD, MPH, ACP Member
A 31-year-old woman with limited access to medical care presented to the San Francisco General Hospital ED with 4 days' duration of fevers, chills, and worsening left-sided abdominal pain. She had been seen in the same ED 2 days before for abdominal pain; after normal results on abdominal CT, she was discharged home. Her abdominal exam on repeated presentation revealed diffuse tenderness to palpation without noted rebound or guarding. She had mild leukocytosis, normal liver function tests, and a normal lipase level. A repeated CT scan of her abdomen and pelvis showed left-sided “adrenal stranding” with concern for adrenal hemorrhage versus infection. She was febrile at the time of admission and was started on broad-spectrum antibiotics.
The patient remained febrile on hospital days 2 and 3, with progressive hyperpigmentation of the skin on her face. A repeated CT performed on hospital day 4 for acute worsening of abdominal pain and hemodynamic instability demonstrated new bilateral adrenal hemorrhage. The patient was transferred to the ICU for close monitoring. Serologic testing confirmed a diagnosis of antiphospholipid antibody syndrome (APLS) with underlying systemic lupus erythematosus (SLE). Therapeutic anticoagulation with heparin was started with plans to bridge to warfarin.
The patient's hospital course was further complicated by adrenal insufficiency, myopericarditis with pericardial effusion, splenic infarcts, renal failure, and refractory immune thrombocytopenia purpura, all thought to be secondary to underlying SLE. She remained in the hospital for 3 months before being discharged home on warfarin and prednisone.
The diagnosis, part 1: APLS
APLS is an autoantibody-mediated condition characterized by arterial and venous thrombosis caused by autoantibodies against phospholipid-binding plasma proteins. APLS occurs in approximately 15% of patients with SLE. It is not known what causes these autoantibodies to develop; however, infection has been suggested as a possible preceding event. Clinical criteria used to diagnose APLS include vascular thrombosis affecting any tissue or organ; pregnancy morbidity, including death of a morphologically normal fetus after 10 weeks' gestation; 1 or more premature births because of eclampsia, severe preeclampsia, or placental insufficiency; and/or 3 or more spontaneous abortions before the 10th week of gestation. The laboratory criteria include a positive lupus anticoagulant, anticardiolipin, and/or anti-beta-2- glycoprotein antibodies at intermediate to high titers on 2 occasions 12 weeks apart. One clinical criterion and one laboratory criterion are needed to diagnose APLS. Treatment in confirmed APLS is lifelong anticoagulation with a goal international normalized ratio (INR) of 2.5 to 3.5 to prevent future thromboses.
The diagnosis, part 2: Adrenal hemorrhage in the setting of APLS
The exact pathophysiology of adrenal hemorrhage in APLS is not fully elucidated. The most widely accepted hypothesis centers on the complex vasculature of the adrenal glands, which have a rich arterial supply and are fed by 3 arteries that divide into 50 to 60 branches. The change from artery to capillary plexus is abrupt, resulting in a “vascular dam.” The capillary plexus then drains into medullary sinusoids that eventually form the central vein. In addition to draining into 1 single vein, the musculature of the central vein is composed of longitudinal muscle bundles, creating a vulnerability to formation of platelet thrombi in areas of turbulent blood flow and stasis, which can develop when the muscles of the vein contract. These anatomic factors, in addition to the hypercoagulable state of patients with APLS, may explain the development of renal vein thrombosis, thereby leading to hemorrhagic infarction of the adrenal glands. A case study of 16 patients with adrenal hemorrhage and underlying APLS has suggested that patients surviving the acute phase of adrenal hemorrhage are likely to have favorable long-term outcomes.
It is interesting to note that although the inciting etiology is clearly different, the pathophysiology of adrenal insufficiency in APLS is similar to that noted with the Waterhouse-Friderichsen syndrome (WFS). WFS was originally characterized in the early 1900s as an acute hemorrhagic necrosis of the adrenal glands associated with meningococcemia but has been more recently associated with severe pneumococcal and staphylococcal infections and other infections as well. While WFS has historically been described in conjunction with bacterial infection, many now place the entity under the umbrella of thrombotic microangiopathy, thus likening it pathologically to APLS. Adrenal hemorrhage and resultant insufficiency in either case require immediate recognition and treatment to minimize associated morbidity and mortality.
- The differential diagnosis for acute abdominal pain is broad; relying on clinical findings and patient history is important, and there may be discordance between clinical symptoms and radiologic findings.
