CASE REPORT
Nagoya J. Med. Sci. 85. 185–194, 2023
doi:10.18999/nagjms.85.1.185

Failure of internal fixation for ankle joint Charcot
neuroarthropathy with beta(2)-microglobulin amyloidosis:
a case report
Yang Zheng1, Jiu-Dan Zhang2, Jie-Feng Huang1 and Ya-Hong Zhu3
Department of Orthopaedics & Traumatology, The First Affiliated Hospital of Zhejiang Chinese MedicalUniversity, Hangzhou, China
2
Department of Endocrinology, The First Affiliated Hospital of Zhejiang Chinese Medical University,Hangzhou, China
3
Emergency Center, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China1ABSTRACT
Charcot neuroarthropathy (CN) is a serious diabetic complication with a poor prognosis and a highrate of misdiagnosis. Furthermore, beta(2)-microglobulin amyloidosis (Abeta2M) makes the diagnosis andtherapy more difficult and complex. This case report highlights the pathophysiology, clinical evaluation,treatment, and prevention of the major diabetic complications associated with CN and Abeta2M that cause
poor quality of life, limit the patient’s ability to walk independently, and are directly or indirectly linkedwith a high risk for lower limb amputation. Ankle CN was discovered in a 36-year-old single female
with a history of type 1 diabetes mellitus and diabetic nephropathy. We performed early internal fixation.
However, because she lived alone and needed hemodialysis three times a week, wearing a brace andnon-weight-bearing were extremely inconvenient. Furthermore, she did not experience any pain and only
some edema; thus, she proceeded to bear weight ahead of schedule without authorization. Due to thepremature weight-bearing and poor compliance, the patient suffered severe bone resorption and infectionand eventually had to undergo amputation. Abeta2M was suggested by bone pathological sections. We
present a case of failed internal fixation of ankle CN with Abeta2M, emphasizing the importance of social
factors and postoperative management.
Keywords: Charcot neuroarthropathy, ankle fracture, diabetic nephropathy, beta(2)-microglobulin
amyloidosis
Abbreviations:
CN: Charcot neuroarthropathy
Abeta2M: beta(2)-microglobulin amyloidosis
CT: computed tomography
ORIF: open reduction and internal fixation
This is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
License. To view the details of this license, please visit (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Received: January 13, 2022; accepted: March 22, 2022
Corresponding Authors: Jie-Feng Huang, PhD; Ya-Hong Zhu, BS
Department of Orthopaedics & Traumatology, The First Affiliated Hospital of Zhejiang Chinese MedicalUniversity, Hangzhou 310006, China (Huang);
Emergency Center, The First Affiliated Hospital of Zhejiang Chinese Medical University,Hangzhou 310006, China (Zhu)
Tel: +86-571-86620271, Fax: +86-571-87034117 (Huang, Zhu),
E-mail: huangjiefeng@zcmu.edu.cn (Huang); 49596006@qq.com (Zhu)185

Yang Zheng, Jiu-Dan Zhang et alINTRODUCTION
Charcot neuroarthropathy (CN) is a chronic, progressive, and destructive arthropathy caused
by long-term diabetes in the majority of patients. The clinical manifestations typically include aunilateral, localized, inflammatory reaction in a focal area of the foot or ankle with erythema,warmth, and swelling.1 CN is frequently misdiagnosed as cellulitis, deep vein thrombosis, orosteomyelitis and causes further bony destruction, the development of neuroarthropathy, and anincreased risk of complications.2 Joint disorganization can be severe and irreversible in patients
who present later in the disease course. Ulceration and infection are prevalent, wreaking havoc
on life, and leading to amputation in some cases.3
Beta(2)-microglobulin amyloidosis (Abeta2M) is an important cause of morbidity in patientswith chronic renal failure and those on dialysis. The precursor protein of the Abeta-2M-amyloid
fibril is beta(2)-microglobulin (beta2M), and an elevated serum level is the main cause ofAbeta2M in patients with kidney failure.4
We share a case of ankle CN combined with Abeta2M that has not been reported and speculate
whether the two are associated.

