Cases from the Seattle VA Hospital and the University of Washington

Cholangitis, tenofovir-induced Fanconi syndrome, and more.

Case 1: High-output heart failure and Graves' disease

Sandra Demars, MD, ACP Member, and Luis Tulloch, MD

The patient

A 59-year-old man presented with a 1-month history of intermittent palpitations, angina, dyspnea, and orthopnea. His only medication was atenolol for hypertension. On physical examination, the patient's resting pulse had increased from a baseline in the 60s to approximately 100 beats/min. He had a mild intention tremor, mild bilateral proptosis, and bilateral carotid bruits. Also noted were a 2/6 systolic murmur at the left upper sternal border, jugular venous distention to 12 cm, 2+ pitting edema to the thighs bilaterally, and warm peripheries. Neither hyperreflexia nor palpable thyromegaly were appreciated. Brain natriuretic peptide (BNP) level was mildly elevated, and cardiac enzymes were normal.

Electrocardiography (EKG) did not reveal ischemic changes, and a chest radiograph demonstrated cephalization of the pulmonary vasculature but no cardiomegaly. Transthoracic echocardiography demonstrated a hyperdynamic left ventricle, increased aortic jet velocity, increased cardiac output, and mild pulmonary hypertension. Subsequently available testing revealed an undetectable thyroid-stimulating hormone (TSH) level. Levels of free T4 and T3 were significantly elevated at 8.1 ng/dL (reference range, 0.8 to 2.7 ng/dL) and 11.2 pg/mL (reference range, 2.3 to 4.2 pg/mL), respectively. Thyroid-stimulating immunoglobulin was 459% (reference range, <140%), and the radioiodine thyroid uptake scan showed diffuse uptake consistent with Graves' disease. The patient's beta-blockade dose was increased, and he was diuresed and started on methimazole. Future plans were made for radioiodine thyroid ablation preceded by a course of corticosteroids in light of his Graves' ophthalmopathy.

The diagnosis

High-output heart failure is a relatively rare complication of thyrotoxicosis. In a large case series of patients presenting with thyrotoxicosis, only 6% had high-output heart failure. High-output heart failure is more common during pregnancy, in patients older than 60 years of age, and in patients with cardiac comorbid conditions or long-standing thyrotoxicosis. Thyrotoxicosis leads to significant circulatory and cardiac changes, including an increase in total blood volume, a decrease in systemic vascular resistance, and disproportionately compensatory increases in sino-atrial node activity and left ventricular contractility. The result is a hyperdynamic state with decreased contractile reserve. The combination of limited contractile reserve with any other insult such as continued increase in preload or a tachyarrhythmia results in high-output heart failure.

The diagnosis of high-output heart failure is made clinically in patients presenting with volume overload associated with warm peripheries and clinical or echocardiographic signs of cardiac hyperactivity. Patients with high-output heart failure caused by thyrotoxicosis may additionally present with thyromegaly, sinus tachycardia or a tachyarrhythmia (most commonly atrial fibrillation), hyperreflexia, and ophthalmopathy (in the case of Graves' disease). The mainstay of therapy for high-output heart failure in these patients is prompt mitigation of thyrotoxicosis, achieved via antithyroid drug therapy and radioiodine ablation.

Methimazole or propylthiouracil results in a rapid reduction of circulating T3 and T4, and the use of these drugs for 1 to 2 months before radioiodine ablation averts the thyroiditis caused by a therapeutic dose of radioiodine. In patients with no contraindications, beta-blockers may be used to alleviate the symptoms and signs of hyperthyroidism. Although propranolol has antithyroid effects at high doses (>160 mg/d), atenolol is preferred due to its beta-1 selectivity and once-daily dosing. Diuretics may be used to treat volume overload, but they must be used judiciously in the context of decreased systemic vascular resistance. High-output heart failure usually resolves completely after resolution of thyrotoxicosis.


  • Consider high-output heart failure in the differential of hyperthyroid patients presenting with volume overload along with warm peripheries and signs of cardiac hyperactivity.
  • Prompt resolution of the underlying condition is the mainstay of treatment for high-output heart failure.

Case 2: Delirium due to primary adrenal insufficiency

Janelle Shin, MD, and Karen Foster-Schubert, MD

The patient

A 61-year-old man with a history of hypothyroidism, hypertension, depression, atrial fibrillation, and recently diagnosed deep venous thrombosis/pulmonary embolism who was receiving anticoagulation presented to his primary care physician with confusion, fatigue, hypotension, and a 20-pound weight loss. According to his wife, the patient had worked as a truck driver until a few months ago, but progressive fatigue, poor appetite, abdominal pain, nausea with emesis, and dizziness necessitated a job change. His vital signs were as follows: temperature, 96.7°F; blood pressure, 88/55 mm Hg; pulse, 55 beats/min; and respiratory rate, 16 breaths/min.

