Bone metabolism in Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a rare disease of not well-defined etiology that involves immune cell activation and frequently affects the skeleton. Bone involvement in LCH usually presents in the form of osteolytic lesions along with low bone mineral density. Various molecules involved in bone metabolism are implicated in the pathogenesis of LCH or may be affected during the course of the disease, including interleukins (ILs), tumor necrosis factor α, receptor activator of NF-κB (RANK) and its soluble ligand RANKL, osteoprotegerin (OPG), periostin and sclerostin. Among them IL-17A, periostin and RANKL have been proposed as potential serum biomarkers for LCH, particularly as the interaction between RANK, RANKL and OPG not only regulates bone homeostasis through its effects on the osteoclasts but also affects the activation and survival of immune cells. Significant changes in circulating and lesional RANKL levels have been observed in LCH patients irrespective of bone involvement. Standard LCH management includes local or systematic administration of corticosteroids and chemotherapy. Given the implication of RANK, RANKL and OPG in the pathogenesis of the disease and the osteolytic nature of bone lesions, agents aiming at inhibiting the RANKL pathway and/or osteoclastic activation, such as bisphosphonates and denosumab, may have a role in the therapeutic approach of LCH although further clinical investigation is warranted.

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Unusual sites of bone involvement in Langerhans cell histiocytosis: a systematic review of the literature

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-01625-z ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Nahid Reisi ◽

Pouran Raeissi ◽

Touraj Harati Khalilabad ◽

Alireza Moafi

Keyword(s):

Systematic Review ◽

Dendritic Cells ◽

Rare Disease ◽

Langerhans Cell Histiocytosis ◽

Case Reports ◽

Langerhans Cell ◽

The Other ◽

Bone Involvement ◽

Intracranial Extension ◽

Pathologic Fractures

Abstract Background Langerhans cell histiocytosis (LCH) is a rare disease that originates from the uncontrolled proliferation and accumulation of bone marrow-derived immature myeloid dendritic cells. Dendritic cells are a type of histiocyte that play an important role in the human immune system and are found in the bone, skin, stomach, eyes, intestines, and lungs. Objective This systematic review aimed to collect and report published case reports of rare bone disease caused by LCH to avoid misdiagnoses or delays in diagnosis. Methods We systematically searched Scopus, PubMed, Embase, and Web of Sciences from August 1, 2000 to December 31, 2019. Studies reporting cases of LCH with rare bone involvement were included. Results We identified 60 articles including 64 cases. Of the identified cases, 31 (48.4%) involved children, and 33 (51.6%) involved adults. Additionally, 46.9% (30 individuals) were from Asian countries. The mean age of the children was 7.6 ± 4.3 years and that of the adults was 36 ± 12 years. The findings indicated that unifocal bone involvements were the most prevalent form of the disease (68.7%), and, overall, the skull and chest wall were the most commonly affected bones in both adults and children. The spine and long bones were the second most commonly affected bones in children, and the spine and jaw were the second most commonly affected bones in adults. Pain and swelling were the most frequent presenting signs among the investigated cases, and loss of consciousness, myelopathy, nerve palsy, visual loss, torticollis and clicking sounds were rare signs. Osteolytic lesions were the most frequent radiologic feature (62.5%), and intracranial hemorrhage, fluid–fluid level, dura and intracranial extension and pathologic fractures were rare radiological features. Total excision, curettage and observation in the unifocal group of patients and systemic chemotherapy in the other groups (i.e., multifocal and multisystem) were the most frequent management approaches. The recovery rates of the unifocal and multifocal groups were 77.3% and 81.8%, respectively, while that of the multisystem group was 55.5%. The rates of recurrence and mortality in the multisystem group were 11% and were higher than those in the other groups. Conclusions LCH is a rare disease that can affect any organ in the human body. However, bone is the most commonly involved organ, and rare bone involvements may be the first or only symptom of the disease due to the rarity of such lesions; a lack of familiarity with them may result in misdiagnosis or delayed diagnosis.

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Paediatric Langerhans Cell Histiocytosis Disease: Long-Term Sequelae in the Hypothalamic Endocrine System

Hormone Research in Paediatrics ◽

10.1159/000517040 ◽

2021 ◽

pp. 1-9

Author(s):

Elisa Vaiani ◽

Guido Felizzia ◽

Fabiana Lubieniecki ◽

Jorge Braier ◽

Alicia Belgorosky

Keyword(s):

