Cases from St. Joseph Mercy Ann Arbor

Amyloid cardiomyopathy, Haemophilus influenzae infection, metastatic melanoma and more.


Case 1: Amyloid cardiomyopathy and thromboembolism

By Sindhu Avula, MD, ACP Resident/Fellow Member; Bathmapriya Balakrishnan, MD, ACP Resident/Fellow Member; and Richard Shellenberger, DO, FACP

The patient

less-thanbgreater-thanFigure 1less-thanslashbgreater-than Endomyocardial biopsy with Congo red stain Areas of red arrow are suggestive of amyloid deposits Image courtesy of the case authors
Figure 1. Endomyocardial biopsy with Congo red stain. Areas of red (arrow) are suggestive of amyloid deposits. Image courtesy of the case authors.

A healthy 65-year-old woman presented with a six-month history of slowly progressive symptoms of congestive heart failure. On presentation, she was afebrile, with a heart rate of 94 beats/min and a blood pressure of 94/62 mm Hg. On examination, she was noted to have 2+ pitting edema to the knees bilaterally and a S4 gallop on cardiac auscultation. Her laboratory evaluation was concerning for an elevated B-type natriuretic peptide (BNP) level of 388 pg/mL. Electrocardiogram (EKG) showed sinus rhythm, right bundle-branch block, and low-voltage complexes in both the limb and precordial leads. Transthoracic echocardiogram (TTE) demonstrated bi-atrial enlargement and biventricular thickening suggestive of an infiltrative cardiomyopathy. A subsequent cardiac MRI revealed late gadolinium enhancement of both ventricles. Additional testing revealed increased serum free light chains with kappa free light chains of 1.04 mg/dL, lambda free lights of 18.10 mg/dL, and a kappa lambda ratio of 0.06 (normal ratio, 0.26 to 1.65). Fat pad and bone marrow biopsies were inconclusive. Endomyocardial biopsy (Figure 1) was consistent with amyloid light-chain (AL) amyloidosis on protein mass spectrometry.

Treatment was initiated with bortezomib-based chemotherapy. During treatment, she developed a small subsegmental pulmonary embolism, which was managed with observation rather than anticoagulation. One month later, she had a pulseless electrical activity cardiac arrest due to a massive pulmonary embolism. Her functional status declined, and heart failure symptoms progressed. She was not considered a candidate for cardiac and stem-cell transplantation. She died within eight months of symptom onset.

The diagnosis

This patient's diagnosis is AL (primary) amyloidosis with amyloid cardiomyopathy. About 4,500 new cases of AL amyloidosis are diagnosed every year, and it continues to be the most common systemic amyloidosis in the United States. Approximately 50% of patients with AL amyloidosis develop cardiac involvement. Amyloid cardiomyopathy may be suggested by low-voltage complexes on EKG and bi-atrial enlargement on TTE. Findings of ventricular wall thickening are not universal. It is important to determine the specific type of amyloidosis, as well as the extent of organ involvement, to outline treatment options. Evaluation includes serum protein electrophoresis and biopsies of the abdominal fat pad and bone marrow. Endomyocardial biopsy can be considered if other investigations are inconclusive. Diffuse and late gadolinium enhancement of the ventricles on cardiac MRI is 88% to 90% sensitive and 90% specific for cardiac amyloidosis. Biopsy specimens are stained with Congo red, thioflavin T, and sulfated Alcian blue. Protein mass spectrometry of the biopsy specimen remains the gold standard test to differentiate the various types of amyloidosis, which will have an impact on therapy, and prognosis. The degree of cardiac involvement is the chief predictor of outcome; AL amyloidosis has a poor prognosis, with survival of approximately six months without treatment.