On physical examination at admission, the patient was confused, unable to provide a history, and showed generalized weakness, unsteady gait, and orthostasis. His skin and mucosa did not exhibit hyperpigmentation. Laboratory findings revealed hyperkalemia (potassium level, 5.2 mEq/L), hyponatremia (sodium level, 126 mEq/L), and acute renal insufficiency (creatinine level, 1.9 mg/dL). All other labs were unremarkable. Abdominal CT and MRI showed bilateral adrenal nodules consistent with lipid-rich adenomas. No definitive diagnosis was made over a prolonged hospitalization that was complicated by health care-associated pneumonia with empyema. Despite treatment for infection, the patient continued to have progressive delirium with visual hallucinations.

The cause of the patient's delirium remained elusive until adrenocorticotropic hormone stimulation testing revealed a prestimulation cortisol level of 0.3 μg/dL (reference range, 6.2 to 19.4 µg/dL) and a poststimulation cortisol level of 0.2 µg/dL. Primary adrenal insufficiency was diagnosed, and the patient was started on hydrocortisone. Within 1 week, his mental status improved significantly to near baseline. He was discharged home on replacement glucocorticoid therapy.

The diagnosis

This patient's delirium was thought to be the result of adrenal insufficiency, which often presents with nonspecific symptoms including fatigue, depression, poor appetite, and weight loss. In many cases, characteristic hyperpigmentation or significant laboratory abnormalities may not be present. The diagnosis of adrenal insufficiency may be delayed until an acute illness precipitates an adrenal crisis that may be accompanied by fevers, dehydration, and continued clinical decline. Despite volume replacement, without specific treatment, progressive mental deterioration and refractory hypotension may ensue.

To our knowledge, only a small number of cases of delirium concurrent with adrenal insufficiency have been reported. In nearly all cases, the initial diagnosis was inconclusive due to nonspecific symptoms, resulting in extended hospitalization. In our case, the lack of response to other treatments and the presence of hypotension, hyponatremia, and delirium prompted testing for adrenal insufficiency. In all cases, administration of hydrocortisone dramatically improved the delirium and other symptoms within a few days.


  • Although adrenal insufficiency is a rare cause of delirium, it should be considered when delirium persists after more common causes have been addressed.
  • When delirium occurs in the setting of adrenal insufficiency, glucocorticoid replacement can provide a rapid and dramatic improvement in mentation.

Case 3: Cholangitis in a young man with familial adenomatous polyposis

Adam Johnson, MD

The patient

A 36-year-old man with a history of familial adenomatous polyposis (FAP) presented to the ED with a 6-hour history of acute-onset right upper quadrant pain, nausea, vomiting, fever up to 102°F, and chills. He had had an uncomplicated prophylactic colectomy at age 28 for FAP. At age 32, an ampullary adenoma was resected by endoscopic retrograde cholangiopancreatography (ERCP); screening endoscopic ultrasonography performed 2 weeks before the current presentation revealed a 2.5-cm mass in the distal common bile duct, concerning for recurrence. His only medication on presentation was the NSAID sulindac. As expected, he had a strong family history of FAP; his father had a colectomy at age 19.

On physical examination, the patient was febrile to 103°F, with a pulse of 113 beats/min and a blood pressure of 111/65 mm Hg, with normal respiratory rate and oxygen saturation. He was warm and diaphoretic and had dry mucous membranes. He was tachycardic. Abdominal examination revealed right upper quadrant and epigastric tenderness. Labs were notable for a doubling of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lipase levels. Total bilirubin level was elevated at 1.9 mg/dL. White blood count was normal. The patient was started on piperacillin-tazobactam and underwent an ERCP with common bile duct stent placement. He quickly defervesced and was discharged after a 3-day hospitalization to complete a 10-day course of antibiotics. He was scheduled for a pylorus-sparing pancreaticoduodenectomy (Whipple procedure), which was performed 2 weeks after discharge.

The diagnosis

The patient's presentation was consistent with cholangitis secondary to biliary obstruction by an ampullary adenoma. FAP is associated with a near 100% incidence of colorectal cancer by age 50 due to a mutation of the apc gene. This mutation is also associated with extracolonic manifestations of cancer, specifically including duodenal ampullary carcinoma. Incidence of ampullary adenomatosis in patients with FAP is close to 90% by age 70, and duodenal carcinomatosis develops in approximately 5% of FAP patients. Recommendation for surveillance versus surgical intervention is based on multiple criteria, including adenoma number, size, histology, and severity of dysplasia.