CASE PRESENTATION
A 36-year-old single female with no history of trauma presented with a 15-day history of
progressive right ankle swelling but little discomfort while walking. She had type 1 diabetes for
23-years and diabetic nephropathy with hemodialysis for 5 years.
A distal tibial fracture with concurrent fibular fracture and valgus malalignment were discoveredin radiographs and computed tomography (CT) scans (Figs. 1 and 2). Deep vein ultrasound ofboth lower extremities indicated no obvious thrombosis. Table 1 lists the laboratory parameters. The
beta2M level was 20,071.6 µg/L. According to the detailed examination results, infection and lower
deep venous thrombosis were excluded. We performed open reduction and internal fixation (ORIF).

Fig. 1 A distal tibial fracture with a concomitant fibular fracture and valgus malalignment
in preoperative radiographs
Fig. 1a: Anteroposterior radiographFig. 1b: Lateral radiograph
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Fig. 2

Comminuted intraarticular fracture of the distal tibia with concurrent fibular fracture
and valgus malalignment in preoperative CT sections
Fig. 2a: Axial CT section
Fig. 2b: Coronal CT section
Table 1

Laboratory parameters

Parameter

Result(normal range)

Unit

Parameter

Result(normal range)

Unit

beta2M

20071.6 (100.0–300.0)

ug/L

FPG

8.96 (3.89–6.11)

mmol/L

HbA1c6.7 (4.0–6.3)%

UA

493 (208–428)μmol/LCre

203 (59–104)μmol/L

AST

1004 (5–40)

U/L

BUN

23.4 (2.9–8.2)

mmol/L

ALT

1216 (10–42)

U/L

ALP

483 (40–150)

U/L

pg/mL

BNP

639.6 (0.0–100.0)^9WBC

6.6 (3.5–9.5)

10 /L

CRP

<1.00 (1–8)

mg/L

Neutrophil

68.9 (50.0–70.0)%

RBC

3.32 (3.68–5.13)

10^12/L

Lymphocyte

18.2 (20.0–40.0)

PLT

243 (125–350)

10^9/L

Monocyte

9.9 (3.0–10.0)

Hb

96 (130–175)

g/L

Eosinophil

2.6 (0.5–5.0)

Blood culture

NegBasophil

0.4 (0.0–1.0)

beta2M: beta(2)-microglobulin
BUN: blood urea nitrogen
ALP: alkaline phosphatase
ALT: alanine aminotransferase
AST: aspartate aminotransferase
Cre: creatinine
BNP: brain natriuretic peptide
FPG: fasting plasma glucose
UA: uric acidHbA1c: glycated hemoglobin
WBC: white blood cells
PLT: platelets
Hb: hemoglobin
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Yang Zheng, Jiu-Dan Zhang et alThe postoperative radiographs (Fig. 3) revealed almost anatomic restoration of the articularsurface and corrected limb alignment. The patient was discharged with an ankle brace after theincision healed well and she was told not to bear weight on the leg for 3 months.
Follow-up radiographs 3 months after ORIF showed separation of the inferior tibiofibularsyndesmosis, articular surface subsidence of the distal tibia, and a periosteal reaction (Fig. 4). The
patient confirmed that she had started to load-bear walk less than 2 months after ORIF. Because

