SQ-LIP-000004 · v1.7 (current) · machine-readable JSON →
Is lipedema underdiagnosed, and can screening tools help identify it?
Also asked as
- Does lipedema often go undiagnosed, and could screening tools improve its detection?
- Is lipedema frequently missed by doctors, and would screening questionnaires help spot it?
- lipedema underdiagnosis screening tools detection
- To what extent is lipedema underrecognized, and can screening instruments aid in identifying affected patients?
Strong and consistent evidence indicates lipedema is widely underdiagnosed and confused with obesity or lymphedema, with diagnostic delays often exceeding 20 years. Several screening questionnaires and measurement tools can help raise suspicion or support differential diagnosis, but none has been validated in large independent prospective cohorts, so diagnosis still relies on clinical judgment.
- Current answer
- Lipedema is very likely underdiagnosed, with convergent support across multiple study designs, geographic settings, and evidence grades.
- Knowledge state
- Probable · Evidence confidence: very low–low (GRADE) · Stability: Stabilizing
- Evidence
- 21 consistent · 0 conflicting · 6 refining / contextual
- ⚠ none indexed yet — the registry may under-detect disconfirming evidence (a known limitation)
- Evidence verification
- 35/37 sources independently verified · 1 need review · 1 source not retrievable
- Main limitation
- No screening or imaging tool has been validated in large independent prospective cohorts; reported diagnostic accuracies (AUCs, CART 100%) come from small, single-setting, mostly…
- Latest change
- This update added a narrative review reinforcing that lipedema is often misdiagnosed as obesity or lymphedema and that earlier recognition can benefit… · v1.7
- Knowledge freshness
- 68% recent · mixed
- Last updated
- 2026-06-14 · v1.7
| Underdiagnosis / underrecognition | increased | moderate (GRADE) | symptom-only |
| Convergent evidence: low clinician awareness, frequent misdiagnosis as obesity/lymphedema, long delays. | |||
| Diagnostic delay | increased | low (GRADE) | symptom-only |
| Mean ~26 yr delay; median 25.5 yr vs 12.1 yr for lymphedema; cohort data, single settings. | |||
| Screening questionnaire discrimination (vs obesity/clinical reference) | improved | low (GRADE) | symptom-only |
| QuASiL-derived tools AUC ~0.86-0.91 but one validated tool had low sensitivity (0.46); not externally validated. | |||
| Clinical algorithm differentiating lipedema vs lymphedema (CART) | improved | low (GRADE) | symptom-only |
| 3-variable CART 100% in-sample accuracy in one prospective cohort; not externally validated. | |||
| Imaging/measurement tool diagnostic performance (DXA, US, CT, QST, BIS, ICG, MR) | mixed | low (GRADE) | symptom-only |
| Individual studies show high AUC/sensitivity, but systematic reviews find inconsistent protocols and no validated single tool. | |||
| Validated standalone screening tool ready for practice | not demonstrated | moderate (GRADE) | symptom-only |
| No tool validated in large independent prospective cohorts; systematic screening not yet standard. | |||
Based on currently indexed evidence, lipedema is very likely underdiagnosed, with convergent support across multiple study designs, geographic settings, and evidence grades. Key findings: (1) ~81% of lipedema patients are classified overweight/obese by BMI alone, causing workup to stop prematurely; (2) only 71% of 115 patients at a specialized Saudi clinic received a clinical diagnosis; (3) low physician awareness (only 46.2% of 251 UK vascular surgeons recognized lipedema), with the condition historically absent from MeSH/EMBASE and ICD-WHO coding as of 2012; (4) Dutch guidelines explicitly state lipedema is frequently misdiagnosed or wrongly classified as an aesthetic problem; (5) a systematic review of 61 studies confirms reliance on observational data with absent standardized diagnostic criteria and validated patient-reported outcomes; and (6) multiple narrative and systematic reviews across countries consistently characterize lipedema as underrecognized, frequently misdiagnosed as obesity or lymphedema (estimated prevalence ~10–12% in adult women, several sources cautioning this figure may be inflated by uncertain diagnosis). Substantial diagnostic delay is documented: a Spanish cohort showed a mean delay of 26.1 years (onset ~20, diagnosis ~46.5), and a prospective cohort found median time-to-diagnosis of 25.5 years for lipedema versus 12.1 years for lymphedema. Diagnosis is further hindered when multiple specialist consultations are required (51.2% needed ≥3 specialists in one Spanish survey). Regarding