Dystrophic calcification as a cause for non healing leg ulcers

Abstract

Despite advances in molecular biology and a repertoire of other therapeutic options, chronic venous leg ulcers remain a significant problem within our society. There are various reasons, both local and systemic, which contribute to the non healing nature of such wounds. Among them, dystrophic calcification (DC) or calcified deposits within the ulcer bed, although rare, is an overlooked and a seldom reported cause. In the presence of DC, wound healing cannot proceed through a timely and orderly manner resulting in a non healing ulcer. In this article, we discuss the aetiology, pathophysiology and the management options of this rarely reported condition. We also report their clinical prognosis using a series of patients with venous ulcers complicated by DC leading to difficulties in healing.

Introduction

Lower extremity ulcers related to chronic venous insufficiency have been estimated to affect 0·2–1% of the population in the developed countries (1, 2). Among all forms of leg ulceration, up to 70% is caused by venous disease (3). The majority of the simple venous ulcers heal with appropriate standard treatment; however, due to various reasons, including calcification within the ulcer bed, some ulcers fail to heal and progress to a chronic venous leg ulcer (CVLU). Although radiological studies have estimated subcutaneous calcification to be present in up to 10% of the patients with chronic venous insufficiency (4), the actual presence of calcified deposits within the ulcer itself is rather uncommon and rarely reported. The presence of calcium deposits within the wound but with normal serum calcium (Ca⁺⁺) and phosphate levels (PO₄) is referred to as dystrophic calcification (DC) — a form of localised deposition of calcium salts in dead or degenerated tissues.

In the absence of frank extrusion of calcium from the ulcer(s), small amounts of calcified deposits within the ulcer bed are frequently overlooked. These calcified deposits impede healing not just, by their presence, splitting the wound open but may also elicit a foreign body reaction in the wound thus perpetuating a chronic inflammatory state. They appear as dark (brownish black) hard deposits adherent to the base and the sides of the wound (Figure 1). Sometimes, they may become embedded in the fibrous tissue within the wound bed. They are difficult to remove, and forced removal may evoke severe pain. The management of this condition is challenging and there is no consensus of opinion regarding its most appropriate treatment.

Figure 1.

Dystrophic calcification in a venous leg ulcer.

In this article, we highlight its significance and clinical prognosis using a series of patients with CVLU complicated by calcified deposits within the wound, leading to delayed healing. In addition to describing the aetiology and pathophysiology, this is the first article, to the authors' knowledge, which discusses the various management options of this rarely reported association.

Case series

Case 1

An 81‐year‐old lady presented with an 18‐month history of bi‐malleolar ulcers in her right leg. The ulcers had minimal granulation tissue, and the surrounding skin demonstrated evidence of venous disease. A venous duplex scan revealed incompetence of both the superficial and the deep venous systems. All bloods, including serum Ca⁺⁺ and PO₄ levels and renal function, were normal. Although there was initial improvement with conservative treatment, Ca⁺⁺ deposits were soon noted in the ulcer bed. The ulcers became painful and extended deep to the tibia resulting in osteomyelitis which settled following treatment with appropriate antibiotics. X‐ray revealed marked subcutaneous calcification. The Ca⁺⁺ deposits were mechanically extracted with forceps during the patient's out‐patient visits. With repeated removal of the calcified material and appropriate conservative treatment, the ulcers progressed towards healing and relief of the patient's symptoms (pain). However, reaccumulation of Ca⁺⁺ was noted after a few months.

Case 2

An 88‐year‐old lady presented with a 6‐month history of a painful ulcer over her left medial malleolus. The surrounding skin revealed evidence of postphlebitic syndrome with lipodermatosclerosis (LDS) and varicose eczema. A venous duplex scan revealed gross postthrombotic changes in the calf veins suggestive of previous deep venous thromboses. Seven months after presentation, calcification was observed in the wound bed. All bloods, including serum Ca⁺⁺ and PO₄ levels and renal function, were unremarkable. X‐ray of the left lower leg demonstrated extensive calcification, both around the ulcer and in the adjacent soft tissues. The calcified material was removed mechanically during her out‐patient visits, but it soon reaccumulated, and the ulcer progressively got worse. Surgical debridement and excision of the ulcer was suggested to the patient but was refused by the patient and her relatives. The ulcer remains static and painful at present.

