Revisiting Heinz-Lippman disease as a complication of chronic venous insufficiency

Chronic venous insufficiency with and without ulceration is a common complication of varicose veins. Heinz-Lippmann disease is a potentially underreported complication of chronic venous insufficiency that involves heterotopic ossification of the peri-wound that might contribute to the chronicity of venous leg ulcers. Most commonly, heterotopic ossification is associated with traumatic injury. We report the cases of three patients with chronic venous insufficiency and no history of trauma who were found to have subcutaneous calcifications consistent with Heinz-Lippmann disease. Osteomyelitis was confirmed in two patients. Physical examination and diagnostic imaging can be helpful in determining the diagnosis. Interventions can include biopsy to rule out osteomyelitis, with subsequent treatment, if needed.

Initially reported in 1960, Heinz, Lippmann, and Goldin found subcutaneous bone formation in 10% of patients with chronic venous insufficiency. 1 Heterotopic ossification (HO) or Heinz-Lippmann disease is an underrecognized complication of chronic venous insufficiency that might be consistent with venous leg ulcers.Abnormal bone formation and osteoblastic activity is found within any site of connective tissues, including muscle and soft tissues, without connection to the periosteum.The most common locations of HO include the elbow, shoulder, pelvis, and thigh. 2 Neurogenic forms of HO, often seen after spinal cord and brain injuries, can also be found around major joints. 3HO is commonly reported in orthopedics after tissue injury or surgery and has a high prevalence (65%) in combat-related amputations. 4,5fter injury, an influx of inflammatory cells and downstream signaling of mesenchymal cells inappropriately activate an osteogenic process, which leads to calcification and bone formation in the soft tissues. 6ongenetic forms of HO are the more prevalent; however, rare genetic forms of HO also exist. 6HO can be associated with a rare childhood, slowly progressive disorder, fibrodysplasia ossificans progressiva, consisting of multiple congenital skeletal malformations caused by ACVR1 mutations. 7Biopsy can worsen the clinical condition by leading to additional spread of heterotopic lesions. 6Progressive osseous heteroplasia, another genetic form of HO, is associated with the GNAS1 gene. 8These lesions favor the skin and subcutaneous tissue. 6O on radiographs is seen as small "eggshell calcifications" that are often represented by palpable hard fixated nodules underneath the skin in patients with chronic venous insufficiency. 6Genetic forms of HO will include a more extensive and advanced ossification with a "cocoon-like web" of HO involved in the connective tissues from the dermis to the skeletal muscles. 9omputed tomography (CT) can demonstrate deeper underlying ossification or a low-density mass not appreciated on physical examination and is helpful to assist in evaluation of the extent of disease.Magnetic resonance imaging findings can vary depending on the stage of maturation and can help with differentiating HO from other malignancies such as sarcoma, which can have calcifications.Positron emission tomography with CT using radiolabeled fluoride (F18) can detect areas of bone formation in nongenetic HO and the genetic HO active state. 10Near-infrared imaging and highfrequency spectral ultrasound are promising for early detection. 11,12he management and treatment of HO are limited.Site-specific classifications have been developed to note the severity of HO inclusive of the clinical and radiographic severity. 13Prophylactic strategies commonly include low-dose radiation and nonsteroidal antiinflammatory drugs, with corticosteroids usually reserved for genetic cases of HO. 5,6 Low-dose radiation carries concern for joint stiffness, malignant transformation, and fracture complications, such as nonunion. 14Treatment strategies include physical therapy and surgical resection.To date and to the best of our knowledge, no cases have been reported of osteomyelitis in the heterotopic bone.We describe the cases of three patients with Heinz-Lippmann disease, diagnosed using various imaging modalities.Two of the three patients were noted to have acute osteomyelitis of the heterotopic bone on pathologic analysis, and one patient presented with a misdiagnosis of her disease.All three patients provided written informed consent for the report of their case details and imaging studies.