screening tools, evidence supports their potential utility while highlighting important limitations, and tools must be judged BY what they detect: most aim to raise clinical suspicion or support differential diagnosis (lipedema vs obesity/lymphedema), NOT to confirm disease or alter its course. Symptom/questionnaire approaches: a simplified 9-item self-applied questionnaire derived from QuASiL achieved AUC 0.912 (7-question model) and 0.8615 (total-score) against expert diagnosis in 109 women; the Brazilian Portuguese QuASiL showed 96.4% comprehension with symptom intensity correlating with limb volume; a validated online questionnaire (cutoff ≥12, AUC 0.86, specificity 0.88 but LOW sensitivity 0.46) estimated 12.3% prevalence among Brazilian women; a Spanish study proposed ≥6 of 13 symptoms as a threshold; and large Spanish cohorts (969, 1069, 1803 patients) propose multi-criterion frameworks (Schingale type classification, modified Wolf/Herbst scales). A prospective cohort CART algorithm using three clinical variables (bruising, body disproportion, spared feet) separated lipedema from lymphedema with 100% in-sample accuracy (not externally validated). Objective/measurement tools under investigation include DXA leg/total fat mass index (AUC 0.90), quantitative sensory testing (combined PPT+VDT z-score, AUCs ~0.86–0.91), bioimpedance spectroscopy, ultrasound subcutaneous-thickness cutoffs (including a proposed clinical-ultrasonographic algorithm for under-recognized abdominal lipedema), non-contrast CT (95% sensitivity, 100% specificity in one review), ICG lymphography/lymphoscintigraphy, MR lymphangiography, and IL-6 genotyping with body-composition indices. However, a moderate-quality systematic review of 20 studies found 13 different imaging/measurement tools with inconsistent protocols and limited clinimetric reporting, and another systematic review found limited diagnostic performance and absence of prospective comparative data. No single screening or imaging tool has been validated in large independent prospective cohorts; diagnosis still relies on clinical grounds due to the absence of specific biomarkers, and systematic screening is not yet standard practice.
A synthesis rendered from the currently indexed evidence — versioned, not a verdict.
⚙ AI consolidation: Claude Opus 4.8 · 2026-06-14 — evidence-bounded; the AI does not opine
This update added a narrative review reinforcing that lipedema is often misdiagnosed as obesity or lymphedema and that earlier recognition can benefit treatment, consistent with the existing answer without changing its conclusions.
Knowledge freshness = share of the 37 indexed evidence sources from the last 5 years (newest 2026, oldest 2008) . Low freshness flags an ageing evidence base — not that the answer is wrong.
Evidence over time
consistent conflicting refining / contextual Each dot is a study, placed by year and coloured by whether the linked claim supports or contradicts the answer. As the surveillance loop runs, claim revisions and new evidence will extend this timeline.
Answer over time
Each node is a published version of the answer — open one to read the answer exactly as it stood then.
Choose a format (Vancouver default). Citing a version captures the evidence state on that date; this page shows the current version — see version history.
Consistent claims
- SCR-LIP-000007 consistent
Because obesity is commonly defined by BMI alone (which disregards fat distribution), lipedema is frequently underdiagnosed when workup stops at an established obesity diagnosis; ~81% of lipedema patients are classified overweight/obese by BMI.
Ultrasound criteria for lipedema diagnosis — Amato et al. (2021) · Amato ACM, 2021 - SCR-LIP-000188 consistent
A simplified 9-item self-applied screening questionnaire (derived from the validated QuASiL) based on clinical diagnostic criteria (post-pubertal women, bilateral symmetric fat deposit below the hip sparing feet, negative Stemmer and Godet signs, pain on palpation, spontaneous bruising) achieved diagnostic discrimination of AUC=0.912 for an individual 7-question predictive model and AUC=0.8615 for a total-score model against expert clinical diagnosis in 109 women (59 with lipedema, 50 without), with the item 'feeling something wrong in the legs' being most discriminative (OR=4.328).
Criação de questionário e modelo de rastreamento de lipedema — Amato et al. (2020) - SCR-LIP-000009 consistent
The Brazilian Portuguese lipedema symptoms questionnaire (QuASiL) was translated, culturally adapted and validated, showing high comprehension and symptom-intensity scores that correlate with limb volume by segmental bioimpedance.