Anterior Pituitary ◽

Langerhans Cell Histiocytosis ◽

Endocrine System ◽

Langerhans Cell ◽

Hormone Deficiency ◽

Bone Lesions ◽

Pituitary Hormone ◽

Multisystem Disease ◽

Anterior Pituitary Hormone

Langerhans cell histiocytosis (LCH) is a disorder of the mononuclear phagocyte system that can affect almost any organ and system. The most common central nervous system (CNS) manifestation in LCH is the infiltration of the hypothalamic-pituitary region leading to destruction and neurodegeneration of CNS tissue. The latter causes the most frequent endocrinological manifestation, that is, central diabetes insipidus (CDI), and less often anterior pituitary hormone deficiency (APD). The reported incidence of CDI is estimated between 11.5 and 24% and is considered a risk factor for neurodegenerative disease and APD. Three risk factors for development of CDI are recognized in the majority of the studies: (1) multisystem disease, (2) the occurrence of reactivations or active disease for a prolonged period, and (3) the presence of craniofacial bone lesions. Since CDI may occur as the first manifestation of LCH, differential diagnosis of malignant diseases like germ cell tumours must be made. APD is almost always associated with CDI and can appear several years after the diagnosis of CDI. Growth hormone is the most commonly affected anterior pituitary hormone. Despite significant advances in the knowledge of LCH in recent years, little progress has been made in preventing long-term sequelae such as those affecting the hypothalamic-pituitary system.

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Langerhans Cell Histiocytosis with Isolated Central Diabetes Insipidus, Low Grade Fever and Sellar Erosion

Trends in Pediatrics ◽

10.5222/tp.2021.86580 ◽

2021 ◽

Author(s):

İclal Okur ◽

Hasan Ari ◽

Semra Çetinkaya ◽

Betül Emine Derinkuyu ◽

Gizem Çağlar ◽

...

Keyword(s):

Diabetes Insipidus ◽

Langerhans Cell Histiocytosis ◽

Bone Structure ◽

Sella Turcica ◽

Langerhans Cell ◽

Central Diabetes Insipidus ◽

Bone Lesions ◽

Warning Sign ◽

Low Grade ◽

First Case

Langerhans cell histiocytosis (LCH) is a rare disease of the monocyte-macrophage system. Although it is known that bone involvement is seen very frequently in cases with LCH, our case is the first case with a lytic-destructive lesion in the bone structure forming sella turcica. A 4-year-old, 5-month-old male patient who applied to our outpatient clinic was diagnosed with Langerhans cell histiocytosis in further examination after the diagnosis of central diabetes insipidus (CDI) was made. On cranial magnetic resonance imaging (MRI), widespread lytic-destructive bone lesions were observed in the bone structure forming the sella (sphenoid bone), sellar destruction not previously described in the literature. Sellar erosion has not been reported before in cases diagnosed with LCH in the literature. The presence of low-grade fever in a patient presenting with isolated CDI is a warning sign for the diagnosis of LCH.

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Serum Levels of miR-148a and miR-21-5p Are Increased in Type 1 Diabetic Patients and Correlated with Markers of Bone Strength and Metabolism

Non-Coding RNA ◽

10.3390/ncrna4040037 ◽

2018 ◽

Vol 4 (4) ◽

pp. 37 ◽

Cited By ~ 15

Author(s):

Giuseppina E. Grieco ◽

Dorica Cataldo ◽

Elena Ceccarelli ◽

Laura Nigi ◽

Giovanna Catalano ◽

...

Keyword(s):

Bone Mineral Density ◽

Type 1 Diabetes ◽

Bone Loss ◽

Bone Metabolism ◽

Bone Remodeling ◽

Bone Mineral ◽

Bone Fragility ◽

Bone Homeostasis ◽

Mineral Density

Type 1 diabetes (T1D) is characterized by bone loss and altered bone remodeling, resulting into reduction of bone mineral density (BMD) and increased risk of fractures. Identification of specific biomarkers and/or causative factors of diabetic bone fragility is of fundamental importance for an early detection of such alterations and to envisage appropriate therapeutic interventions. MicroRNAs (miRNAs) are small non-coding RNAs which negatively regulate genes expression. Of note, miRNAs can be secreted in biological fluids through their association with different cellular components and, in such context, they may represent both candidate biomarkers and/or mediators of bone metabolism alterations. Here, we aimed at identifying miRNAs differentially expressed in serum of T1D patients and potentially involved in bone loss in type 1 diabetes. We selected six miRNAs previously associated with T1D and bone metabolism: miR-21; miR-24; miR-27a; miR-148a; miR-214; and miR-375. Selected miRNAs were analyzed in sera of 15 T1D patients (age: 33.57 ± 8.17; BMI: 21.4 ± 1.65) and 14 non-diabetic subjects (age: 31.7 ± 8.2; BMI: 24.6 ± 4.34). Calcium, osteocalcin, parathormone (PTH), bone ALkaline Phoshatase (bALP), and Vitamin D (VitD) as well as main parameters of bone health were measured in each patient. We observed an increased expression of miR-148a (p = 0.012) and miR-21-5p (p = 0.034) in sera of T1D patients vs non-diabetic subjects. The correlation analysis between miRNAs expression and the main parameters of bone metabolism, showed a correlation between miR-148a and Bone Mineral Density (BMD) total body (TB) values (p = 0.042) and PTH circulating levels (p = 0.033) and the association of miR-21-5p to Bone Mineral Content-Femur (BMC-FEM). Finally, miR-148a and miR-21-5p target genes prediction analysis revealed several factors involved in bone development and remodeling, such as MAFB, WNT1, TGFB2, STAT3, or PDCD4, and the co-modulation of common pathways involved in bone homeostasis thus potentially assigning a role to both miR-148a and miR-21-5p in bone metabolism alterations. In conclusion, these results lead us to hypothesize a potential role for miR-148a and miR-21-5p in bone remodeling, thus representing potential biomarkers of bone fragility in T1D.

