Cases from the Medical College of Wisconsin

Cases of pheochromocytoma, Kikuchi-Fujimoto disease, and more.


Case 1: Pheochromocytoma

By Karen Thompson, MD; Christa Koeller, MS; and Yogita Segon, MD, ACP Member

The patient

A 68-year-old man presented to the ED with a home systolic blood pressure of approximately 280 mm Hg. In the ED, he reported headaches, vomiting, and chest pressure. His blood pressure was 230/148 mm Hg.

Four weeks prior, he had presented to another ED with headaches, diaphoresis, chest heaviness, and a blood pressure of 230/148 mm Hg. He was admitted and treated with clonidine, metoprolol, and lisinopril. A renal Doppler ultrasound had shown no renal artery stenosis, and thyroid function testing was normal. His blood pressure improved and he was discharged home. Renin/angiotensin levels, plasma free metanephrine level, and 24-hour urine metanephrine level were pending at the time of that discharge. Several days later, his plasma free metanephrine level was found to have been 1,744 pg/mL (reference range, 0 to 145 pg/mL). He was then referred to the endocrine clinic. His 24-hour urine metanephrine level came back as 4,331 μg/L (reference range, 82 to 500 μg/L).

Figure 1 MRI of the abdomen with contrast showing a 28-cm right adrenal lesion consistent with pheochromocytoma
Figure 1. MRI of the abdomen with contrast showing a 2.8-cm right adrenal lesion, consistent with pheochromocytoma.

His current visit to the ED was one day prior to a scheduled endocrine outpatient visit. He was admitted to the ICU and started on a nicardipine drip. MRI of the abdomen and pelvis revealed a 2.8-cm right adrenal lesion, which was suspicious for a pheochromocytoma (Figure 1). He was then started on doxazosin. After his blood pressure was controlled, he was discharged home with a plan to start atenolol as an outpatient and follow up with endocrine surgery in three to four weeks.

The diagnosis

The diagnosis is pheochromocytoma, a rare catecholamine-secreting tumor derived from chromaffin cells of the adrenal medulla. The prevalence is about 0.1% in patients with hypertension. In about 70% of diagnosed patients, these tumors are sporadic, with the rest being related to genetic syndromes. The clinical presentation can be highly variable; however, the classic triad of periodic episodes of headaches, diaphoresis, and tachycardia is seen in fewer than 50% of patients. Hypertension is a dominant sign and can be either episodic or sustained. Other associated symptoms are nausea, vomiting, abdominal pain, anxiety, panic attacks, and polyuria.

Catecholamine crisis can lead to heart failure, pulmonary edema, arrhythmias, and intracranial hemorrhage. Initial testing should include measurement of plasma free metanephrine or 24-hour urine metanephrine. Plasma free metanephrine has a sensitivity of 96% to 100% and a specificity of 85% to 89%. Urine metanephrine has a 98% specificity and a sensitivity of up to 97%. When clinical suspicion is high, plasma free metanephrine is the preferred test due to high sensitivity; when clinical suspicion is low, urine fractionated metanephrine is likely a better test given its high specificity. In patients with both clinical suspicion and metanephrine values at least three times greater than the upper limit of normal, the diagnosis of pheochromocytoma is highly likely.

Imaging modalities for identifying the tumor include CT, MRI, or metaiodobenzylguanidine (MIBG) scintigraphy. MRI is optimal for detecting pheochromocytomas and is somewhat better than CT for identifying extra-adrenal pheochromocytomas and paragangliomas. MIBG scintigraphy is useful in hereditary syndromes and malignant pheochromocytomas.

Treatment requires resection of the tumor. It is essential to start preoperative alpha-receptor blockage (e.g., phenoxybenzamine, doxazosin) about two weeks before surgery to prevent hypertensive crisis during surgery. Because patients are volume-constricted, liberal salt intake and hydration are necessary to avoid severe orthostasis. A beta-blocker should be added once alpha blockage is achieved to manage reflex tachycardia.