Although patients with cardiac amyloidosis are at a high risk of bleeding due to increased vessel fragility, they are also at an increased risk for thromboembolic disease caused by dysfunction and mechanical stasis in the atria. While there remains ongoing debate as to whether anticoagulation is appropriate for all patients with subsegmental pulmonary embolism, observation is recommended only for patients in whom the risk of recurrence of venous thromboembolism (VTE) is considered low. Amyloid cardiomyopathy should be considered a significant risk factor for VTE recurrence, and as such, systemic anticoagulation is recommended in this setting. Moreover, it is important for all cardiac amyloidosis patients with atrial fibrillation to receive anticoagulation regardless of their score on common risk indices. Even for patients in sinus rhythm, a transesophageal echocardiogram is required to rule out atrial thrombus. A diminutive transmitral “A” wave on TTE, which indicates mechanical stasis of blood, is an indication to start anticoagulation in these patients.

Pearls

  • Cardiac involvement occurs frequently in AL amyloidosis (50%) and carries a poor overall prognosis.
  • Amyloid cardiomyopathy should be considered a significant VTE risk factor, which should be factored into treatment decisions for anticoagulation in patients with thrombotic complications.

Case 2: Invasive nontypeable Haemophilus influenzae infection

By Dima Youssef, MD, ACP Resident/Fellow Member; Zeyad Sako, MD, ACP Resident/Fellow Member; and Richard Shellenberger, DO, FACP

The patient

A 62-year-old woman presented with altered mental status and severe left knee pain two weeks after an arthroscopic meniscal repair. She was immunocompetent and had no history of splenectomy. On presentation, she was febrile, tachycardic, and hypotensive. Physical examination revealed limited range of motion of her left knee, with erythema, warmth, tenderness, and a significant effusion. Her labs were notable for leukocytosis (26.1 thou/mcL; normal range, 4.0 to 10.0 thou/mcL) with bandemia. Her erythrocyte sedimentation rate and C-reactive protein levels were elevated at 59 mm/h (normal level <30 mm/h) and 30.7 mg/dL (normal level <0.5 mg/dL), respectively. Broad-spectrum antibiotics were empirically initiated after arthrocentesis was performed and blood cultures were obtained. The patient was taken for emergent operative debridement and irrigation. Blood and operative cultures grew nontypeable Haemophilus influenzae. Antibiotics were narrowed based on susceptibilities. She improved and was discharged with oral antibiotics.

The patient presented again seven days after discharge with chest pain and severe dyspnea. She was tachycardic but otherwise afebrile and normotensive. On physical examination, a new diastolic murmur was appreciated throughout the precordium, although best heard at the right upper sternal border. There were no cutaneous manifestations of infective endocarditis, including rash, Osler nodes, Janeway lesions, or splinter hemorrhages. Transthoracic echocardiography revealed an aortic valve vegetation with severe regurgitation. Blood cultures did not demonstrate persistent Haemophilus bacteremia. The patient underwent a bioprosthetic aortic valve replacement. A six- week course of intravenous ceftriaxone was completed, and the patient recovered completely.

The diagnosis

Haemophilus influenzae is a pleomorphic gram-negative coccobacillus that is divided into typeable (A-F) and non-typeable forms based on the presence or absence of polysaccharide capsule. A ubiquitous colonizer of the nasopharynx, it is a common cause of limited disease, including otitis media and sinusitis in children, but can cause severe, invasive diseases including pneumonia, meningitis, endocarditis, and septic arthritis. Surveillance data suggest increasing incidence of invasive H. influenzae. Type B H. influenzae, previously the most prevalent H. influenzae infection, has declined in the U.S. and worldwide since the introduction of a conjugate vaccine in 1987. Nontypeable H. influenzae now leads the incidence of invasive disease across all age groups. Both typeable and nontypeable invasive H. influenzae can cause significant morbidity and mortality (25% case fatality rate) independent of the presence or absence of a functional spleen. The largest burden of invasive nontypeable H. influenzae is in children under five years old and adults over 65 years of age, at 1.6 and 4.6 per 100,000 population, respectively.