  • In a patient presenting with cholangitis and a history of FAP, consider ampullary adenomatosis as the mechanism of biliary obstruction.
  • Patients with FAP are at risk for duodenal carcinomatosis and should receive surgical intervention or screening endoscopies based on such criteria as adenoma number, size, histology, and dysplasia severity.

Case 4: Tenofovir-induced Fanconi syndrome

Thomas W. DeCato, MD, ACP Member

The patient

A 63-year-old man with a history of HIV disease (CD4 count, 193 cells/μL; viral load undetectable) presented with nausea and abdominal pain of 2 weeks' duration. He additionally reported a 2 month history of anorexia and fatigue. He was adherent to highly active antiretroviral therapy (efavirenz, emtricitabine, and tenofovir) in addition to trimethoprim/sulfamethoxazole prophylaxis. He had no history of opportunistic infections.

On presentation, vital signs were within normal limits. On physical examination, he appeared cachectic. Cardiovascular and pulmonary exam were unremarkable. He had normal bowel sounds and mild tenderness to palpation throughout his abdomen without rebound or guarding. The patient had no lymphadenopathy, rashes, or edema. Serum chemistries were notable for a sodium level of 122 mEq/L, a potassium level of 3.1 mEq/L, a chloride level of 88 mEq/L, a bicarbonate level of 19 mEq/L, a blood urea nitrogen level of 12 mg/dL, a creatinine level of 0.74 mg/dL, and a glucose level of 113 mg/dL. Lactate, calcium, and magnesium levels were within normal limits, but phosphate level was critically low at 0.7 mg/dL. Urinalysis revealed significant glucosuria.

The findings of severe hypophosphatemia, hypokalemia, and metabolic acidosis suggested proximal tubular renal dysfunction, most likely related to tenofovir. This medication was discontinued, and the patient's combination antiretroviral therapy was modified. Potassium and phosphate were repleted. All electrolytes had normalized before discharge without scheduled repletion except for phosphate, which subsequently normalized in the month after discharge.

The diagnosis

This patient was diagnosed with tenofovir-induced Fanconi syndrome. Fanconi syndrome is a generalized transport defect of the proximal renal tubules. The cardinal features include hypophosphatemia, glucosuria with normal serum glucose levels, and generalized wasting of amino acids and low-molecular-weight proteins. Other common findings are metabolic acidosis from bicarbonate wasting, hypokalemia, hyponatremia, and hypouricemia. Fanconi syndrome can be hereditary or acquired. Acquired Fanconi syndrome is most commonly the result of drug toxicity. Platinum-containing and alkalating agents, aminoglycosides, valproic acid, and many antiviral drugs have all been linked to Fanconi syndrome.

While the incidence of Fanconi syndrome is low (<1%) in patients taking tenofovir, proximal tubule dysfunction can develop months or years after treatment initiation. Patients may complain of polyuria, bone pain, or proximal muscle weakness. The diagnosis is made primarily by the constellation of laboratory findings consistent with proximal tubular dysfunction. Treatment consists of removal of the offending agent and correction of electrolyte disturbances. Recovery of proximal tubular function can take weeks to months.


  • Fanconi syndrome is characterized by glucosuria in the absence of hyperglycemia, hypophosphatemia, metabolic acidosis, hypokalemia, and hyponatremia.
  • Treatment of medication-related acquired Fanconi syndrome consists of stopping the offending agent with concurrent electrolyte replacement; recovery can take months and may ultimately be incomplete.

Case 5: Fever and diarrhea in an immunosuppressed host

Peter Hunt, MD, ACP Member

The patient

A 55-year-old man with a history of dual kidney/liver transplant due to polycystic kidney and liver disease 8 years previously presented with profuse, frequent, nonbloody watery diarrhea and fever. The patient had been in the Philippines for 2 months and developed diarrhea 4 weeks after returning. He remained adherent with his daily tacrolimus, mycophenolate, and prednisone (5 mg) for the entirety of his trip. During his trip, he was treated for presumed pneumonia with a 2-week course of an unknown antibiotic by a local doctor. He reported drinking only bottled or boiled tap water.