About 90% of pheochromocytomas and paragangliomas are benign. Since metastasis can occur decades after initial diagnosis, patients should undergo annual biochemical screening.

Pearls

  • When clinical suspicion for pheochromocytoma is high, plasma free metanephrine should be tested (high sensitivity); when suspicion is low, urine fractionated metanephrine (high specificity) is a better option.
  • In patients with pheochromocytoma, it is essential to start preoperative alpha-receptor blockage about two weeks before surgery to prevent hypertensive crisis during surgery.

Case 2: Kikuchi-Fujimoto disease

By Pinky Jha, MD, FACP; Samantha Durbin, MD; and Sanjay Bhandari, MD, ACP Member

The patient

Figure 2 Maculopapular rash over the abdomen
Figure 2. Maculopapular rash over the abdomen.

A 54-year-old woman with a history of hypertension and chronic kidney disease presented with fevers, chills, generalized weakness, headache, nausea, diarrhea, dizziness, and painful neck swelling for three to four weeks. She had developed a generalized pruritic skin rash about one week prior. On admission, she was in mild distress due to pruritus and afebrile, with tender lymphadenopathy throughout the right side of her neck, a diffuse maculopapular rash over the torso and extremities (Figure 2), and right upper quadrant tenderness.

Laboratory tests showed an elevated creatinine level of 2.14 mg/dL (patient baseline, 1.6 to 1.8 mg/dL; reference range, 1.1 to 1.3 mg/dL), white blood cell count of 1.7 × 106 cells/L (reference range, 4.4 to 5.9 × 106 cells/L), erythrocyte sedimentation rate of 65 mm/h (reference range, 0 to 40 mm/h), aspartate aminotransferase level of 105 U/L (reference range, 13 to 44 U/L), alanine aminotransferase level of 75 U/L (reference range, 8 to 66 U/L), and lipase level of 65 unit/L (reference range, 13 to 60 unit/L ).

A CT scan of the abdomen and pelvis showed multiple enlarged retroperitoneal and pelvic lymph nodes, a 1.9-cm cystic lesion in the right adnexa, and multiple bilateral lobar hepatic cysts. She was started on supportive care with IV hydration and antipruritic agents. An extensive workup for infectious and autoimmune processes, including tuberculosis, Epstein-Barr virus, cytomegalovirus, herpes simplex virus (HSV), HIV, toxoplasmosis, and syphilis, was completed. In addition, she was tested for systemic lupus erythematosus (SLE). The only positive results were IgG and IgM antibodies for HSV-1 and HSV-2. All other studies were negative or normal. A skin biopsy showed dermatitis consisting of lymphocytes and histiocytes with scattered necrotic keratinocytes. Cervical lymph node biopsy result showed necrotizing lymphadenitis. The patient was discharged home with supportive care.

The diagnosis

The diagnosis in this case is Kikuchi-Fujimoto disease (KFD), an idiopathic and self-limited cause of lymphadenitis. KFD, also known as histiocytic necrotizing lymphadenitis, was originally reported in 1972 in Japan. Patients present with localized lymphadenopathy, fever, and leukopenia in up to half of the cases.

The exact pathogenesis is unknown, but bacterial, viral, or autoimmune causes have been suggested in the literature. Epstein-Barr virus, human T-cell leukemia virus type 1, human herpesvirus type 6, B19 parvovirus, cytomegalovirus, Brucella, Yersinia enterocolitica, HSV, and parainfluenza virus have been implicated as infectious causes. An autoimmune mechanism has also been proposed because KFD is seen in conjunction with SLE. It usually runs a benign course and resolves in one to four months. Disease recurrence is unusual.

The most common presenting features are cervical lymphadenopathy, leukopenia, and fever. Lymph node biopsy is the confirmatory test. The characteristic histology of KFD is single or multiple areas within the lymph node that contain necrosis and histiocytic cellular infiltrate. The capsule of the node may be invaded, and perinodal inflammation is common. Cultures and stains for organisms are negative.