- Recognizing the clinical constellation of symptoms comprising acute adrenal insufficiency in a patient with APLS is essential, as evidence demonstrates favorable long-term outcomes if the acute phase of the illness is survived.
Case 2: Sulfadiazine-induced crystal nephropathy
Jing-Yu Pan, MD, ACP Member
A 49-year-old man with a history of AIDS, a last known CD4 cell count of 6 cells/µL, and a history of central nervous system (CNS) toxoplasmosis was admitted for evaluation of acute renal failure. He had been hospitalized 2 weeks earlier for altered mental status and was found to have a ring-enhancing lesion in the basal ganglia and positive toxoplasma serologies. He was treated for CNS toxoplasmosis with the standard regimen of pyrimethamine and sulfadiazine. The patient's altered mental status improved, and he was discharged from the hospital. Seven days after discharge, routine labs drawn at a follow-up visit were notable for an elevated creatinine concentration of 7.72 mg/dL.
Before the patient took sulfadiazine and pyrimethamine, his renal function was normal. Given his clinical history, his new kidney injury was most concerning for medication-induced renal failure. Urine microscopy revealed no cast but many red blood cells. Non-contrast CT of the abdomen and pelvis showed obstructing dense crystalline casts in both distal ureters with proximal ureteral dilatation. After a urologic consult, bilateral ureteral stents were urgently placed. Analysis of the sediment obtained during the procedure showed that the calculi were composed of a sulfadiazine metabolite. After the stents were placed, the patient's renal function rapidly normalized.
The prevalence of sulfadiazine-induced crystal nephropathy leading to acute renal failure ranges from less than 1% to 29%. Most case reports of this occurrence have been in patients with HIV/AIDS being treated for toxoplasmosis. Sulfadiazine is renally metabolized, and the excreted forms of the drug are weak acids that precipitate into crystals in tubular lumens when urine pH falls. These crystals can obstruct the collecting system and result in hydroureteronephrosis. Patients can be completely asymptomatic, or they may present with new-onset abdominal or flank pain. Factors that predispose patients to this condition include severe volume depletion, excessive drug dosing for corresponding glomerular filtration rate, and metabolic derangements that drastically affect urinary pH. Microscopic examination of the urine may reveal red blood cells mixed with crystals resembling “shocks of wheat.”
Treatment for sulfadiazine-induced crystal nephropathy should target relieving the obstruction, and ureteral catheterization or nephrostomy tube placement may be necessary to relieve the obstructed collecting system. Withdrawal of sulfadiazine and aggressive fluid resuscitation are also standard therapies; usual vigilance to monitor for postobstructive dieresis is also warranted. Dialysis to remove remaining sulfadiazine from the bloodstream may also be considered. Treatment of toxoplasmosis can continue with trimethoprim-sulfamethoxazole if not otherwise contraindicated; however, if sulfadiazine must be resumed, concurrent therapy to alkalinize the urine is required, and the patient must take special care to stay adequately hydrated.
- If new-onset acute kidney injury occurs in a patient taking sulfadiazine, the urine sediment should be closely examined for sulfadiazine crystals to investigate the possibility of crystal nephropathy.
- When discharging patients with sulfadiazine treatment, physicians should warn them to stay well hydrated to avoid crystalluria.
Case 3: Considering a low anion gap
Lawrence Haber, MD
A 59-year-old man without significant medical history presented with 5 days of increasing fatigue and mild confusion. The patient took no prescription or over-the-counter medications and reported no tobacco, drug, or excessive alcohol use. The physical examination was unrevealing except for low-grade tachycardia and lethargy. Laboratory studies revealed a serum calcium level of 13.9 mg/dL, an albumin level of 4.1 g/dL, a creatinine concentration of 1.78 mg/dL, and an anion gap of 3 mmol/L. The patient received vigorous IV hydration with normalization of both his calcium and creatinine, but the low anion gap persisted. On further evaluation, serum protein electrophoresis revealed an M-component and a bone survey demonstrated diffuse lytic lesions of the skull and axial skeleton. After immunofixation and bone marrow biopsy, IgG multiple myeloma was diagnosed. The patient received a dose of IV bisphosphonate before discharge and was scheduled for follow-up in the hematology clinic to discuss treatment options for his myeloma.
This patient presented with symptomatic hypercalcemia secondary to newly diagnosed multiple myeloma. While derangements from his initial chemistry panel resolved with hydration, the etiology of the hypercalcemia remained unclear. The differential diagnosis of hypercalcemia may be broad but is narrowed when examined in conjunction with a low anion gap.