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PP – 10-YEAR FOLLOW- UP OF A SINGLE-SYSTEM LANGERHANS CELL HISTIOCYTOSIS - MULTIFOCAL BONE INVOLVEMENT

Oral Surgery Oral Medicine Oral Pathology and Oral Radiology ◽

10.1016/j.oooo.2016.09.149 ◽

2017 ◽

Vol 123 (2) ◽

pp. e66

Author(s):

RENATA MENDONÇA MORAES ◽

JOYCE GIMENEZ MENON ◽

JULIANA ROCHA VERRONE ◽

JOSÉ DIVALDO PRADO ◽

FERNANDO AUGUSTO SOARES ◽

...

Keyword(s):

Langerhans Cell Histiocytosis ◽

Langerhans Cell ◽

Bone Involvement ◽

Single System

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Langerhans-Cell Histiocytoses - Epidemiology, Classification, Clinical Features, Diagnosis, Complications, Treatment and Prognosis

Journal of Biomedical and Clinical Research ◽

10.1515/jbcr-2016-0001 ◽

2016 ◽

Vol 9 (1) ◽

pp. 3-16 ◽

Cited By ~ 1

Author(s):

Vera E. Papochieva ◽

Dimitrinka S. Miteva ◽

Penka I. Perenovska ◽

Guergana Petrova

Keyword(s):

Langerhans Cell Histiocytosis ◽

Eosinophilic Granuloma ◽

Langerhans Cell ◽

Unknown Etiology ◽

Bone Lesions ◽

Multisystem Disease ◽

The Past ◽

System Disease ◽

Young Smokers ◽

Underlying Pathology

Summary Histiocytoses comprise a group of diverse diseases of unknown etiology with various clinical presentation and evolution. The underlying pathology is characterised by accumulation and infiltration of variable numbers of cells of the monocyte-macrophage line in the affected tissues and organs. Histiocytoses are divided into three major classes: Langerhans cell histiocytosis (LCH), non- Langerhans cell histiocytosis, and malignant histiocytic disorders. The term LCH (also known in the past as histiocytosis X) encompasses the following rare diseases: Eosinophilic Granuloma, Hand-Schuller-Christian disease, Letterer-Siwe disease, Hashimoto-Pritzker disease, in which accumulation of pathologic Langerhans cells (LCs) leads to tissue damage. LCs usually reside in the skin and ensure protection against infections by destroying foreign substances. LC accumulation is caused by antigen stimulation and inadequate immune response. Thus, clinical LCH manifestations range from isolated disease with mono- or multifocal bone lesions to disseminated multisystem disease. LCH is a rare disease, affecting mainly children and young smokers, aged 20-50 years. Lung involvement in LCH usually presents as a mono-system disease and is characterized by Langerhans cell granulomas (LCG) infiltrating and impairing the distal bronchioles. The definite diagnosis is based on lung biopsy of CAT selected LCG areas. So far, there is no an effective treatment, but the better understanding of the mechanisms involved in the pathogenesis of the disease would help in the development of effective therapeutic strategies in the future.

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A case of fixation amnesia in Langerhans cell histiocytosis involving the central nervous system

Neurology neuropsychiatry Psychosomatics ◽

10.14412/2074-2711-2020-6-117-123 ◽

2020 ◽

Vol 12 (6) ◽

pp. 117-123

Author(s):

L. V. Lukina ◽

V. A. Mikhailov ◽

N. I. Ananyeva ◽

G. E. Mazo ◽

L. I. Sitnik ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Langerhans Cell Histiocytosis ◽

Correct Diagnosis ◽

Brain Lesion ◽

Clinical Findings ◽

Langerhans Cell ◽

Unknown Etiology ◽

Bone Lesions ◽

The Central Nervous System

Langerhans cell histiocytosis (LCH) is a rare disease with hitherto unknown etiology and pathogenesis. It is extremely rare for clinicians to encounter histiocytic lesions of the central nervous system (CNS); the proportion of cases of which is only 1–4% of all polysystemic and multifocal bone lesions. The paper describes a clinical case of fixation amnesia in a female patient with focal brain lesions in LCH. It depicts the most characteristic clinical features and presents an algorithm for the diagnosis of histiocytic brain lesion. The results of the experimental psychological examination of the patient are considered in detail and the clinical presentations of fixation amnesia are described. There are neuroimaging data showing the lesions in the hypothalamic-pituitary region and temporal bone, which involve the auditory structures. The clinical findings have led to the conclusion that both the clinical and neuroimaging patterns of histiocytic lesions in the CNS are non-specific, which complicates the diagnostic search in LCH. For correct diagnosis and timely treatment, it is necessary to perform a biopsy of the pathological focus, followed by histological and immunohistochemical examination of the material.

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