Fig. 3Radiographs taken the day following ORIF (open reduction and internal fixation) reveal
near-anatomic repair of the articular surface as well as corrected limb alignment
Fig. 3a: Anteroposterior radiographFig. 3b: Lateral radiographFig. 4Radiographs taken 3 months after ORIF (open reduction and internal fixation) showing separationof the inferior tibiofibular syndesmosis and subsidence of the distal tibia articular surface,accompanied by the periosteal reaction
Fig. 4a: Anteroposterior radiographFig. 4b: Lateral radiograph
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Charcot Joint with amyloidosis

she lived alone and needed hemodialysis three times a week, wearing a brace and not being
able to bear weight were extremely inconvenient. Furthermore, she did not experience any pain,
only some edema; thus, she proceeded to bear weight ahead of schedule without authorization.
The patient presented with right limb edema and a normal skin temperature 5 months afterORIF. She did not experience any pain, even while walking, and her ankle remained active (Fig.
5). A deep vein ultrasound was normal as before. Radiographs (Fig. 6) showed bone resorption ofFig. 5 The patient presented with right limb swelling 5 months after ORIF (open reduction
and internal fixation), but the ankle was active
Fig. 5a: Right limb swellingFig. 5b: Extension of the ankle joint
Fig. 5c: Flexion of the ankle joint

Fig. 6 Radiographs taken 5 months after ORIF (open reduction and internal fixation) showingbone resorption of the distal tibial articular surface, the looseness of internal fixation,and fracture of a locking screw
Fig. 6a: Anteroposterior radiographFig. 6b: Lateral radiograph
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Yang Zheng, Jiu-Dan Zhang et al

the distal tibial articular surface and failure of the internal fixation. Although we had repeatedly
warned the patient that weight-bearing was not allowed, she was more inclined to walk withweight-bearing because she did not feel any pain.
The swelling in the right limb had worsened 3 weeks later, particularly near the pretibialFig. 7 Limb photograph taken 6 months after ORIF (open reduction and internal fixation), showingsignificant swelling, particularly near the pretibial incision, accompanied by a fluctuating mass

Fig. 8 Radiographs 6 months after ORIF (open reduction and internal fixation) showingbone resorption of the distal tibial articular surface and talus, significantly looseness ofinternal fixation, and fracture of a locking screw
Fig. 8a: Anteroposterior radiographFig. 8b: Lateral radiograph
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incision, and she could not walk without pain (Fig. 7). Gray pus was extracted from the anterior
tibial swelling, and a bacterial culture revealed Staphylococcus aureus. Radiographs showed more
severe bone resorption of the distal tibial articular surface and talus, as well as displacement of
the internal fixation (Fig. 8).
We finally performed a sub-knee amputation as a reasonable option for the severe bone damage
and infection. The postoperative limb anatomy revealed hyperemic gray pus from the middle
tibia to the ankle, as well as distal tibial and talus bone resorption (Fig. 9).

Fig. 9 Limb photograph at autopsy showing the infection from the middle part of the tibia to the ankle
The distal tibial articular surface and most of the talus were resorbed.

Fig. 10 Distal tibial biopsy: higher magnification (Congo red stain, 400×) showing amyloidosis
Fig. 10a: Congo red staining was positive.
Fig. 10b: Congo red staining was positive.
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Yang Zheng, Jiu-Dan Zhang et al

Pathological slices of bone tissue revealed inflammatory cell infiltration. Congo red staining
was positive, indicating Abeta2M (Fig. 10).
The patient received intravenous Cefotiam antibiotic therapy for 7 days. She was discharged
from the hospital 2 weeks after the amputation, and the incision healed well. Unfortunately, thepatient died of a severe lung infection 6 months later.