Most hospital-based clinicians are familiar with the evaluation of an elevated anion gap but less familiar or comfortable with the approach to an abnormally low anion gap. The most common cause of a decreased anion gap is laboratory error, since the anion gap is a calculated value dependent on 3 to 4 measured variables; errors in assay of any of these variables can disrupt the true value. Once the value has been confirmed, we often look for a decrease in unmeasured serum anions. Albumin is the most common negatively charged protein in serum and constitutes the bulk of a normal anion gap. A decrease in serum albumin can thus lead to a decrease in the anion gap. The true anion gap can be approximated by adding 2.3 mmol/L to the anion gap for each 1 g/dL below a normal albumin of 4 g/dL.
If hypoalbuminemia does not exist, the next step is to investigate the possibility of an increase in unmeasured cations. These cations may be electrolytes not included in the anion gap calculation, such as potassium, magnesium, calcium, or lithium. Unmeasured cations may also arise, however, in the form of positively charged abnormal serum proteins from monoclonal (such as multiple myeloma) or polyclonal (such as HIV immune dysregulation or chronic inflammatory states) gammopathies, although not all abnormal serum proteins will be positively or negatively charged at physiologic pH. Finally, laboratory assay limitations should be accounted for, including serum sodium underestimation in severe hypernatremia or chloride overestimation in cases of halide ion intoxication.
- The limited differential diagnosis of a low anion gap is useful to hospital-based physicians, as it may reveal unrecognized disorders.
- The anion gap must be corrected for the albumin level to ensure an accurate result.
Case 4: Fulminant Burkitt's lymphoma: Splenic rupture, lactic acidosis, and tumor lysis syndrome
Margarita Sotelo, MD
A 65-year-old man with atrial fibrillation (AF), chronic obstructive pulmonary disease (COPD), type 2 diabetes mellitus, congestive heart failure (CHF), and stage 3 chronic kidney disease presented to the hospital with 3 weeks of abdominal distention and pain. He described early satiety, nausea, weight gain, fatigue, dyspnea, cough, and wheezes. He had no fevers or night sweats. He recalled no abdominal trauma. Vital signs on presentation were within normal limits. The physical examination was notable for diffuse wheezes in both lungs. His abdomen was distended, with normal bowel sounds and diffuse mild tenderness. Laboratory examination revealed the following: a normal complete blood count, liver function tests, and albumin; HIV-1 antibody negative; venous blood gas with pH 7.37 and pCO2 40 mm Hg; elevated anion gap of 22; and abnormal coagulation studies with an international normalized ratio of 2.4 (on warfarin) and a partial thromboplastin time of 36.8 seconds. CT of the abdomen and pelvis with IV contrast demonstrated a possible 3-cm splenic laceration with surrounding hematoma without extravasation, as well as moderate ascites.
The patient was admitted to the general surgery service with a diagnosis of splenic laceration. Serial hemoglobin levels and abdominal examination were stable. The serum lactic acid level continued to rise despite aggressive IV fluid resuscitation (see Table for subsequent laboratory values). He developed a rapid ventricular rate associated with his known AF, but no hemodynamic instability or hypoxia. Aggressive IV fluid administration resulted in an exacerbation of his CHF, and he was successfully diuresed. Treatment with prednisone for presumed COPD exacerbation was also initiated, and he was transferred to the medicine service on hospital day 9 for further evaluation of persistent lactic acidosis (LA).
Subsequently available ascites cytology revealed a high-grade lymphoma, and rasburicase was started on hospital day 15 for tumor lysis syndrome (TLS). On hospital day 17, the patient was transferred to the ICU because of hypotension and altered mental status. He transiently improved with intubation, fluids, hemodialysis, vasopressors, broad-spectrum antibiotics, and stress-dose steroids, but his hemodynamic instability persisted. After ongoing discussion with the patient's family, the decision was made to pursue comfort measures, given his poor prognosis. He died 24 days after presentation. His lab values are below.
