Systemic Oxalosis Mimicking Transthyretin Amyloid Cardiomyopathy

Abstract

Background

Technetium-99m pyrophosphate (Tc-99m PYP) scintigraphy is a noninvasive imaging modality in the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM), though false positive results may result in adverse clinical outcomes.

Case Summary

A 53-year-old man with a history of heart failure with reduced ejection fraction and end-stage renal disease presented with upper extremity weakness and hypervolemia. Tc-99m PYP scintigraphy was suggestive of ATTR-CM. However, transthyretin genetic testing was negative, and endomyocardial biopsy was without evidence of amyloid deposition. The patient later died, and autopsy revealed myocardial oxalate deposition concerning for primary vs secondary hyperoxaluria.

Discussion

Although Tc-99m PYP scintigraphy is a sensitive and specific modality for the detection of ATTR-CM, clinicians should recognize other infiltrative cardiomyopathies causing false positivity such as systemic oxalosis.

Visual Summary

History of Presentation

A 53-year-old Black man with a history of heart failure with reduced ejection fraction (HFrEF), anuric end-stage renal disease (ESRD) managed with peritoneal dialysis (PD), type 2 diabetes mellitus (DM), and hypertension (HTN) presented with bilateral upper-extremity weakness. On examination, he had jugular venous distension to the earlobe and 1+ bilateral pitting edema. There was visible muscular atrophy of the bilateral forearms and thenar areas. Strength testing revealed 4/5 grip strength in the upper extremities and 3/5 strength in the lower extremities.

Past Medical History

The patient had been diagnosed with chronic kidney disease 5 years before presentation, attributed to long-standing HTN and DM. His chronic kidney disease progressed to ESRD requiring PD 2 years later. He was diagnosed with HFrEF 3 months before his current presentation during a hospitalization for volume overload.

Differential Diagnosis

The combination of bilateral upper-extremity weakness, HFrEF, N-terminal pro–B-type natriuretic peptide of 135,660 pg/mL, and troponin of 150 ng/L raised concern for amyloidosis. Although the markedly elevated N-terminal pro–B-type natriuretic peptide exceeds levels typically observed in cardiac amyloidosis, the finding was interpreted in the context of underlying ESRD, which can significantly elevate levels and limit their diagnostic specificity. Other conditions that were considered included cervical myelopathy, chronic inflammatory demyelinating polyradiculoneuropathy, diabetic neuropathy, and other inherited neuropathies.

Investigations

Transthoracic echocardiography demonstrated moderate global hypokinesis with an estimated left ventricular ejection fraction of 30%-40%, moderate concentric hypertrophy of the left ventricle (interventricular septal diastolic thickness: 1.47 cm), grade II diastolic dysfunction, and bi-atrial enlargement (Figure 1). The right ventricle size and systolic function were preserved, with tricuspid annular plane systolic excursion of 2.2 cm. Additional findings included mild mitral regurgitation, mild aortic stenosis, and trace pericardial effusion.

Figure 1.

Cardiac Imaging and Biopsy Findings From Our Patient with False Positive Scintigraphy Because of Systemic Oxalosis

(A) Transthoracic echocardiography in parasternal short-axis views with concentric left ventricular hypertrophy (interventricular septal diastolic thickness: 1.47 cm) and biatrial enlargement (left) and in apical 4 chamber (right) view; (B) technetium-99m pyrophosphate scintigraphy scintigraphy with diffuse grade 3 myocardial uptake on planar imaging (left) and single-photon emission computed tomography fusion image in axial plane shows circumferential uptake in the left ventricle, most pronounced in the lateral wall (right); (C) endomyocardial biopsy with hematoxylin and eosin stain under depolarized light without evidence of amyloid deposition; and (D) retrospective re-evaluation of the endomyocardial biopsy obtained pre mortem, with hematoxylin and eosin stain under polarized light, now revealing deposition of crystals (performed post mortem following autopsy findings).