Case 3

A 71‐year‐old lady presented with an 8‐month history of painful, extensive ulceration over her left gaiter region. Examination revealed a classic venous ulcer with surrounding LDS and varicose eczema. Extensive calcification was found in the ulcer base, which was refractory to mechanical removal in the out‐patient clinics. She was hence referred to have complete surgical excision of the ulcer and skin grafting. This yielded good results, and she has not developed recurrence of the ulcer after 10 years. However, 5 years after surgery, she developed new ulceration in the adjacent area which also was associated with the development of calcified deposits. She was also noted to have extensive subcutaneous calcification around the ulcers. The ulcer remains static, and further surgical intervention in the form of complete ulcer excision and grafting is being contemplated at present.

Discussion

Distinction has to be made between subcutaneous calcification in chronic venous insufficiency and the actual presence of calcified deposits within the ulcer, although they may coexist. The former, identified radiologically, is mostly an incidental finding, while the latter may be seen or felt within the ulcer bed. Similarly, the role of the mere presence of subcutaneous calcification (in the absence of calcification within the wound) in causing CVLU is unclear, but it is acknowledged that calcified deposits within the wound bed impede healing (5, 6). This article specifically focuses on the role of calcified deposits within the ulcer leading to non healing and discusses the management options.

Ca⁺⁺ is a divalent cation which plays a role in a variety of physiological functions in humans such as skeletal and myocardial muscle contraction, neurotransmission and blood coagulation. In addition, it is the primary mineral in the bony skeleton. Only 10% of the total body Ca⁺⁺ is soluble (50% biologically active and 50% bound to albumin or other anions) and present in extra‐ and intracellular fluid whilst the remaining 90% is present as crystalline substances (e.g. hydroxyapatite). Despite tight regulation of serum Ca⁺⁺ by various regulatory hormones (parathyroid hormone, calcitonin and vitamin D), calcification (deposition of insoluble calcium salts) and ossification (deposition of calcium salts within the collagen matrix laid by osteoblasts) in cutaneous tissues occur in various organs and is frequently reported (although not in wounds) in the medical literature.

Incidence

There are no accurate estimates about the actual incidence of calcified deposits within venous ulcers, although various studies have reported the incidence of subcutaneous calcification in chronic venous insufficiency. Lindner (1953) (7) described 20 patients with postphlebitic syndrome, of whom, eight had radiological evidence of subcutaneous calcification. In 1960, Lippman and Goldin (4) evaluated 600 patients with chronic venous insufficiency and found radiological evidence of subcutaneous calcification in 60 patients. More recently, Piry et al. (1992) (8), in a study of 40 patients with chronic venous insufficiency, reported the presence of subcutaneous calcification in up to seven patients.

Types of calcification

Cutaneous calcification could be divided into four main categories: (i) dystrophic, (ii) metastatic, (iii) idiopathic and (iv) iatrogenic (Table 1) (9, 10). (i) DC occurs as a result of local tissue injury and/or a persisting local abnormality such as a wound. In the context of a wound, continued inflammatory state, presence of nonviable or necrotic tissue or alterations in the cellular or extracellular components (collagen, elastin, proteoglycans, etc.) may precipitate calcification. In DC, the Ca⁺⁺ and PO₄ metabolism and their serum levels are normal; the internal organs remain unaffected. (ii) In metastatic calcification, there is abnormal Ca⁺⁺ and/or PO₄ metabolism, leading to hypercalcaemia or hyperphosphataemia; serum calcium levels may be elevated. This may lead to the calcification of normal cutaneous, subcutaneous and deep tissues. (iii) The cause of idiopathic calcification, as the name suggests, is unknown. In the absence of a precipitating cause and aberrant Ca⁺⁺ and/or PO₄ metabolism (and normal serum Ca⁺⁺), there is abnormal deposition of Ca⁺⁺ in subcutaneous tissues. Examples of this condition include idiopathic calcification of the scrotum in young men and subdermal calcified nodules over the head or extremities in otherwise healthy people. (iv) Iatrogenic calcification is a recognised complication of intravenous calcium chloride and calcium gluconate therapy. Elevated local tissue concentration of Ca⁺⁺ and tissue damage may result in the appearance of calcified nodules; the condition is painful but self‐limiting.