This case describes a fulminant presentation of sporadic Burkitt's lymphoma, a highly aggressive type of non-Hodgkin's lymphoma. It involves translocations in the MYC oncogene that result in a proliferation index of nearly 100%. There is a high propensity for TLS, which can be precipitated by corticosteroids. This reflects the extreme chemosensitivity and high-grade nature of Burkitt's lymphoma. Tumor lysis syndrome arises from rapid cellular proliferation and turnover causing release of intracellular metabolites. Resultant hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia can yield renal failure, cardiac arrhythmias, seizures, or death. Tumor burden, proliferative rate, and treatment sensitivity are all risk factors for TLS. Lactate dehydrogenase is a marker for high rate of proliferation and of TLS. High-grade lymphomas, acute leukemias, and rapidly proliferating tumors are traditionally associated with the greatest risk. Renal failure, volume depletion, hypotension, and acidic urine also increase risk by reducing clearance of metabolites.
The patient's splenic abnormality most likely represents primary splenic involvement with Burkitt's lymphoma. In a review of 845 cases of atraumatic splenic rupture, the most common types were neoplastic, infectious, inflammatory, and drug-related. Additionally, the patient's elevated lactic acid reflected his poor prognosis since lactic acidosis is a rare complication of hematologic malignancies and appears to be an indicator of reduced survival.
- In patients with known or suspected malignancy and risk factors for the development of tumor lysis syndrome, it is important to implement preventive measures to mitigate harm.
- Unexplained lactic acidosis can be a manifestation of hematologic malignancy, either alone or in combination with TLS, and portends a poor prognosis in such cases.
Case 5: Lepromatous leprosy
Jack Chase, MD
A 34-year-old man was sent by his primary care clinician to the San Francisco General Hospital dermatology clinic for a progressive rash. The patient, originally from the Philippines, had developed a puffy, darkened area of skin near his right sideburn followed by a similar lesion on his left forearm approximately 1 year before immigrating to the United States. After settling in the San Francisco Bay Area, he developed additional generalized lesions over his trunk, arms and legs. He reported no systemic symptoms. He lived with his wife and reported no illicit substance use, and his only medical history was a work-related laceration repaired with skin sutures 10 years ago.
On examination, the patient was afebrile with normal vital signs and appeared well. He had a generalized eruption of spongy, raised dermal nodules over his trunk, arms, and legs in addition to the index lesion on his face.
The lesions were slightly darker than his underlying skin tone, non-blanching, and completely anesthetic to touch and to pinprick. The remainder of his physical examination was normal, as were laboratory studies, which included complete blood count, metabolic panel, antinuclear antibodies, rapid plasma reagin, and antibodies to HIV. A punch biopsy was performed of a lesion on the left forearm.
The Fite stain of the punch biopsy demonstrated a large number of acid-fast bacilli per high-power field.
The diagnosis in this case is multibacillary lepromatous leprosy. Leprosy, also called Hansen's disease, is a chronic mycobacterial infection with worldwide prevalence, most prominently in Southeast Asia. Leprosy is characterized by 1 or more skin lesions with sensory loss and may include peripheral neuropathy with nerve thickening, often involving the ulnar, posterior tibial, common peroneal, and great auricular nerves. Extremity neuropathy can lead to secondary traumatic and infectious complications, ultimately causing deformity or amputation. Patients with advanced disease may demonstrate “leonine” facies, or prominent thickening of the skin, eyebrow alopecia, and nasal cartilage destruction. The precise method of transmission has not been discovered. Mycobacterium leprae are found in high concentration in nasal secretions, and respiratory transmission is favored. Humans and armadillos are the only known reservoirs of M. leprae in the world.
The diagnosis of leprosy is confirmed by skin-punch biopsy or slit-skin smears, evaluated with staining for acid-fast bacilli. Two classifications exist: Ridley-Jopling (clinical exam and testing) and World Health Organization (exam only). Multidrug treatment and duration are based on classification: dapsone and rifampicin for paucibacillary/tuberculoid disease (lower mycobacterial burden), with the addition of clofazimine for multibacillary/lepromatous disease.
Historically, social stigma due to physical deformity and fear of transmission led to quarantine of affected individuals. In 2003, the World Health Organization enacted a “final push strategy” for leprosy elimination via clinical decision support, improved access to diagnostic methods and multidrug therapy in low-resource communities, and combated social stigma to promote recognition and treatment. Since 2004, the worldwide yearly rate of new leprosy cases has decreased by 50%.
- Leprosy, also known as Hansen's disease, is a chronic mycobacterial disease causing insensate skin lesions and peripheral neuropathy. It can yield severe disability due to neuropathic injury when untreated.
- Prevalent worldwide, Hansen's disease is highly treatable, and standardized multidrug treatment regimens are available and subsidized by the World Health Organization in low-resource settings as part of its disease elimination program.