Tradução, adaptação cultural e validação do questionário de avaliação sintomática do lipedema (QuASiL) — Amato et al. (2020) - SCR-LIP-000062 consistent
A narrative review of 2020–2025 evidence concludes that systematic lipedema screening is necessary when studying pain–inflammation relationships in women with obesity, because unrecognized lipedema may cluster pain within peripheral fat phenotypes and bias comparisons between android and gynoid obesity groups.
Dor crônica e biomarcadores inflamatórios em mulheres com obesidade: Impacto dos Fenótipos Adiposos e Lipedema — Silva et al. (2026) - SCR-LIP-000064 consistent
In a cross-sectional study of 115 female patients in Saudi Arabia, only 71% received a clinical diagnosis of lipedema despite presenting to a specialized clinic, and the study authors characterize this as a high underdiagnosis rate requiring increased awareness.
Characteristics and Clinical Features of Patients with Lipedema in Saudi Arabia: A Cross-sectional Comprehensive Assessment — Alosaimi et al. (2024) · Lipedema awareness and knowledge level among medical doctors in Turkey: A cross-sectional study highlighting the diagnosis and treatment gap — Bagatir et al. (2025) - SCR-LIP-000065 consistent
In a cohort of 1803 Spanish lipedema patients, 60.6% were diagnosed during reproductive years with a mean age of 42.9 years, and the study presents a novel clinical assessment approach including multiple comorbidity markers (e.g., suspected high intestinal permeability in 99%, bilateral trochanteric pain in 97.4%, ligamentous hyperlaxity in 95.8%) that may help physicians better identify and understand the condition.
Clinical Signs at Diagnosis and Comorbidities in a Large Cohort of Patients with Lipedema in Spain — Simarro Blasco et al. (2025) - SCR-LIP-000364 consistent
In a cross-sectional survey of 969 Spanish lipedema patients, diagnoses used the Schingale type I-IV classification (type III 41.7%, type IV 36.8%, type II 17.8%, type I 3.7%) and a modified Wolf/Herbst 13-criteria symptom scale; the authors validated a threshold of ≥6 of 13 symptoms (Mann-Whitney p=0.666 showing no distributional difference between diagnosed and undiagnosed groups), and diagnosis often required multiple consultations (51.2% needed ≥3 specialists).
The Advanced Care Study: Current Status of Lipedema in Spain, A Descriptive Cross-Sectional Study — Carballeira Braña & Poveda Castillo (2023) - SCR-LIP-000068 consistent
Dutch lipedema guidelines conclude that lipedema is frequently misdiagnosed or wrongly classified as an aesthetic problem, and recommend a minimum data set of repeated clinical measurements (waist circumference, limb circumferences, BMI, and psychosocial distress scoring) to ensure early detection.
First Dutch guidelines on lipedema using the international classification of functioning, disability and health — Halk & Damstra (2017) - SCR-LIP-000069 consistent
Lipedema is often unrecognized or misdiagnosed despite an estimated prevalence of 10% in the overall female population, and diagnosis currently relies on clinical grounds alone due to the lack of specific biomarkers or objective measuring instruments.
Lipedema—Pathogenesis, Diagnosis, and Treatment Options — Kruppa et al. (2020) · Lipedema: Clinical Features, Diagnosis, and Management — Mortada et al. (2025) · Lipoedema is not lymphoedema: A review of current literature — Shavit et al. (2018) · Lipedema: What we don’t know — van la Parra et al. (2023) - SCR-LIP-000359 consistent
This systematic review of 61 articles found that lipedema diagnosis relies largely on clinical features from observational cohorts, case series, and expert consensus with few randomized trials, and concluded that standardized diagnostic criteria and validated patient-reported outcomes are still lacking.
Lipedema Diagnosis, Clinical Manifestations, and Therapeutics: A Systematic Review — Vazirnia et al. (2026) - SCR-LIP-000275 consistent
Using a previously validated online screening questionnaire (cutoff ≥12 points, AUC 0.8615, specificity 0.88, sensitivity 0.46, PPV 0.767), a population-representative study estimated lipedema prevalence at 12.3% among Brazilian women aged 18-69, corresponding to roughly 8.8 million women with suggestive symptoms.