Table 1.

Different types of cutaneous calcification

Type	Mechanism	Metabolic disturbance	Conditions where it may be seen
Dystrophic	Result of local tissue injury or abnormalities	None; calcium and phosphate metabolism andtheir serum levels are normal Internal organs unaffected	Chronic venous insufficiency, connective tissue diseases, trauma, panniculitis, porphyria cutanea tarda, pseudoxanthoma elasticum, cutaneous neoplasms, Ehlers–Danlos syndrome
Metastatic	Caused due to underlying aberration in calcium and/or phosphate metabolism	Abnormal calcium and/or phosphate metabolism leading to hypercalcaemia or hyperphosphataemia Leads to widespread calcification of cutaneous, subcutaneous and deep tissues (blood vessels, kidneys, lungs and gastric mucosa)	Chronic renal failure, neoplasms (usually malignant), hypervitaminosis D, Milk–Alkali syndrome, sarcoidosis, Albright hereditary osteodystrophy, pseudoxanthoma elasticum
Idiopathic	No underlying cause identified	Calcium and phosphate metabolism and their serum levels are normal Internal organs usually unaffected	Seen in the scrotum (of boys and young men), around major joints (tumoral calcinosis), progressive osseous heteroplasia and head or extremities (subepidermal calcified nodules)
Iatrogenic	Due to extravasation of calcium chloride or calcium gluconate during intravenous therapy	Calcium and phosphate metabolism and their serum levels are normal Elevated tissue concentration of calcium at the site of extravasation Internal organs unaffected	Not associated with any particular disease or disorder

Pathophysiology of DC

DC is encountered in areas of necrosis of any type. Although it may simply represent evidence of previous cellular injury, it is often also a cause for organ dysfunction as seen in the damaged heart valves and the aorta. Although the exact aetiology of DC in venous insufficiency remains obscure, the general pathogenesis of DC involves initiation and propagation, leading to the formation of crystalline calcium phosphate (11). Initiation of intracellular calcification occurs in the mitochondria of dead or dying cells that have lost their ability to regulate intracellular Ca⁺⁺, leading to a large influx of Ca⁺⁺. It is also possible that cell necrosis creates a more acidic environment that lacks certain calcification inhibitors. Once the intracellular Ca⁺⁺ and PO₄ solubility product is exceeded, crystallisation is initiated and propagated within the mitochondria, causing cellular respiration failure, necrosis and death; the formation of crystalline calcium phosphate mineral in the form of an apatite similar to the hydroxyapatite of bone is the end result of this process. Histologically, Ca⁺⁺ salts are recognised as either fine granules or small deposits in the dermis or as large amorphic deposits in the subcutaneous fat. It is also visible to the naked eye and appears as gritty, sandlike grains or a firm, rock hard material.

Management

The management of this condition is challenging. The presence of calcified deposits within CVLU is frequently misdiagnosed as fibrotic tissue, and hence, there is limited published work discussing its appropriate management. No series is sufficiently large to evaluate the effectiveness of different modalities of treatment, and prospective trials are precluded by the relative rarity of this association. The little information we have is obtained not from controlled studies but rather from isolated case reports (6, 12, 13). Furthermore, many articles over the years describe and discuss subcutaneous calcification (5, 14, 15, 16), although calcified material was not clinically evident in the ulcer crater of all patients. Based on our experience, some forms of treatment which may be effective are discussed below.

Conservative

This should be considered to be the first line of management. Calcified deposits are dry which leads to hard deposits in the wound bed. A hydrogel dressing which donates moisture to the wound might be effective in debriding (lifting off) the calcified deposits. In addition, because chronic wounds accumulate necrotic tissue and slough in the wound bed, a hydrogel dressing may also be effective in facilitating autolytic debridement. However, there is insufficient evidence to support any particular form of wound dressing (therapy) over the other.