DISCUSSION
Classically, HO presents in a young adult, usually male, with a history of trauma or orthopedic surgery. 6However, our patients were predominantly postmenopausal women with chronic venous insufficiency and no reported history of trauma.Concomitant autoimmune disorders such as rheumatoid arthritis, CREST (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia) syndrome, dermatomyositis, and lupus have been reported in association with nontraumatic HO. 6 Comorbidities such as hypertension, hyperlipidemia, diabetes, obesity, and anemia are also reported and were also prevalent in our patients.A total of eight case reports were reviewed after a search of the PubMed and MEDLINE databases.Of these, one report noted a history of trauma or burns for the affected patients, and a second reported a history of tibial fracture in the affected leg. 1 The remaining patients had no reported trauma.Several reports noted pathologic findings consistent with heterotopic bone formation. 15,16All eight reports noted various imaging modalities used in conjunction with the clinical examination, including radiography and CT.
Venous insufficiency, which is caused by poor valvular compliance of the deep and superficial venous systems,  leads to reflux of blood and swelling of the lower extremities. 17This swelling, if left untreated, can lead to chronic inflammation and mechanical stress, which can result in venous stasis ulcers.The lack of a traumatic or surgical event as the inciting factor for ossification in Heinz-Lippman disease is thought to be due to the presence of this chronic inflammation and mechanical stress. 6As such, treatment of chronic venous insufficiency and lower extremity edema is essential in the treatment and prevention of this condition.Treatment ranges from conservative to surgical.Patients begin with leg elevation, compression garments, and/or weight loss (if applicable) and could progress to venous ablation, vein stripping, or sclerotherapy, if conservative measures are not successful. 18outine fluorescent imaging can help determine the bacterial load and identify HO lesions in the dermal and subdermal areas of the skin.We found that routine fluorescent imaging with our MolecuLight camera (MolecuLight Inc) can also help determine the bacterial load and identify HO lesions in the dermal and subdermal areas of the skin.As noted in the images from our three patients, areas with known calcifications demonstrated fluorescence on imaging.The color of fluorescence has been shown to correlate with certain bacterial species, with red indicating porphyrinproducing bacteria such as S. aureus and cyan indicating P. aeruginosa. 19,20This can provide a useful adjunct to wound care specialists with similar imaging capabilities; however, more study is needed.
Caution in the workup to search for other diagnoses or an inciting cause is advised.A holistic approach to healing these wounds could be necessary to help optimize closure.This would include addressing factors that could  put the patient at greater risk of poor wound healing such as health literacy, access to treatment, cost of treatment, and aversion to treatment due to pain at the wound site. 21

From
the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead a ; the Department of Vascular Surgery, Northwell Health, Manhasset b ; the Northwell Health Comprehensive Wound Care Center, North Shore University Hospital, Lake Success c ; and the Department of Radiology, Northwell Health, Manhasset.d Correspondence: Alisha Oropallo, MD, FACS, Northwell Health Comprehensive Wound Care Center, North Shore University Hospital, 1999 Marcus Ave, Ste M6, Lake Success, NY 11042 (e-mail: aoropallo@northwell.edu).The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest.2468-4287 Ó 2023 The Author(s).Published by Elsevier Inc. on behalf of Society for Vascular Surgery.This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).https://doi.org/10.1016/j.jvscit.2023.101408