Most adults with septic arthritis due to H. influenzae have predisposing factors, including but not limited to trauma, diabetes mellitus, systemic lupus erythematous, rheumatoid arthritis, splenectomy, and lymphoma. A favorable outcome is reported in most patients. Endocarditis due to Haemophilus species is very rare, with only 0.8% to 1.3% of endocarditis cases having these bacteria documented as the cause. It generally has a favorable prognosis in adults.

Pearls

  • Nontypeable H. influenzae is a clinically significant pathogen that can cause severe infections with significant morbidity and mortality, even without history of splenectomy.
  • Haemophilus endocarditis is rare and has a favorable prognosis in adults.

Case 3: Pleural fluid eosinophilia and metastatic melanoma

By Bathmapriya Balakrishnan, MD, ACP Resident/Fellow Member, and Richard Shellenberger, DO, FACP

The patient

An active 56-year-old man presented with a month of progressive shortness of breath. He also described low-grade fevers and right-sided pleuritic chest pain. His medical history included a superficial melanoma of unknown stage on the left upper arm, which was removed ten years prior with no evidence of metastatic disease.

less-thanbgreater-thanFigure 2less-thanslashbgreater-than Malignant melanoma positively stained for MITF1 Photomicrograph scaled to microns pictured at 20times magnification Image courtesy of the case authors
Figure 2. Malignant melanoma, positively stained for MITF1. (Photomicrograph scaled to microns, pictured at 20× magnification.) Image courtesy of the case authors.

On presentation, his oxygen saturation on room air was 92%. He was otherwise hemodynamically stable and afebrile. There were reduced breath sounds from the middle to lower zones of the right hemithorax without crackles or wheezes. He did not have lymphadenopathy, and his cardiovascular examination was unremarkable. His laboratory workup was largely unremarkable except for a mild leukocytosis and peripheral eosinophilia of 1.0 thou/mcL. A large right pleural effusion was noted on chest X-ray. CT of the chest demonstrated a large right-sided pleural effusion with compressive atelectasis, and a 3.1 × 2.6-cm mass abutting the posterior pleura in the right lower hemithorax. Thoracentesis revealed a hemorrhagic, eosinophil-predominant (41%) exudative effusion without evidence of malignancy on cytology. During video-assisted thoracoscopic (VATS) exploration, biopsy samples were taken of the pleura, intralobular nodule, and pleural mass. Biopsy samples were positive for HMB-45 and MITF1 (Figure 2) but negative for Ber-EP4, CK5, and calretinin. Immunohistochemical analysis of biopsy samples confirmed the diagnosis of stage IV metastatic melanoma. He began immune therapy using nivolumab and ipilimumab.

The diagnosis

Pleural fluid eosinophilia (PFE) is defined by pleural fluid with a differential including more than 10% eosinophils. The most common causes of PFE are malignancy (26%), followed by idiopathic (25%) and parapneumonic (13%) disease. Malignancies commonly associated with PFE are lung cancer, lymphoma, mesothelioma, and metastatic carcinoma. Other important causes of PFE include pleural irritation, surgery or trauma, exposure to asbestos or medications (e.g., warfarin, sulfa, nitrofurantoin, isotretinoin), infections, and pulmonary embolism.

Primary cutaneous melanoma is cured by surgical excision, but metastatic spread occurs in 30% of cases, most often to the lung. Intrathoracic metastases of melanoma include pulmonary nodules (61.5%), mediastinal lymphadenopathy (7%), pleural effusion (2%), lytic bony lesions (0.8%), extra-pleural mass (0.8%), and combined lesions (28%).

Pleural mesothelioma and melanoma share certain clinical and imaging characteristics, and immunohistochemical markers of biopsy samples help to differentiate these entities. Premelanosomes, melan-A, S-100, MITF1, and HMB-45 are well-defined surface markers for melanoma, while cytokeratin (CK) 5/6, CK 8/18, carcinoembryonic antigen, melanocortin, and calretinin are mesothelioma markers.