NSAIDs are the mainstay of treatment. Steroids are indicated for severe disease associated with SLE. Lymph node biopsy is crucial for diagnosis, especially because this disease can be mistaken for SLE, malignant lymphoma, lymph node tuberculosis, or, rarely, adenocarcinoma. Increased awareness of this disorder among clinicians and pathologists may help prevent misdiagnosis and inappropriate treatment.

Pearls

  • Kikuchi-Fujimoto disease is a benign and self-limited syndrome characterized by regional lymphadenopathy with tenderness, predominantly in the cervical region, usually accompanied by mild fever.
  • The diagnosis is confirmed by histopathological examination of an affected lymph node.

Case 3: Thyrotoxic periodic paralysis

By Pinky Jha, MD, FACP, and Samantha Durbin, MD

The patient

A 29-year-old Asian man with a one-year history of recurrent generalized muscle weakness presented to the ED reporting inability to move his upper and lower extremities. His symptoms had begun abruptly that morning, when he was unable to stand and exit a train due to lower-extremity weakness, which progressed to generalized weakness over the course of one hour. He reported palpitations, sharp chest pain, and mild shortness of breath associated with the weakness. Additionally, he reported a 20 to 30-lb weight loss over the past year. He reported three similar episodes of muscle weakness lasting several hours in the past year.

On physical exam, the patient's heart rate was 120 beats/min and blood pressure was 153/81 mm Hg. Cardiac exam revealed tachycardia with a regular rhythm and no murmurs. Examination of the lungs and abdomen was unremarkable. He had a diffusely enlarged, nontender, non-nodular thyroid, diminished deep tendon reflexes in both lower extremities with marked lower-extremity proximal muscle weakness and tremors, and marked truncal weakness with an inability to support a seated posture. He also had a pruritic-urticarial skin rash on his trunk and bilateral upper and lower extremities.

Routine chemistry, liver enzymes, and complete blood count were normal except for a potassium level of 1.9 mmol/L (reference range, 3.5 to 5 mmol/L) and a magnesium level of 1.2 mg/dL (reference range, 1.6 to 2.6 mg/dL). An electrocardiogram showed sinus tachycardia (126 beats/min). Two hours after initiation of IV potassium and magnesium replacement, the patient's neurologic symptoms resolved.

Follow-up studies were performed to determine the cause of the patient's hypokalemia. Urine sodium and potassium and serum aldosterone and renin levels were normal. Thyroid-stimulating hormone (TSH) level was markedly abnormal at 0.01 IU/mL (reference range, 0.3 to 5.5 IU/mL). Both triiodothyronine and thyroxine levels were elevated at 320 ng/dL (reference range, 65 to 164 ng/dL) and 3.81 ng/dL (reference range, 0.58 to 1.64 ng/dL), respectively, as were thyroid peroxidase antibody and TSH receptor antibody levels.

The patient was started on methimazole and propranolol. While in the hospital, the patient developed a pruritic skin rash consistent with acute urticaria, likely related to his autoimmune thyroid disease, which improved with diphenhydramine. He was discharged home with planned endocrinology follow-up.

The diagnosis

The patient was diagnosed with thyrotoxic periodic paralysis in the setting of Graves' disease. There are several types of periodic paralysis associated with metabolic and electrolyte abnormalities, and of these, hypokalemic periodic paralysis is the most common. This disorder is most commonly seen in Asian men ages 20 to 40 years and is characterized by episodic hypokalemia and diffuse paralysis. Hypokalemic periodic paralysis may be familial with autosomal dominant inheritance or may be acquired in patients with thyrotoxicosis. The condition primarily affects the lower extremities and is secondary to thyrotoxicosis.

Hypokalemia in thyrotoxic periodic paralysis is thought to occur as a result of thyroid hormone sensitization of the Na+/K+-ATPase and an intracellular potassium shift. Excess thyroid hormone activates beta-adrenergic receptors, which subsequently activate the Na/K-ATPase and cause a net intracellular potassium shift, resulting in muscle hyperpolarization and transient paralysis. Attacks may be provoked by stress, such as a viral illness or fatigue, or by certain medications such as beta-agonists, insulin, or steroids.