Prevalência e fatores de risco para lipedema no Brasil — Amato et al. (2022) - SCR-LIP-000358 consistent
The authors propose a clinical-ultrasonographic diagnostic algorithm for abdominal lipedema using maximum criteria (symmetric abdominal fat deposition + ultrasonographic evidence + inelastic skin), major criteria (pain on palpation + non-response to diet/exercise), and minor criteria (easy bruising + heaviness), correlating abdominal involvement with lipedema stage (31% in stage II, 70% in stage III).
Abdominal Lipedema: Clinical Diagnosis and Management Through a Proposed Diagnostic Algorithm — Bruno & Cilluffo (2025) - SCR-LIP-000277 consistent
In non-obese lipedema patients, standardized QST (DFNS protocol) revealed selective alterations in only 2 of 13 parameters at the affected lateral thigh—elevated pressure pain (PPT, AUC 0.9075) and reduced vibration detection (VDT, AUC 0.8638)—and a combined PPT+VDT z-score score was proposed as a rapid diagnostic test for lipedema.
Non-obese lipedema patients show a distinctly altered Quantitative Sensory Testing profile with high diagnostic potential — Dinnendahl et al. (2023) - SCR-LIP-000199 consistent
In a DXA body composition study, the leg fat mass/total fat mass index distinguished lipedema patients from healthy controls with AUC=0.90 (sensitivity 0.95, specificity 0.73 at cutoff 0.383) across all BMI strata, with elevated leg fat proportion (0.451 vs 0.354) and inverted trunk/legs ratio (0.960 vs 1.502), while appendicular lean mass and total bone density did not differ.
Body Composition Assessment by Dual-Energy X-Ray Absorptiometry: A Useful Tool for the Diagnosis of Lipedema — Buso et al. (2022) - SCR-LIP-000280 consistent
This reply letter states that lipedema is frequently underdiagnosed and confused with obesity and lymphedema (worsened by phonetic similarity among 'lipedema', 'lipidemia', and 'lipemia'), and defends an ultrasound diagnostic cutoff incorporating dermal and subcutaneous thickness (mean subcutaneous thigh thickness 20.9 mm in lipedema vs 12.67 mm in controls).
Reply letter to the editor regarding ultrasound examination for en-suite measurements in lipedema — Amato & Saucedo (2022) - SCR-LIP-000284 consistent
This narrative review describes lipedema as a common but rarely diagnosed condition frequently confused with obesity, emphasizing that early recognition based on the diagnostic triad of spontaneous pain, pressure pain, and easy bruising is essential to prevent progression.
Lipedema, a hardly known disease: diagnosis, associated illnesses and therapy — Wenczl & Daróczy (2008) · Lipedema and obesity: A narrative review and treatment protocol. — Rathod S, Pouwels S, Schmidt J. (2026) - SCR-LIP-000285 consistent
A systematic review reported that lipedema is poorly recognized clinically—only 46.2% of 251 Vascular Society of Great Britain and Ireland consultants recognized it (Tiwari 2006)—and that it was absent from MeSH/EMBASE and ICD-WHO as of 2012, while non-contrast CT showed 95% sensitivity and 100% specificity and the spared foot dorsum (negative Stemmer sign) helps distinguish lipedema from lymphedema.
Lipedema: an overview of its clinical manifestations, diagnosis and treatment of the disproportional fatty deposition syndrome – systematic review — Forner‐Cordero et al. (2012) - SCR-LIP-000191 consistent
Bioimpedance spectroscopy of regional tissue fluid distinguished lipedema from Dercum's disease (lower leg/arm R0 ratio in lipedema, p<0.001) and detected stage 1 lipedema versus matched controls (leg/arm ratio R0 p=0.01, R1 p=0.007), with leg extracellular water increasing across lipedema stages (p=0.03), proposing BIS as an objective adjunct biomarker for diagnosis and staging.
Lipedema and Dercum's Disease: A New Application of Bioimpedance — Crescenzi et al. (2019) - SCR-LIP-000287 consistent
In a case-control study, carriers of the IL-6 rs1800795 G allele had a 5.92-fold higher risk of lipedema (OR=5.92, 95%CI 1.983–17.711, p<0.001), and DXA-derived body composition indices (reduced WHR 0.73 vs 0.79, higher lower-limb FM% 48.90% vs 42.55%) combined with genetic analysis were proposed as tools for differential diagnosis between lipedema, normal-weight obesity, and obesity.