Pearls

  • The most common cause of PFE is malignancy, and 30% of malignant melanomas metastasize to the lung.
  • Immunohistochemical markers help to differentiate between pleural mesothelioma and pleural melanoma.

Case 4: Ingestion of model car racing fuel

By Shraddha Desai, MD, ACP Resident/Fellow Member, and Richard Shellenberger, DO, FACP

The patient

A 51-year-old woman with chronic obstructive pulmonary disease, alcohol use disorder, and history of attempted suicide by benzodiazepine overdose presented for evaluation of agitation and visual hallucinations after substance ingestion. The patient's husband found her screaming and actively hallucinating. Empty bottles of mouthwash, a model car racing fuel, antifreeze, and perfume were found by her husband as potentially ingested substances.

On physical exam, she was hypertensive to 144/105 mm Hg and tachycardic to 152 beats/min but was otherwise hemodynamically stable. She could follow basic commands but would not answer any questions. Laboratory testing revealed metabolic acidosis with an anion gap of 30. Labs were also significant for a creatinine level of 55.57 mg/dL (reference range, 0.44 to 1.03 mg/dL), serum osmolality of 378 mOsm/kg (reference range, 275 to 295 mOsm/kg), and osmolal gap of 87 mOs/kg (reference range, <10 mOsm/kg). Urine toxicology was significant for a methanol level of 175.5 mg/dL (reference range, 0 to 1.0 mg/dL) and acetone level of 6.3 mg/dL (reference range, 0 to 1.0 mg/dL).

Treatment was initiated with urgent hemodialysis, fomepizole and continuous sodium bicarbonate infusion for her methanol poisoning, acidosis, and acute kidney injury. Supplementation with pyridoxine, thiamine, folic acid, and folinic acid were recommended by Poison Control. Remarkably, her creatinine level improved to 4.71 mg/dL by the end of the second hospital day, after which hemodialysis was no longer required. Her hospital course was complicated by encephalopathy and alcohol withdrawal. She was eventually discharged to an inpatient rehabilitation facility for treatment of alcohol use disorder and depression. At discharge, she had signs of mild cognitive impairment, which manifested as abnormalities in speech and language, memory loss, apraxia, and dysnomia. Her creatinine level on the day of discharge had normalized to 0.58 mg/dL.

The diagnosis

This patient exhibited the acute effects of the ingestion of model car racing fuel which contains methanol and a fuel additive called nitromethane. Methanol intoxication results in oxidation of the parent alcohol into a toxic metabolite, formic acid, which is responsible for causing anion gap metabolic acidosis. Inebriation and sedation are early manifestations of methanol ingestion. Later toxic effects of formic acid are retinal injury, optic disc hyperemia, afferent pupillary defect, and ischemia or hemorrhage of the basal ganglia. Severity of symptoms correlates with the degree of metabolic acidosis. It is important to recognize that the osmolal gap is elevated only in the presence of parent alcohols like methanol; thus, plasma osmolal gap is insensitive in late presentations, as most of the parent alcohol has already been metabolized to formic acid. Mortality in methanol poisoning correlates strongly with the degree of acidosis and formic acid levels.

The other component of racing fuel, nitromethane, is a topical irritant, and acute ingestion is largely nontoxic. Nitromethane absorbs on the same chromophore on the spectrophotometer as creatinine, causing a spurious elevation of creatinine when the most common method of laboratory measurement is used. This patient had acute kidney injury; however, the level of creatinine elevation was exaggerated by the nitromethane confounding the spectrophotometer. Other substances, including dopamine, bilirubin, and certain cephalosporin antibiotics, can cause spurious elevations in creatinine as well.

Pearls

  • Methanol intoxication is life-threatening and can present with altered mental status, anion gap metabolic acidosis, and acute kidney injury. The toxic effects are primarily due to metabolism of methanol to formic acid.
  • Nitromethane can cause a spurious elevation in creatinine measurement and should be considered in the setting of substance ingestion and a markedly elevated creatinine level.