Pulmonary Capillary Hemangiomatosis or Hepatopulmonary Syndrome in a Patient with CREST Syndrome
The diagnostic challenges of pulmonary complications in patients with CREST syndrome (Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia) often require careful differentiation between rare vascular pathologies. A recent case report described a patient with CREST syndrome who developed progressive dyspnea and was diagnosed with pulmonary capillary hemangiomatosis (PCH) based on clinical history and histology. However, critical gaps in diagnostic methodology and conflicting evidence raise questions about the validity of this conclusion. This article explores the clinical, imaging, and histopathological nuances that challenge the diagnosis of PCH in CREST syndrome and proposes hepatopulmonary syndrome (HPS) as a more plausible alternative.
CREST Syndrome and Pulmonary Hypertension
CREST syndrome, a limited form of systemic sclerosis, is associated with vascular abnormalities, including pulmonary hypertension (PH). Pulmonary arterial hypertension (PAH) is a well-documented complication of CREST syndrome, occurring in approximately 10–15% of patients. The gold standard for diagnosing PAH is right heart catheterization (RHC), which confirms pre-capillary hypertension when mean pulmonary artery pressure (mPAP) is ≥25 mmHg, pulmonary artery wedge pressure (PAWP) is ≤15 mmHg, and pulmonary vascular resistance (PVR) exceeds 3 Wood units. In the discussed case, RHC was not performed, leaving the diagnosis of PAH unverified. This omission is significant, as PAH in CREST syndrome typically correlates with histopathological changes such as plexiform lesions and medial hypertrophy, which were not explicitly described in the original report.
Challenges in Diagnosing Pulmonary Capillary Hemangiomatosis
PCH, a rare cause of PAH, is characterized by abnormal capillary proliferation within alveolar septa. Histologically, it manifests as alveolar wall thickening due to excessive capillary networks, often accompanied by hemosiderin-laden macrophages. The original case attributed PCH to CREST syndrome based on lung biopsy findings of capillary proliferation. However, critical diagnostic criteria for PCH were unmet. For instance, bronchoalveolar lavage (BAL) with Perl’s staining—a standard test to detect iron-laden macrophages indicative of microvascular hemorrhage—was not reported. Additionally, high-resolution computed tomography (HRCT) findings of diffuse centrilobular ground-glass opacities, while suggestive of PCH, are nonspecific and overlap with other vascular pathologies.
The treatment response further complicates the diagnosis. The patient received ambrisentan, an endothelin receptor antagonist, with reported improvement. However, studies such as the AMBITION trial (2015) have shown that monotherapy with ambrisentan in PAH is associated with clinical deterioration and increased hospitalization rates. This paradoxical response raises doubts about the underlying pathology, as PCH typically requires combination therapy or targeted interventions like pulmonary vasodilators.
Hepatopulmonary Syndrome: An Overlooked Differential
Hepatopulmonary syndrome (HPS), a complication of liver cirrhosis or portal hypertension, is characterized by pulmonary vascular dilatation leading to ventilation-perfusion mismatch and hypoxemia. Pathologically, HPS involves pre-capillary and capillary dilation without alveolar wall thickening—a distinction from PCH. In the discussed case, the lung biopsy reportedly showed vascular dilation rather than capillary proliferation, aligning more closely with HPS.
A 10-year-old boy with telangiectasia, hypoxia, and similar HRCT findings was diagnosed with HPS in the authors’ clinical practice. Contrast-enhanced CT angiography revealed diffuse pulmonary vascular dilatation, while RHC confirmed normal PAWP and elevated mPAP. Histopathology demonstrated CD31-positive endothelial cells lining dilated vessels, consistent with HPS. These findings contrast sharply with the original case’s biopsy, which lacked hallmark features of PCH.
Linking CREST Syndrome to Hepatopulmonary Syndrome
The association between CREST syndrome and HPS may be mediated by primary biliary cirrhosis (PBC), a known comorbidity in CREST patients. PBC can progress to cirrhosis and portal hypertension, triggering HPS through mechanisms involving nitric oxide (NO) overproduction and pulmonary vasodilation. In the original case, liver function tests or evidence of cirrhosis were not discussed, creating a diagnostic blind spot. However, the coexistence of CREST syndrome and PBC has been documented, suggesting that undetected liver pathology could explain the pulmonary manifestations.
Imaging and Histopathological Discrepancies
HRCT findings in the original case included ground-glass opacities, which are nonspecific and seen in both PCH and HPS. However, CT angiography in HPS typically reveals dilated peripheral pulmonary vessels and “spongiform” parenchymal changes, whereas PCH may show interlobular septal thickening. The absence of reported pulmonary artery dilation (>3 cm) in the original case further weakens the PCH diagnosis.
Histologically, PCH requires demonstration of capillary proliferation within alveolar walls, often with hemosiderosis. In contrast, the authors’ HPS case showed inter-alveolar vascular dilation without wall thickening. The original biopsy description of “intense capillary proliferation” conflicts with these findings, suggesting either misinterpretation or variability in pathological sampling.
Clinical Implications and Diagnostic Recommendations
Misdiagnosing PCH in CREST syndrome has significant therapeutic consequences. PCH management often includes anticoagulation and targeted PAH therapies, whereas HPS may require liver transplantation or nitric oxide modulation. The authors emphasize the need for a standardized diagnostic approach:
- Right Heart Catheterization: Mandatory for confirming PAH and measuring hemodynamic parameters.
- Bronchoalveolar Lavage: Perl’s staining to detect hemosiderin-laden macrophages.
- Liver Function Evaluation: Assessment for cirrhosis or portal hypertension.
- Contrast-Enhanced CT Angiography: To differentiate vascular dilatation (HPS) from capillary proliferation (PCH).
Conclusion
The diagnosis of PCH in CREST syndrome remains contentious without rigorous hemodynamic and histopathological validation. The absence of RHC data, conflicting treatment responses, and histologic features more aligned with vascular dilation suggest that hepatopulmonary syndrome is a more plausible explanation. Clinicians should consider HPS in CREST patients with hypoxemia and prioritize comprehensive liver and vascular assessments to guide appropriate therapy.
doi.org/10.1097/CM9.0000000000000596
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