The role of IL-6 gene polymorphisms in the risk of lipedema — Di Renzo L et al. (2020) - SCR-LIP-000288 consistent
In a prospective cohort of 138 lipedema and 111 lymphedema patients, a CART algorithm using only three clinical variables (bruising, body disproportion, and non-swollen/spared feet) classified lipedema versus lymphedema with 100% accuracy, and the median time from symptom onset to diagnosis was markedly longer in lipedema (25.5 years vs 12.1 years for lymphedema, p<0.0001).
Building evidence for diagnosis of lipedema: using a classification and regression tree (CART) algorithm to differentiate lipedema from lymphedema patients — FORNER-CORDERO et al. (2025) - SCR-LIP-000198 consistent
In 50 lipedema patients versus 50 controls, ICG lymphography and lymphoscintigraphy revealed slower superficial lymph flow (ICG reached upper calf in 8% vs 56%, p<0.0001), more numerous and dilated/tortuous lymphatic vessels, higher fluorescence intensity, higher skin water concentration in the feet (p=0.000189), and increased subcutaneous tissue stiffness, supporting their utility in diagnosing lipedema.
Lower Limb Lipedema–Superficial Lymph Flow, Skin Water Concentration, Skin and Subcutaneous Tissue Elasticity — Zaleska et al. (2023)
Conflicting claims
- None indexed yet.
Refining / contextual
- SCR-LIP-000063 context
Lipedema is often misdiagnosed and affects approximately 11% (about 1 in 9) of adult women.
Observational Study of Ultrasound-Assisted Liposuction for Lower Limb Lipedema on 191 Female Patients — Hersant et al. (2026) · Lipedema: A Relatively Common Disease with Extremely Common Misconceptions — Buck & Herbst (2016) · Lipedema: A Call to Action! — Buso et al. (2019) · Lipedema: Progress, Challenges, and the Road Ahead — Cifarelli (2025) - SCR-LIP-000067 refines
Reviews of imaging and measurement tools for lipedema find multiple modalities in use (ultrasound, lymphoscintigraphy, CT, MRI/MR-lymphangiography, DXA) but inconsistent protocols, measurement locations, and outcome analysis, with limited clinimetric reporting from small heterogeneous cohorts — preventing recommendation of any single tool for clinical practice.
Assessment Tools to Quantify the Physical Aspects of Lipedema: A Systematic Review — Eason et al. (2025) · Diagnostic imaging in lipedema: A systematic review — van la Parra et al. (2024) - SCR-LIP-000279 context
This editorial commenting on Crescenzi et al. (2023) emphasizes the lack of reliable lipedema biomarkers and highlights noncontrast 3T MR lymphangiography—which reveals subcutaneous adipose tissue edema and increased lymphatic load—as a promising imaging biomarker that could aid differential diagnosis between lipedema and obesity, while noting small sample sizes limit current evidence.
Editorial for “Subcutaneous Adipose Tissue Edema in Lipedema Revealed by Noninvasive 3T Magnetic Resonance Lymphangiography” — Wang (2023) - SCR-LIP-000281 context
In a cross-sectional online survey, lipedema patients more frequently reported hypermobility (44% in adulthood, ~60% in childhood), joint pain, and multisystem symptoms than lymphedema patients, and the authors note lipedema remains underdiagnosed and should be reconceptualized as a systemic connective tissue disorder.
Lipedema and Hypermobility Spectrum Disorders Sharing Pathophysiology: A Cross-Sectional Observational Study — Fiengo & Sbarbati (2025) - SCR-LIP-000282 context
A systematic review of molecular and cellular lipedema research estimated worldwide prevalence at approximately 11% among women, noting this figure is inflated by underdiagnosis and acknowledged diagnostic limitations, but the review focused on molecular biology and did not evaluate screening tools.
Lipedema Research—Quo Vadis? — Ernst et al. (2023) - SCR-LIP-000283 context
In a cohort of 83 women with clinically diagnosed lipedema, symptoms began at a mean age of 20.4 years but diagnosis occurred at a mean age of 46.5 years, indicating a mean diagnostic delay of 26.1 years, while lymphoscintigraphy showed lymphatic alterations in 47% of patients across all clinical stages.