DISCUSSION
CN is divided into four stages in the modified Eichenholtz classification, including “active”(stages 0, 1, 2) and “inactive” (stage 3) stages to indicate whether the process is in the acuteor reconstructive stage, which is related to the method and timing of the operation.2,5-7 Despite
the fact that our patient did not exhibit “vanishing bone” in radiographs or a CT scan at thefirst appointment, the pathological fractures had already developed, placing her in stage 1 (activestage) of the classification system.
CN treatment should be managed by a multidisciplinary team, including strict unloading,casting, and surgical reconstruction. The goals are to achieve osseous stability, maintain theintegrity of the foot and ankle, and prevent ulceration.8 There is no universal agreement on thebest time or method for surgical intervention.
Many studies have reported that surgical treatment should be considered during stage 3(inactive CN) when the acute inflammatory changes have subsided.9-11 Less edema, less inflammatory products, and fewer soft tissue and wound complications are all advantages of surgicalintervention at this stage.10 Similar to high-energy trauma to the foot and ankle, high levels ofedema and inflammation increase the risk for postoperative wound complications. Waiting forthe later stages of CN may provide a better physiological mechanism for bone and skin healing.
However, the CN process can take several months to resolve. Waiting for later stages makes it
more difficult to reduce consolidated deformities, increasing the possibility that an osteotomy may
be required to rectify the bone deformities. In addition, many deformities progress during thewaiting period, and soft tissues can break down and become infected. Therefore, some experts
believe that active CN may be the best time for surgery, as the deformities are fresh and flexible
and are easy to reduce, similar to other acute fractures.3,12,13 Active disease may also offer thebest bone quality compared to later stages of CN.
Most experts believe that ankle CN seems more likely to fail during non-surgical correction
and has a higher risk for severe deformity, necessitating early surgical intervention.14 Experts
concur that direct ankle joint expansion fusion should be performed for first-stage ankle joint
CN.15 In addition, some authors suggest that ORIF can be employed as the primary operation forpatients with inactive CN and no wound or infected tissue.16 We performed surgery at the “active”
stage, as the present patient had a substantial ankle fracture with instability. We adopted ORIF
to preserve the function of the ankle joint and prevent additional aggravation of the deformity.
Many studies have shown that health education is important, and poor adherence to treatment recommendations, particularly off-loading, may negatively affect outcomes.17 Patients with
suboptimal compliance have a longer duration of acute Charcot syndrome and a higher risk
for foot ulceration and amputation than those with better compliance, according to a long-term
retrospective study.18 Although we repeatedly reminded this patient that weight-bearing wasforbidden within 3 months, her compliance was poor, and she began bearing weight withoutauthorization in less than 2 months. Eventually, she experienced severe bone loss and infection.
Abeta2M is a type of systemic amyloidosis that is specifically seen in patients with chronic
renal disease. However, the precise mechanism of Abeta2M remains unclear. The precursor
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protein of Abeta2M-amyloid fibril is beta2M, and an increase in the serum level is the primarycause of Abeta2M in patients with kidney failure.19 Osteolytic lesions are often found around thesynovial membrane with deposits of Abeta2M-amyloid. Osteoclastogenesis and active osteoclastic
bone resorption are found, while osteoblastic bone formation is absent in the lesion most likely
associated with the inflammation caused by infiltrating macrophages/monocytes into the Abeta2Mamyloid deposits. The precise mechanism of this inflammatory change is unknown. More researchis required to elucidate the association between Abeta2M-amyloid accumulation and progressivebone destruction.4 Our patient’s laboratory results indicated that beta2M was quite high (20,071.6µg/L). The pathological bone biopsy showed positive Congo Red staining, suggesting that thepatient had bone amyloidosis. We speculate that there is a relationship between CN and Abeta2M
in patients with diabetic nephropathy, but this requires further studies to confirm.
In conclusion, we believe that poor compliance, premature weight-bearing, and missed identification of Abeta2M were the primary causes of this patient’s failure. Given that the patient was asingle woman who required hemodialysis three times a week, and wearing a non-weight-bearing
brace was inconvenient, we should have thought twice before choosing surgical treatment.

AUTHOR CONTRIBUTIONYZ and JDZ served as co-first authors.

ACKNOWLEDGMENT
We express sincere gratitude to China Scholarship Council (CSC) for their financial support
to Yang Zheng (No. 202108330196).

CONFLICTS OF INTEREST
The authors declare that they have no conflict of interest.

FUNDING
This work was supported by Zhejiang Provincial Natural Science Foundation (LY20H270012)
and Zhejiang Administration of Traditional Chinese Medicine (2022ZB112, 2020ZB090).

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