On presentation, he was febrile to 103°F, tachycardic, and normotensive. Laboratory testing revealed a polymorphonuclear neutrophil-predominant leukocytosis without eosinophilia. Chemistry panel was notable for a CO2 of 18, a creatinine level slightly above baseline at 1.3 mg/dL, and a sodium level of 131 mEq/L. Stool studies were obtained, and IV hydration and empiric ciprofloxacin were started. Clostridium difficile testing was negative. Stool culture grew nontyphoid Salmonella sensitive to ciprofloxacin. The patient's symptoms resolved within 48 hours, and he was discharged to complete a course of antibiotics. Blood cultures remained negative, but 2 days after discharge, stool ova and parasite tests were positive for Strongyloides stercoralis; the patient was contacted, and a course of ivermectin was prescribed.

The diagnosis

This immunocompromised traveler was diagnosed with infectious diarrhea, with stool cultures positive for both nontyphoid Salmonella and Strongyloides stercoralis. Infectious diarrhea in the immunocompromised host has a broad differential including bacteria, parasites, viruses, and fungi. C. difficile is the most common bacterial cause of diarrhea in the immunocompromised. Immunosuppressed patients, including solid organ transplant recipients, are at increased risk of Salmonella bacteremia from a gastrointestinal source. Our patient's symptoms resolved with treatment for Salmonella, and it is presumed this infection was acquired locally. His Strongyloides infection was an asymptomatic infection presumed to have been acquired abroad. Immunosuppressed patients with Strongyloides are at increased risk for hyperinfection syndrome with dissemination of larvae into multiple organ systems including heart, lung, and the central nervous system. Therefore, immunosuppressed patients with exposure risk should be tested and treated for Strongyloides, even if they are asymptomatic.


  • Immunosuppressed patients with likely infectious diarrhea are at increased risk for bacteremia and should be treated empirically while cultures are pending.
  • Strongyloides in the immunosuppressed host should be treated even if the patient is asymptomatic, given the increased risk of hyperinfection syndrome.

Case 6: Pericarditis in a dialysis patient

Anila Finnegan, MD

The patient

A 69-year-old man with end-stage renal disease on hemodialysis was admitted for subjective fevers and severe intermittent chest pain of 10 days' duration. The patient reported pain in the mid-chest that increased with deep inspiration and was worse in a supine position. He reported missing 2 sessions of hemodialysis within the previous 2 weeks.

Cardiac examination was remarkable for jugular venous distension, peripheral edema, and distant heart sounds with no murmur or friction rub. EKG demonstrated nonspecific ST-segment changes in the inferior leads. Laboratory results were significant for a blood urea nitrogen level of 85 mg/dL and a creatinine level of 14 mg/dL, elevated from baseline values of 50 mg/dL and 10 mg/dL, respectively. Echocardiography revealed a normal ejection fraction and moderate-sized pericardial effusion without tamponade; the effusion was noted to be stable in size compared to an echocardiogram 1 month prior. The patient was treated with daily hemodialysis sessions for 1 week, but his symptoms did not resolve. He was then started on colchicine (dose-adjusted for end-stage renal disease), after which his symptoms improved within 2 days and he was discharged home.

The diagnosis

This patient was given a presumptive diagnosis of dialysis-associated pericarditis on the basis of noted physical findings and the onset of symptoms following missed dialysis sessions. The cause of dialysis-associated pericarditis is widely believed to be inflammation caused by the accumulation of toxic metabolites in the setting of inadequate hemodialysis. It often presents without the classic diffuse ST elevations on EKG classically seen in pericarditis.

The management of dialysis-associated pericarditis differs from the management of other forms of pericarditis in that symptoms may resolve with adequate hemodialysis alone in up to two-thirds of cases. Treatment with steroids may be associated with significant adverse effects and an increased rate of recurrence. The use of NSAIDs has not been shown to be effective in achieving resolution of symptoms. Although not well studied in the management of dialysis-associated pericarditis, colchicine has been shown to be an effective treatment for acute pericarditis in patients without severe renal dysfunction. In this setting, colchicine has been associated with rapid resolution of symptoms (persistence of symptoms at 72 hours in 19.2% of patients treated with colchicine vs. 40% of patients receiving a placebo) and with decreased rates of recurrence. Colchicine may be effective in the treatment of dialysis-associated pericarditis when symptoms are not resolved with hemodialysis alone.


  • The standard treatment of dialysis-associated pericarditis is initiation of daily hemodialysis, which is associated with resolution in up to two-thirds of cases.
  • NSAIDs and steroids have not been shown to be effective in treatment of dialysis-associated pericarditis, and renally dosed colchicine may prove to be an important therapeutic alternative.