Hallazgos linfogammagráficos en pacientes con lipedema — Forner-Cordero et al. (2018)
Major uncertainty
No screening or imaging tool has been validated in large independent prospective cohorts; reported diagnostic accuracies (AUCs, CART 100%) come from small, single-setting, mostly in-sample studies with heterogeneous protocols, and the true population prevalence remains uncertain because high estimates may themselves reflect imperfect screening (e.g., low-sensitivity questionnaires).
Version history
- SQ-LIP-000004 · v1.7 — 2026-06-14 — This update added a narrative review reinforcing that lipedema is often misdiagnosed as obesity or lymphedema and that earlier recognition can benefit treatment, consistent with the existing answer without changing its conclusions. · view this version
- SQ-LIP-000004 · v1.6 — 2026-06-02 — Answer recompiled after human curation of the claim set. · view this version
- SQ-LIP-000004 · v1.5 — 2026-06-02 — Answer recompiled after human curation of the claim set. · view this version
- SQ-LIP-000004 · v1.4 — 2026-05-31 — This update added numerous candidate diagnostic/screening modalities (QST PPT+VDT score, DXA fat-distribution index, bioimpedance spectroscopy, ultrasound thickness cutoffs, non-contrast CT, ICG and MR lymphangiography, IL-6 genotyping, and a 3-variable CART classifier with 100% accuracy) plus stronger documentation of long diagnostic delays (~25–26 years) and low clinician recognition (46.2% of UK vascular surgeons), reinforcing underdiagnosis while expanding the still-unvalidated toolkit. · view this version
- SQ-LIP-000004 · v1.3 — 2026-05-31 — Answer recompiled after human curation of the claim set. · view this version
- SQ-LIP-000004 · v1.2 — 2026-05-31 — This update substantially expanded the evidence base by adding multiple new supporting studies—including large Spanish cohorts (1069 and 1803 patients), a Saudi Arabian clinic study, a Turkish physician survey, two systematic reviews on imaging and measurement tools, a 61-study systematic review confirming chronic underdiagnosis, Dutch guidelines recommending a minimum measurement data set, and several additional narrative reviews—collectively strengthening the conclusion that lipedema is underdiagnosed across diverse geographic and clinical settings while also refining the assessment of screening tools by documenting their inconsistency and lack of prospective validation. · view this version
- SQ-LIP-000004 · v1.1 — 2026-05-31 — This update added two new pieces of evidence: a 2026 narrative review explicitly calling for systematic lipedema screening to prevent misclassification in pain–inflammation research, and a 2026 surgical cohort that corroborates underdiagnosis by describing lipedema as 'often misdiagnosed' and citing ~11% prevalence, though neither study addresses screening tool validation. · view this version
- SQ-LIP-000004 · v1.0 — 2026-05-30 — founding index (27 claims) · view this version
Key references
DOI:10.1177/02683555211002340 · DOI:10.1590/1677-5449.200114 · DOI:10.1590/1677-5449.200049 · DOI:10.36557/2674-8169.2026v8n2p869-884 · DOI:10.1097/prs.0000000000012217 · DOI:10.1097/gox.0000000000001043 · DOI:10.1002/oby.22597 · DOI:10.1111/obr.13953 · DOI:10.1097/gox.0000000000006173 · DOI:10.1177/02683555251332998 · DOI:10.3390/biomedicines13123049 · DOI:10.3390/ijerph20176647 · DOI:10.1089/lrb.2024.0102 · DOI:10.1111/obr.13648 · DOI:10.1177/0268355516639421 · DOI:10.3238/arztebl.2020.0396 · DOI:10.1055/a-2530-5875 · DOI:10.1111/iwj.12949 · DOI:10.1016/j.bjps.2023.05.056 · DOI:10.1111/ijd.70227 · DOI:10.1590/1677-5449.202101981 · DOI:10.1007/s00266-025-05192-1 · DOI:10.1101/2023.04.25.23289086 · DOI:10.1159/000527138 · DOI:10.1002/jmri.28400 · DOI:10.1177/02683555211068953 · DOI:10.3390/jcm14207195 · DOI:10.3390/jpm13010098 · DOI:10.1016/j.remn.2018.06.008 · DOI:10.1556/oh.2008.28490