Treatment of thyrotoxic periodic paralysis includes prevention of potassium shifts via nonselective beta-blockade, careful repletion of potassium, and treatment of the underlying thyroid disease. Periodic paralysis can be life-threatening if not treated, but early diagnosis and rapid correction of potassium abnormalities can resolve the symptoms quickly and completely. A workup to rule out possible underlying causes is important to prevent the recurrence of paralysis.

Pearls

  • Thyrotoxic periodic paralysis is a rare disorder characterized by episodic hypokalemia and diffuse paralysis in a patient with thyrotoxicosis.
  • Attacks can be provoked by viral illness or medications such as beta-agonists, insulin, or steroids.

Case 4: Acute intermittent porphyria

By Cameron Malone, MD; Lucian Dorneanu, MD, ACP Resident/Fellow Member; Sanjay Bhandari, MD, ACP Member; Sushma Raju, MD; and Pinky Jha, MD, FACP

The patient

A 21-year-old female army recruit undergoing basic training was admitted to another facility with severe abdominal pain, nausea, and vomiting. Pertinent workup included an unremarkable abdominal CT, a sodium level of 116 mmol/L (reference range, 136 to 145 mmol/L), and a hemoglobin level of 17 g/dL (reference range, 11.3 to 15.1 g/dL). On hospital day 3, the patient developed severe chest pain associated with tachycardia (heart rate >120 beats/min), hypertension (180/90 mm Hg), and a mildly elevated troponin level (0.015 ng/mL; reference range, <0.010 ng/mL). The patient had an unremarkable transthoracic echo and CT angiogram of the chest. The patient was transferred to our facility for further management.

Upon arrival, she had a blood pressure of 173/85 mm Hg and a heart rate of 110 beats/min. Physical examination revealed diffuse abdominal tenderness and inability to sit up without support. The rest of the exam was unremarkable with no focal neurological deficits. Laboratory results were remarkable for a sodium level of 126 mmol/L and a hemoglobin level of 15.6 g/dL. Urinary studies were consistent with syndrome of inappropriate antidiuretic hormone secretion. Daily IV hemin infusions were started. Her symptoms, vitals, and labs gradually improved over five days. She was discharged with resolved symptoms. Laboratory results available after discharge showed urine porphobilinogen level of 30.6 mg/L (reference range, 0.0 to 2.0 mg/L), urine delta-aminolevulinic acid (ALA) level of 8.7 mg/24 hours (reference range, 0.5 to 5.1 mg/24 hours), and red blood cell porphobilinogen deaminase (PBGD) level of 3.7 Nm/s/L (reference range, ≥7 Nm/s/L).

The diagnosis

The diagnosis is acute intermittent porphyria (AIP), an inherited deficiency of the heme biosynthetic enzyme PBGD. AIP is rare, affecting around 1 in 75,000 people worldwide. Acute attacks are caused by a deficiency of PBGD, which leads to accumulation of porphobilinogen in the cytoplasm. Acute attacks are characterized by abdominal pain associated with autonomic, neurological, and psychiatric symptoms. Episodes can be precipitated by stress, medication, menstruation, or acute illness. Testing for suspected AIP includes a random urine porphobilinogen level. Urine ALA and porphyrin levels are also elevated in AIP. Decreased erythrocyte PBGD activity is seen in approximately 90% of patients, including during asymptomatic periods.

An elevated urine porphobilinogen level is suggestive of AIP and warrants treatment with hemin, but genetic testing is required for definitive diagnosis. Diagnosing AIP is difficult because the symptoms are variable and nonspecific; however, the condition should be considered as a differential diagnosis in the patient with unexplained abdominal pain.

Pearls

  • AIP should be considered as a differential diagnosis in an individual with unexplained neurovisceral symptoms.
  • Elevated urine porphobilinogen levels are sufficient to initiate treatment with hemin; treatment should not be delayed pending confirmatory testing.

