Plantar soft tissues and Achilles tendon thickness and stiffness in people with diabetes: a systematic review

Six electronic databases were systematically searched by the first reviewer (B.K.) for studies published from database inception until 1st October 2020. The databases were: EBSCOhost (AMED, CINAHL, MEDLINE), ProQuest (Health & Medical Collection, Nursing & Allied Health Database), and Web of Science. No date restrictions were imposed, however, studies were restricted to those published in English and in peer-reviewed journals only. Boolean operators and relevant MeSH terms were used and keywords were adapted for each database (Additional file 1).

Studies which met criteria in the following five categories were eligible for inclusion. (1) Population: cohorts comprised of adults 18 years old and above were included; experiments conducted on animals, artificial tissues, cadavers or minors below 18 years old were excluded. (2) Interventions: no restrictions set. (3) Comparison: studies which had made a comparison between cohorts with and without diabetes were included; non-comparative studies, specifically studies which had not included a control group of otherwise healthy adults, were excluded. (4) Outcomes: in-vivo assessments of either thickness and/or stiffness of plantar soft tissues and/or the AT were included; in-vitro studies, studies which assessed other body parts or internal body organs, or technical studies solely evaluating the physics or engineering of the measurement technique were excluded. (5) Type of study: quantitative primary research studies published in peer-reviewed journals were included; qualitative studies, case reports, commentaries, conference proceedings, narrative reviews, and studies published in non-peer reviewed journals were excluded.

All articles retrieved in the search were first exported to RefWorks for removal of duplicates and subsequently exported to Covidence. Two reviewers (B.K. and R.B.) independently screened all titles and abstracts against pre-established inclusion and exclusion criteria. Articles which appeared to be eligible were retrieved in full and assessed by both reviewers. Upon mutual agreement for inclusion, the reference lists of included articles were additionally screened. This iterative process was performed until no further articles could be included. Where full-text articles could not be accessed, university library services were employed and authors contacted directly; this was successful on six occasions. Throughout this process, discrepancies were first resolved by consensus between the two reviewers (B.K. and R.B.) with adjudications sought from a third reviewer (J.W.) where required.

All included studies were appraised for their methodological quality using a modified critical appraisal tool for quantitative studies developed by McMaster University [24]. This modified tool comprehensively evaluates 14 different aspects of methodological quality, categorised under the domains: study purpose, literature, design, sample, outcome, assessment technique, results, conclusions and implications. Quality assessment was performed by the first reviewer (B.K.) and checked in full by the second reviewer (R.B.). As the thresholds for distinguishing between study quality grades have not been established, study quality was scored upon mutual agreement by two reviewers (B.K. and R.B.). Assessment rubrics [25] provided by McMaster University to guide the completion and interpretation of each criterion were adhered to, and where additional criteria were applied by the reviewers, these are detailed as follows.

A descriptive synthesis was conducted using summary data from individual studies to identify the directionality of PTT, PTS, ATT and ATS changes in people with diabetes when compared to their controls. Absolute values for PTT and ATT were further extracted. Where sufficient data permits, subgroup analysis was undertaken to identify the presence of any anatomical variations across the plantar aspect of the foot and the length of the AT, and to explore how findings may compare across cohorts with different diabetes-related complications. This includes people with DPN or people with either an active or history of DFUs.

All 35 papers included were non-randomised observational studies assessed to be of low quality. Overall, the degree of reporting was deemed to be inadequate for the following components of methodological quality: study design, sample size justifications, strategies to reduce confounding, reliability and validity of outcome measures utilised, and assessment techniques (Table 2).

For PTS, 18 different outcome metrics were adopted across 19 studies (Table 3). Of these, two or more metrics were utilised by six studies. For ATS, four different outcome metrics were noted across five studies. These include an elastographic colour map [38], shear wave velocity [33, 35], Young’s modulus [41], and a measurement of the slope over the last 20% of tendon deformation from fitting the force-deformation data to a third-order polynomial [68].

The main findings for PTT, PTS, ATT and ATS outcomes are tabulated in Table 4.

This systematic review investigated the evidence for differences in plantar soft tissue and AT thickness and stiffness in people with and without diabetes. The general consensus among studies was that diabetes is associated with a significant increase in PTS, however the differences in PTT is not significant. Studies also found that diabetes is associated with a significant increase in ATT, however the differences in ATS is not significant.

Extensive methodological heterogeneities and deficiencies was a key finding of this systematic review. Sample sizes were seldom justified (3%, 1/35). Additionally, reporting was generally inadequate across the domains of study designs and the reliability and validity of outcome measures. Case definition for participants with diabetes and subgroups formed on the presence and history of DFU or DPN were often absent or inadequately defined. Furthermore, the risk of selection bias cannot be eliminated in the majority of studies as only 6% of studies adopted a consecutive sampling method for recruiting people with diabetes; the remaining 94% of studies (33/35) made no mention of their sampling strategy for their cohorts with diabetes.

No gold standard assessment techniques have been established for tissue thickness and stiffness assessments and this was reflected in the diverse approaches reported in this review. Studies that employed novel biomedical technologies and tissue engineering outcomes are additionally not easily reproduced and are not well understood in clinical settings. Ultrasound-based techniques were favoured – utilised by 80% of studies (16/20) investigating PTT, 47% of studies (9/19) investigating PTS, 89% of studies (8/9) investigating ATT, and 100% of studies (5/5) investigating ATS – but standardisation in its usage is lacking. Ultrasound-based techniques are also known to be highly dependent on the knowledge, experience and skill of the operator [69]. Therefore, the extent to which outcomes have been reliably measured is important. However, no mention of reliability was made in 60% of studies (21/35).