Light chain testing—including serum and urine protein electrophoresis with immunofixation and serum free light chain assay—was within normal limits. Technetium-99m pyrophosphate (Tc-99m PYP) with single-photon emission computed tomography imaging demonstrated diffusely increased radiotracer uptake (grade 3) along the left ventricular myocardium and heart-to-contralateral chest ratio of 2.27, consistent with transthyretin-related cardiomyopathy (ATTR-CM).

Electromyography and nerve conduction studies revealed severe and diffuse loss of sensory and motor amplitudes in the upper extremities, with mixed axonal and demyelinating features, favoring diffuse polyneuropathy. Nerve conduction studies could not be performed in the distal legs because of previous amputations. The diffuse features of his demyelination were greater than expected for diabetic neuropathy, suggesting an occult secondary process. Nerve and muscle biopsy were recommended but deferred by the patient.

Management (Medical/Interventions)

The patient underwent genetic testing for transthyretin (TTR), which was negative, ruling out hereditary ATTR. Given the patient's relatively young age and the rapid clinical decline—features atypical for wild-type ATTR-CM—an endomyocardial biopsy (EMB) was performed, which did not demonstrate amyloid deposition by Congo red staining. He was suspected of having HF secondary to ESRD and inadequate dialysis on PD, for which transition to intermittent hemodialysis was recommended.

Outcome and Follow-Up

The patient was discharged with outpatient follow-up but was later admitted with acute hypercapnic respiratory failure requiring intubation. His hospital course was complicated by tamponade and cardiac arrest, followed by resuscitation. Because of a poor prognosis, he transitioned to comfort-focused care and died shortly thereafter.

An autopsy demonstrated abundant oxalate crystal deposition in the left ventricle myocardium, septum, and kidneys (Figure 2). Bilateral kidneys had stones present in the renal calyces. Postmortem mass spectrometry analysis demonstrated negative ethylene glycol levels in kidney tissue, minimizing suspicion for toxic ingestion. Given the low suspicion for systemic oxalosis before autopsy, the patient did not undergo genetic or urine testing in his lifetime, nor was oxalate deposition specifically evaluated for on his EMB pre mortem. Preliminary postmortem genetic testing for known primary hyperoxaluria–associated genes (AGXT, GRHPR, HOGA1) via the RenalZoom panel was negative, raising concern for gene-elusive primary hyperoxaluria vs secondary hyperoxaluria.

Figure 2.

Autopsy Images Demonstrating Myocardial and Renal Oxalate Deposition in the Setting of Systemic Oxalosis

(A) Myocardium pathology demonstrating numerous colorless, birefringent, rosette-shaped calcium oxalate crystals. There is no inflammatory reaction. (B) Kidney pathology demonstrates large chunks of calcium oxalate deposits, which also shows findings of chronic kidney disease, including glomerulosclerosis, tubular atrophy, and interstitial fibrosis.

Discussion

Contemporary diagnosis of ATTR-CM typically relies on grade 2 or 3 uptake on nuclear scintigraphy in the setting of negative light chain testing.¹ TTR gene sequencing is necessary to distinguish hereditary TTR from wild-type TTR.¹ This case illustrates a rare cause of false positive Tc-99m PYP scintigraphy. Although previous studies report sensitivity exceeding 99% and a specificity of 86% for the diagnosis of ATTR-CM, there is increased recognition of diagnostic limitations, including false positive results.2, 3, 4, 5 Diagnostic estimates are largely derived from cohorts with high pretest probability, often consisting of patients referred to specialized amyloidosis centers. Thus, diagnostic performance may be lower in broader populations, particularly when pretest probability is lower. In our patient, the combination of negative TTR genetic testing, atypical demographic characteristics, and a clinical trajectory more rapid than typical for wild-type ATTR-CM ultimately prompted EMB for further evaluation. Tc-99m PYP primarily binds to myocardial microcalcifications; thus, theoretically any disease process caused by calcium-containing deposits can act as a substrate for radiotracer binding and mimic ATTR on scintigraphy.2, 3, 4, 5 Identified culprits including light chain amyloid cardiomyopathy, hydroxychloroquine toxicity, hyperphosphatemia, and, rarely, alternative cardiomyopathies, such as hypertrophic cardiomyopathy, have been described.2, 3, 4 Oxalate deposition is another such example, though there is only one prior case report describing this entity.⁵