CASE REPORT Patient 1 .
A 68-year-old man had a history of renal transplant secondary to chronic renal insufficiency, pulmonary hypertension, obstructive sleep apnea, essential hypertension, hyperlipidemia, controlled diabetes mellitus type 2 with neuropathy, and coronary artery disease after coronary stenting.He had been taking daily prednisone 2.5 mg for >1 year's duration.He presented with edema of the lower extremities, varicosities, and a nonhealing wound (Fig 1).His numeric pain rating scale score was 5 of 10.Physical examination revealed intact pulses with palpable nodules noted underneath the skin to the peri-wound, which were confirmed by radiography (Fig 2).Fluorescence imaging revealed calcifications and red fluorescence, which suggested local infection with Staphylococcus aureus (Fig 3).Local wound care involved excisional and mechanical debridement with biopsy of the calcification.Pathologic examination of the biopsy specimen revealed calcification without evidence of osteomyelitis.A standing venous reflux study demonstrated significant reflux of >500 ms of the great saphenous vein.The patient was compliant to compression therapy and underwent radiofrequency ablation.Improvement in the wound size was noted but without complete wound closure.The patient declined further wide excision and skin grafting.Patient 2. A 64-year-old woman with a history of chronic venous insufficiency, type 2 diabetes mellitus with neuropathy, hypertension, anemia, and obesity presented with a nonhealing venous leg ulcer of >1 year's duration (Fig 4).She presented with a previous clinical diagnosis of pyoderma gangrenosum.Her symptoms included pain out of proportion to the physical findings with a numeric pain rating scale score of 10 of 10.Physical examination revealed palpable calcifications within the wound that could be seen on CT (Fig 5).Biopsy of the calcification was noted on pathologic examination to be consistent with HO with acute osteomyelitis.Fluorescent imaging demonstrated multiple calcifications of the peri-wound with underlying S. aureus and Pseudomonas aeruginosa (Fig 6).Culture confirmed P. aeruginosa, Enterococcus faecalis, and S. aureus.The patient was treated with trimethoprim/sulfamethoxazole (Bactrim DS; Hoffman-La Roche) and cephalexin 500 mg daily.Also, 60 mg of prednisone was initiated, with a 3-week taper to 5 mg daily.Her symptoms of pain resolved.

Fig 1 .
Fig 1. Plain photograph of chronic venous stasis ulcer in a 68-year-old man.

Fig 3 .
Fig 3. Fluorescent image taken with MolecuLight camera showing areas of red fluorescence (white arrow) consistent with S. aureus and small, punctate areas of fluorescence (yellow arrow) consistent with palpable calcifications.

Fig 4 .
Fig 4. Plain photograph of chronic venous stasis ulcer in a 64-year-old woman.

Fig 6 .
Fig 6.MolecuLight image showing red fluorescence consistent with S. aureus (white arrow), cyan fluorescence consistent with P. aeruginosa (blue arrow), and punctate areas of fluorescence (yellow arrow) consistent with palpable calcifications.

Fig 7 .
Fig 7. Significant decrease in wound size in patient 2 after treatment with antibiotics, steroids, and radiofrequency ablation.
Aggressive management of comorbidities and early recognition of lower extremity calcifications are important.Local wound care includes proper hygiene with excisional and mechanical debridement, if needed.Fluorescent imaging can help determine further management of care.Our patients had a delay of treatment before referral to our wound center.The treatment options are limited once extensive calcifications are present.Early identification of HO is recommended.A poor prognosis of wound healing for these ulcerations can ensue, especially for patients with extensive calcifications.CONCLUSIONS HO can be a complication of chronic venous insufficiency and ulcerations.Most patients have a prolonged course of a nonhealing ulceration.A missed diagnosis is common.However, routine physical examination, fluorescent imaging, radiography, CT, and/or MRI can confirm the diagnosis.The risk of osteomyelitis should be considered and, if present, treated.Biopsy of calcifications can be necessary to determine the presence of underlying osteomyelitis.Prolonged and poor wound healing is eminent without wide local excision.

Fig 8 .
Fig 8. Plain photograph of chronic venous stasis ulcer in a 63-year-old woman.

Fig 9 .
Fig 9. MolecuLight image showing red fluorescence consistent with S. aureus (white arrow), cyan fluorescence consistent with P. aeruginosa (blue arrow), and punctate areas of fluorescence (yellow arrow) consistent with palpable calcifications.

Fig 10 .
Fig 10.Plain radiograph showing long segments of calcifications in the affected extremity.