Case 5: Nonuremic calciphylaxis

By Peter Cote, MD; Sushma Raju, MD; Sanjay Bhandari, MD, ACP Member; and Pinky Jha, MD, FACP

The patient

Figure 3 Right lateral lower extremity demonstrating nonuremic calciphylaxis
Figure 3. Right lateral lower extremity demonstrating nonuremic calciphylaxis.

A 59-year-old man with a history of sarcoidosis (treated with prednisone), pulmonary hypertension, stage 3 chronic kidney disease, type 2 diabetes, and nonischemic cardiomyopathy presented to the ED with a two-week history of bilateral leg swelling and pain. Physical examination revealed no fever, with normal blood pressure, mild tachycardia (heart rate, 90 to 100 beats/min), and bilateral pitting edema to the mid-thigh. The lower extremities were warm, erythematous, and tender with multiple, irregular shallow ulcers with a fibrinous base. The surrounding skin was black with ill-defined, 1- to 3-cm dusky patches and indurated subcutaneous nodules (Figure 3). Dark-brown plaques and deeper calcaneal ulcers were observed on both feet. Neurovascular examination of the lower extremities was normal.

Laboratory results were notable for a white blood cell count of 17 × 106 cells/L (reference range, 4.4 to 5.9 × 106 cells/L), a blood urea nitrogen level of 70 mg/dL (reference range, 6 to 23 mg/dL), a creatinine level of 2.7 mg/dL (patient's baseline, 0.9 to 1.2 mg/dL; reference range, 0.70 to 1.30 mg/dL), normal calcium and phosphorus levels, a parathyroid hormone level of 99 pg/mL (reference range, 15 to 72 pg/mL), and a 25-hydroxyvitamin D level of 20 ng/mL (reference range, 30 to 100 ng/mL). Infectious workup and vasculitis serologies were negative. Punch biopsy was remarkable for occlusive fibrin clots and calcium vessel deposition with minimal vessel occlusion on von Kossa stain. The patient was treated with sodium thiosulfate, which resulted in mild improvement. He has since had frequent soft-tissue infections leading to recurrent hospitalizations.

The diagnosis

The diagnosis is nonuremic calciphylaxis, also known as calcific uremic arteriolopathy. It is an infrequent phenomenon that occurs in end-stage renal disease and after renal transplantation.

When calciphylaxis presents in patients without kidney disease and earlier stages of chronic kidney disease, it is termed nonuremic calciphylaxis. The pathophysiology behind calciphylaxis remains unclear. The most widely accepted theory involves arteriolar calcification and thrombosis, leading to necrosis of the overlying skin tissue. Early presentation involves painful plaques, purpura, and subcutaneous nodules, often with violaceous discoloration. Lesions progress to become necrotic ulcerations with eschar formation and subsequent infection. Risk factors include long-term use of warfarin or glucocorticoids, female sex, hyperparathyroidism, malignancy, and alcoholic liver disease. Diagnosis is made with biopsy showing septal panniculitis as well as calcification, microthrombosis, and fibrointimal hyperplasia of dermal arterioles. Von Kossa and Alizarin Red stains increase the possibility of calcium detection. Laboratory evaluation should include a workup for hyperparathyroidism, kidney disease, liver disease, inflammatory disease, and hypercoagulable states.

There is currently no approved treatment for calciphylaxis. However, sodium thiosulfate three to four times weekly (tailored to renal function) and surgical debridement represent the current standard of care. Sodium thiosulfate has antioxidant and vasodilatory properties and can halt the ability of adipocytes to induce calcification of vascular smooth-muscle cells. Little data exist to guide duration of therapy. Patients with nonuremic calciphylaxis have a one-year mortality rate of 25% to 45%, whereas patients with calcific uremic arteriolopathy have a rate of 45% to 80%. A common cause of death is sepsis from superinfection of nonhealing ulcers.

Pearls

  • Nonuremic calciphylaxis refers to calciphylaxis in a patient without end-stage renal disease and is histologically similar to calcific uremic arteriolopathy.
  • Nonuremic calciphylaxis is associated with primary hyperparathyroidism, connective tissue disease, chronic kidney disease, and steroid and warfarin use.

Other cases in this issue