Hyperoxaluria may be classified as either primary or secondary in etiology. Primary hyperoxaluria, which has 3 known subtypes, is an autosomal recessive condition characterized by impaired metabolism of oxalate, leading to increased urinary oxalate excretion and eventual systemic deposition due to progressive renal failure (Table 1).⁶ Clinical manifestations include recurrent oxalate nephrolithiasis, nephrocalcinosis, progressive nephropathy, and systemic deposition causing cardiomyopathy, neuropathy, retinopathy, and pathologic fractures.⁶ Type 1 typically presents early in childhood as renal failure, whereas type 2 can be more indolent and manifest as renal failure in adulthood.⁶ In our patient, the absence of symptomatic nephrolithiasis and coexisting HTN and DM likely obscured recognition of hyperoxaluria as an underlying etiology of renal disease. The patient never had a kidney biopsy, which may have allowed for an earlier diagnosis. Postmortem genetic testing was negative for known genes associated with primary hyperoxaluria, though this does not exclude the diagnosis, as prior studies demonstrate that a subset of patients with a clinical phenotype consistent with primary hyperoxaluria lack identifiable mutations, reflecting genetic heterogeneity.⁷ Additionally, because pathogenic variants associated with primary hyperoxaluria have been characterized predominantly in populations of European ancestry, disease-causing variants in under-represented populations may be less recognized.⁷ Secondary hyperoxaluria is primarily driven by increased intestinal oxalate absorption or excessive oxalate intake, although ethylene glycol ingestion is an important toxic etiology.⁸ In patients with ESRD, impaired renal clearance may additionally result in systemic oxalate accumulation and tissue deposition.⁹ In our patient, serum oxalate levels were not obtained during his lifetime, precluding definitive classification. Furthermore, his long-standing PD, which is generally less effective than hemodialysis for oxalate clearance, likely contributed to progressive oxalate accumulation.⁶ Although the extensive multiorgan involvement suggests an underlying primary process, a definitive distinction between primary hyperoxaluria and secondary oxalosis cannot be made.

Table 1.

Comparison of Clinical Characteristics, Imaging Findings, and Diagnostic Work-Up for ATTR-CM and Systemic Hyperoxaluria