Studies further differed in their measurement techniques. Using PTT for example, while the majority of studies (70%, 14/20) measured PTT as the distance between skin and bone, overall six different methods of measurements were observed. Combined with the use of different assessment techniques and examination of different anatomical sites, these wide-ranging methodological heterogeneities made it difficult to compare and synthesise results across studies. The lack of standardisation also renders derivation of normal and diagnostic cut-off values extremely challenging and hampers routine clinical utility for at-risk screening, detection and longitudinal monitoring.

On the plantar aspect of the foot, areas at high risk of ulceration are the apices of the toes, metatarsal heads, medial aspect of the midfoot and the heel [4]. This systematic review observed that evidence for the differences in PTS is more consistent across included studies than PTT (Additional file 5). However, regional variations in either PTT or PTS appear modest. This implies that other risk factors such as tissue load, in the presence of structural tissue changes, may be more important for the development of DFU rather than either factor alone. These findings reinforce the multi-factorial nature of plantar DFU pathogenesis [5, 6] and the need for further mechanistic and outcome focused research.

The lifetime incidence of DFUs is estimated to be up to 35% [6]. DFU recurrence rates are also high, with the pooled global recurrence rates estimated in a meta-analysis to be 22.1% per person-year (95% CI, 19.0–25.2%) [21]. However, the extent to which plantar soft tissue changes contribute to either the development of primary ulcerations or its recurrence is little understood. No firm conclusions can be drawn from this review, as only 6% of studies (2/35) directly compared either active or healed DFU sites with never-ulcerated sites. Additionally, none of the included studies measured differences in PTT or PTS at the apices of the toes. Combining the paucity of studies primarily investigating these associations with the methodological shortfalls identified in existing studies, the clinical significance of tissue thickness or stiffness changes in its role in contributing towards plantar DFUs remains unclear.

Achilles tendon changes in diabetes are recognised to potentially alter ankle biomechanics [16], increase forefoot plantar pressures and contribute to tissue breakdown [70]. This systematic review identified that people with diabetes, particularly those with DPN and DFU, may have a thicker AT but reduced AT stiffness. The International Working Group on the Diabetic Foot (IWGDF) guidelines [71] recommend AT lengthening procedures to be considered as a potential management option for the prevention of DFU recurrence. It is not clear what the implications of these findings are for such procedures. The authors of this systematic review are unaware of studies that have specifically investigated the association of either ATT or ATS with AT lengthening procedures and this merits further investigation.

Thickening in tendons are often regarded as pathological clinically [17, 72]. While the site of localised thickening could be important, this review and the evidence synthesised does not elucidate. It is further uncertain if a thicker or thinner AT, stiffer or less stiff AT, presenting simply by virtue of its different thickness or stiffness when compared to an otherwise healthy cohort, can therefore be viewed as pathological in diabetes. To the best of the authors’ knowledge, the normative values of ATT or ATS have not been established in a cohort of people with diabetes, such that even in the absence of symptomology, said AT changes should therefore be regarded as tendinopathic.

Asymptomatic AT pathologies are common in athletic and general populations [73‐76]. While AT structural changes do not always trigger tendon pain [77], this could arguably be more prevalent in people with diabetes due to masking from DPN. However, the lack of symptoms may not negate the potential for occult AT thickness or stiffness changes to persist in its alterations to gait. To this end, this systematic review contributes to this research gap by providing indicative ATT values from included studies (Additional file 4). The extensive heterogeneity in outcome metrics prevented similar consolidations in findings for ATS. Further work is required and advances in technology may afford greater insights into the ATT and ATS changes in diabetes.

It is further unclear to what extent baseline factors such as age, sex, BMI, duration of diabetes and glycaemic control are associated with soft tissue changes in diabetes. In this systematic review, the differences between groups with diabetes and control groups in age, sex and BMI were statistically not significant in 40% of studies which appears to reduce the potential for confounding. However, studies reviewed have documented poor correlations between age with PTT [37, 40], PTS [40] and ATT [33] differences; BMI with PTT and PTS differences [40]; duration of diabetes with PTT [40], PTS [40] and ATT [33] differences; as well as HbA1c levels with PTT [39, 40], PTS [40] and ATT [33] differences between people with and without diabetes. Strong correlations have however been found between triglyceride levels and PTS differences in the heel for people with diabetes [40]. Nonetheless, it was difficult to tease out whether soft tissue alterations were due to the adequacy of glycaemic control, chronicity of hyperglycaemia, hypertriglyceridemia, severity of DPN or other potential confounders in demographics. This requires careful attention in future studies.

This systematic review has several strengths. The review included all studies published to date on the topic, including a body of knowledge from the biomedical technology field where assessment techniques were utilised in cohorts of people with diabetes and associated risk factors for DFU. Extensive search strategies were employed with detailed, careful and critical assessment to identify risk of bias. The review is, however, limited by the methodological deficiencies of included studies. The critical appraisal tool by McMaster University [24] has also not been validated and the threshold for distinguishing between grades of methodological quality have not been established. Substantial methodological heterogeneities prevented the conduct of meta-analysis which further limits the review. Additionally, two papers with similar cohorts may have contributed to the observed heterogeneity. However, since no pooled analysis was undertaken, the effect on the precision of the estimated outcome is unclear.