Mechanical removal

Removal of the calcium deposits with a pair of forceps should be attempted if the patient is able to tolerate the procedure. Forced removal may provoke severe pain, and in such instances, a topical anaesthetic cream such as Emla^®[combination of lidocaine (lignocaine) and prilocaine] applied 30–60 min prior to debridement may be effective. If the patient is unable to tolerate either, then a hydrogel dressing (discussed above) should be used to lift off the calcified deposit and removal is attempted at the patient's next visit. If the deposits are minimal, regular extraction may lead to some improvement in symptoms, although temporary, as observed in Case 1.

Surgical removal

The role of surgery, under general anaesthesia, to remove the calcified deposits is very limited. This is due to the fact that many patients are elderly and frail and may not withstand the procedure. In addition, patients (and sometimes relatives) are not keen on surgical removal (as in Case 2), particularly because these calcified deposits frequently recur.

Surgical excision of the ulcer with or without skin grafting

Peled et al. (1982) (5) observed the failure of ulcerations associated with DC (n = 5) to respond to conservative treatment and suggested radical excision of the ulcer and skin grafting to be the definitive therapy. In addition, if the ulcer becomes excruciatingly painful, as happens in some patients, and leads to recurrent episodes of infection, complete excision of the ulcer and the ulcer bed and coverage of the area with split‐skin grafting is a suitable option (Case 3). Shave therapy is one such treatment where the ulcer (venous) including the ulcer bed is excised along with any surrounding LDS (17). This area could then be covered with split‐skin grafting (18). If the area is very large, fascial pedunculated rotation flaps (19) have been purported to be useful, although the evidence is limited; similarly, the role of autologous full‐thickness punch grafts (20) and cultured autologous and allogenic keratinocyte sheets (21) to cover the exposed area have not been evaluated in this condition. Patients who undergo surgical excision and grafting should however be warned of the possibility of new areas of ulceration and subsequent calcification as observed in Case 3.

Other modalities of treatment such as extracorporeal shock‐wave lithotripsy (ESWL), in addition to renal and gallbladder calculi, have been used to treat calcified deposits such as those over the abdomen and within the shoulder joint (chronic calcifying tendonitis) (22). However, ESWL should be avoided around bones, particularly in the elderly with osteoporosis, because there is the potential for iatrogenic fractures. It is therefore not recommended in the treatment of calcification in lower limb ulcers. Likewise, a variety of medical modalities such as aluminium hydroxide, disodium etidronate, intralesional corticosteroids and a diet low in calcium and phosphate have been attempted in the past, but none is established in the management of DC in CVLU.

Care in the community

Leg ulcer care in the UK is currently predominantly provided by community nurses (23, 24). In addition, with the recent emergence of community leg ulcer clinics, it is estimated that over 80% of all patients with leg ulcers are cared for by district or practice nurses or by the patients' relative (25). These community clinics staffed by specialist nurses are shown to be both clinically effective and cost‐efficient (26, 27). In view of this, the drive towards community‐centred care for patients with leg ulcers is expanding. Therefore, all healthcare professionals (HCPs) in the community, caring for patients with CVLU, should be aware of calcification to be a cause for intransigent CVLU. If the ulcer fails to heal despite appropriate treatment, the presence of any calcified deposit should be actively looked for. If calcified material is noted, pertinent blood tests, X‐rays and duplex scans should be requested to rule out other causes of aberrant calcium deposition (renal failure, connective tissue disorders, endocrine pathologies, neoplasms, etc.). If these are unremarkable, then mechanical removal of the calcified material should be attempted (along with appropriate dressings and compression bandages). If this does not yield appreciable clinical benefit, the patients should be referred to a specialised wound or surgical clinic in the hospital without undue delay. It also needs to be pointed out that apart from CVLU, calcification can occur in any chronic ulcer such as a pressure ulcer or a long‐standing abdominal wound.

Conclusion

DC within ulcer beds, although rare, is an overlooked cause for a non healing venous leg ulcer. In the presence of DC, healing is inhibited or halted leading to a static, painful wound. The HCPs working in the community should be aware of this association and acknowledge that DC complicating a venous ulcer might be a possible reason why such ulcers persist despite appropriate conservative management.