	ATTR-CM	Systemic Hyperoxaluria
Etiology	Deposition of misfolded transthyretin caused by either variant or wild-type (nonhereditary) TTR	Primary: impaired metabolism of hepatic oxalate Secondary: increased dietary intake, fat malabsorption, or impaired intestinal degradation
Prevalence	∼60 per 1,000,000; increasingly recognized, particularly among HFpEF and elderly populations	Primary: Type 1 (80% of cases): 1 per 1,000,000 Type 2 (∼10% of cases): rare Type 3 (∼10% of cases): rare Secondary: undefined, varies by patient population and etiology
Non-cardiac clinical manifestations	-MSK: bilateral CTS, biceps tendon rupture, lumbar spinal stenosis, trigger fingers -GI: diarrhea, constipation -Neurologic: autonomic or peripheral neuropathy	-Renal/urologic (key feature): recurrent nephrolithiasis, nephrocalcinosis, progressive CKD leading to ESRD -MSK: bone pain, fractures, synovitis, peripheral gangrene -GI: anorexia, hepatomegaly -Neurologic: peripheral neuropathy
Imaging findings	-TTE with LVH, biatrial enlargement, diastolic dysfunction, aortic stenosis, reduced GLS with apical sparing pattern -CMR with classically subendocardial or transmural LGE, though findings may be heterogeneous, patchy, or absent; elevated native T1 -Nuclear scintigraphy (PYP, HDP, DPD) with grade 2/3 uptake	-Renal ultrasound or CT for kidney stone burden and echogenicity -TTE with LVH, biatrial enlargement, diastolic dysfunction -CMR (less well characterized) with heterogeneous, diffuse subendocardial LGE ∗Systemic oxalosis can cause false positive Tc-99m PYP scintigraphy
Diagnostic evaluation	1. Initial labs for AL rule out: SPEP/UPEP/IFE, serum free light chains 2. Noninvasive diagnosis: Tc-99m PYP/HDP/DPD scintigraphy 3. Genetic testing: TTR gene sequencing to distinguish hereditary vs wild-type	1. Initial labs: serum creatinine, eGFR, urinalysis for oxalate, 24h urinary oxalate, plasma oxalate concentration 2. Genetic testing (autosomal recessive): AGXT (type 1), GRHPR (type 2), HOGA1 (type 3)
Indications for tissue biopsy	EMB is indicated if 1. monoclonal gammopathy is present 2. ongoing suspicion despite negative or equivocal scintigraphy 3. suspicion for alternate diagnosis despite positive scan	Renal biopsy: can be considered for evaluation with polarized light microscopy and the presence of birefringent oxalate crystals. EMB: If there is suspicion for myocardial involvement, EMB can be considered. Liver biopsy with enzyme activity: can be considered if genetic testing is inconclusive

AGXT = alanine-glyoxylate aminotransferase; ATTR-CM = transthyretin amyloid cardiomyopathy; CMR = cardiac magnetic resonance; CKD = chronic kidney disease; CTS = carpal tunnel syndrome; CT = computed tomography; DPD = 3,3-diphosphono-1,2-propanodicarboxylic acid; eGFR = estimated glomerular filtration rate; EMB = endomyocardial biopsy; ESRD = end-stage renal disease; GLS = global longitudinal strain; GI = gastrointestinal; GRHPR = glyoxylate/hydroxypyruvate reductase; HDP = hydroxymethylene diphosphonate; HFpEF = heart failure with preserved ejection fraction; HOGA1 = 4-hydroxy-2-oxoglutarate aldolase; IFE = immunofixation electrophoresis; MSK = musculoskeletal; SPEP = serum protein electrophoresis; Tc-99m PYP = technetium-99m pyrophosphate scintigraphy; TTE = transthoracic echocardiogram; UPEP = urine protein electrophoresis.

There is only one other case report describing hyperoxaluria-mediated cardiomyopathy diagnosed by echocardiogram, cardiac magnetic resonance (CMR) imaging, and EMB.¹⁰ Cardiac amyloidosis and oxalosis may be indistinguishable on an echocardiogram alone, whereas CMR imaging can provide some diagnostic clarity. Given the rarity of the disease, CMR patterns in systemic oxalosis are not well defined, though it has been shown that systemic oxalosis can demonstrate a heterogeneous, diffuse subendocardial late gadolinium enhancement (LGE) that can involve the entire myocardium. Although ATTR-CM typically demonstrates subendocardial or transmural LGE, it is important to note that CMR imaging findings may also be patchy or even absent in a subset of patients, particularly early in the disease course or in less advanced phenotypes (Table 1).^1,10 Because of clinical instability and ESRD, our patient did not undergo CMR imaging. Systemic oxalosis and amyloidosis share substantial clinical overlap, including nephropathy, neuropathy, and restrictive cardiomyopathy. ESRD further complicates the evaluation of suspected ATTR-CM as imaging features, including increased wall thickness and biatrial enlargement, may overlap. Additionally, light chain testing may be more challenging to interpret in ESRD, complicating the exclusion of AL amyloidosis.¹ Moreover, suboptimal oxalate clearance in patients receiving hemodialysis predisposes to systemic oxalate deposition, which may confound the interpretation of Tc-99m PYP scintigraphy, as was observed in our patient.⁹ Collectively, these factors reduce the specificity of ATTR-CM diagnostic algorithms in patients with ESRD and support consideration of histopathologic confirmation when clinical features are discordant. Unfortunately, in our case, following a negative EMB, systemic oxalosis was not considered, reflecting both the rarity of disease and its under-recognition as a potential cause of cardiomyopathy.⁶

Conclusions

This case highlights systemic oxalosis as a rare but highly morbid cause of false-positive myocardial uptake on Tc-99m PYP scintigraphy. As nuclear scintigraphy is increasingly utilized in the evaluation of ATTR-CM, clinicians must remain vigilant of causes of false positivity, especially when the clinical picture is not consistent with the presentation of ATTR-CM. Recognition of systemic oxalosis as a potential mimic of ATTR-CM is critical as reliance on Tc-99m PYP or established diagnostic pathways alone may lead to delays in appropriate management and misdiagnosis.

Funding Support and Author Disclosures

Dr. Vaishnav has received consulting fees from Alnylam, BridgeBio, and Pfizer. The other authors have nothing to disclose.

Take-Home Messages

• •Clinical features of systemic oxalosis can overlap with cardiac amyloidosis.
• •Systemic oxalosis is important to consider in a patient with restrictive cardiomyopathy and systemic manifestations of disease.
• •Although technetium-99m Pyrophosphate scintigraphy is specific for transthyretin-related cardiomyopathy, other infiltrative diseases such as oxalosis can cause false positive results and lead to misdiagnosis.

Visual Summary.

Timeline of Clinical Course, Diagnostic Evaluation, and Identification of Systemic Oxalosis Mimicking Transthyretin Amyloid Cardiomyopathy

5 y prior to presentation	A 48-y-old man was diagnosed with CKD, presumed to be in the setting of uncontrolled HTN and type 2 diabetes mellitus.
2 y before presentation	He continued to have progression to ESRD and was initiated on PD.
3 mo before presentation	He presented with volume overload and acute hypoxemic respiratory failure in the setting of a COVID pneumonia. TTE demonstrated a newly reduced LVEF of 30%-40%. Ischemic evaluation was deferred, and he was discharged with outpatient follow-up.
At presentation	He was hospitalized with bilateral upper extremity weakness and hypervolemia. TTE showed LVEF of 35%-40% with biatrial enlargement. PYP scan demonstrated grade 3 uptake, consistent with ATTR-CM. Serum and urine protein studies for monoclonal gammopathy were negative. He underwent TTR genetic testing, which was negative. He was initially concluded to have wtATTR-CM.
6 mo after presentation	Because of clinical features inconsistent with wtATTR-CM (young age and rapid decline), he underwent EMB without evidence of amyloid deposition. He was suspected of having ESRD-associated heart failure.
1 y after presentation	He presented with acute hypercapnic respiratory failure requiring intubation. Because of refractory shock with poor overall prognosis, he transitioned to comfort care measures only and died shortly afterward. His autopsy was notable for extensive oxalate deposition in the myocardium, consistent with systemic oxalosis secondary to primary vs secondary hyperoxaluria.

Timeline of clinical events in our patient illustrating the progression to ESRD on PD, development of cardiomyopathy and neuropathy, positive Tc-99m PYP scintigraphy suggesting ATTR-CM, negative endomyocardial biopsy for amyloidosis, and eventual postmortem diagnosis of systemic oxalosis with myocardial oxalate deposition. The figure highlights key diagnostic milestones and clinical features that complicate differentiation between systemic oxalosis and ATTR-CM.

ATTR-CM = transthyretin amyloid cardiomyopathy; CKD = chronic kidney disease; EMB = endomyocardial biopsy; ESRD = end-stage renal disease; HTN = hypertension; PD = peritoneal dialysis; Tc-99m PYP = technetium-99m pyrophosphate scintigraphy; TTR = transthyretin.