Although modern treatment strategies in childhood malignancies have tremendously improved patient survival, pediatric cancer patients receiving irradiation and/or chemotherapy in combination with hematopoietic stem cell transplantation (HSCT) are at high risk of developing endocrinological complications [1
]. This generally includes growth failure, hypothyroidism, and gonadal dysfunction [2
]. Moreover, metabolic diseases have emerged as a part of late complications in patients who received HSCT, including insulin resistance [5
], diabetes mellitus [5
], dyslipidemia [5
], central or abdominal obesity [5
], and fatty liver disease [6
]. Interestingly, metabolic diseases have been diagnosed in the absence of obesity or high body mass index (BMI) [5
] and were found associated with total body irradiation (TBI), which is commonly used within the myeloablative conditioning for HSCT [8
Within a cohort comparing n
= 21 pediatric patients with acute lymphoblastic leukemia who had received HSCT to cancer patients without HSCT (n
= 31) and obese controls (n
= 30), Wei et al. found that these patients had a higher incidence of insulin resistance and glucose intolerance [13
]. Moreover, using dual energy X-ray absorptiometry (DEXA) scan analysis, they also found a very different paradigm shift in body fat distribution characterized by increased central to peripheral adiposity, reduced subcutaneous and increased visceral fat towards higher visceral fat depots in patients with HSCT, resembling a lipodystrophic phenotype [13
Lipodystrophies (LD) are a group of rare diseases affecting the growth or distribution of body fat, either characterized by complete loss of adipose tissue (generalized LD) or loss of distinct adipose tissue depots (partial LD). Depending on their pathogenic mechanism, LDs can be further divided into familial/genetic and acquired LDs (for an overview, see [14
]). Thus, LDs comprise a large number of different disease entities, some of them so rare that they have only been described in a handful of cases so far [15
]. Therefore, a European registry for patients with lipodystrophy (the ECLip registry, ClinicalTrials.gov (NCT03553420)) has been set up to provide a basis for international cooperation and data acquisition [16
LDs are often accompanied by metabolic complications, including insulin resistance, hypertriglyceridemia, non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome [14
Within the last 15 years, several patients who developed partial LD after HSCT in early life were described, suggesting that this disease might be a distinct entity among the late metabolic sequelae of stem cell transplantation [18
As HSCT has been recognized as a cause for lipodystrophy, this disease entity, referred to as “Acquired Partial Lipodystrophy associated with total body irradiation and hematopoietic stem cell transplant” or “HSCT-associated lipodystrophy”, has been included in the ECLip registry to facilitate documentation and further research of this rare condition. In this review, we aim to summarize all cases described so far and to discuss common risk factors as well as potential underlying mechanisms of the disease.
2. Clinical Cases
Although metabolic alterations and changes in body fat distribution seem to be a common late effect of bone marrow transplantation (BMT), the appearance of lipodystrophy is less common. Within the last years, several patients were described who developed lipodystrophy after pediatric HSCT.
In 2006, Rooney and Ryan described a female patient who received allogeneic BMT in combination with TBI and cyclophosphamide treatment at the age of 14 due to acute lymphoblastic leukemia (ALL) [21
]. One year after treatment, she was diagnosed with sclerodermatous graft-versus-host disease (GVHD), which was successfully treated with prednisolone, cyclosporin, and thalidomide over a total period of two years [21
]. Nine years after transplantation, the patient developed partial lipodystrophy, mainly at the legs, forearms, thighs, and buttocks. Partial LD was accompanied by diabetes mellitus, hypertriglyceridemia, and markedly low adiponectin levels. Interestingly, liver function was normal apart from slightly elevated liver transaminases. As this phenotype resembled Dunnigan-type lipodystrophy (familial partial lipodystrophy type 2, FPL2), mutations in the lamin A (LMNA) gene, the underlying genetic cause of FPL2, were excluded by sequencing. As the areas of lipoatrophy corresponded well to the sites of cutaneous GVHD, the authors hypothesized that GVHD or immunosuppressive treatment could be the underlying cause of LD development [21
A similar phenotype of body fat distribution was found in a later report describing five cases of LD who received HSCT in childhood due to leukemia or neuroblastoma [18
]. As in the aforementioned case, the five patients developed subcutaneous lipoatrophy in the gluteal regions and the extremities, while fat depots in the cheeks, neck, and abdomen were preserved. Mutations in the LMNA gene were absent in four patients, while in the last patient, no genetic examination was performed. All patients had received either allogeneic (n
= 4) HSCT or autologous peripheral blood stem cell transplantation (n
= 1) in combination with TBI and intensive chemotherapy due to metastasis or relapse. As a consequence of HSCT, most (n
= 4) patients developed GVHD, which was treated with chronic immunosuppressive therapy. Metabolic derangements were evident in all patients including hyperinsulinemia (n
= 4), diabetes mellitus (n
= 2), dyslipidemia (n
= 5), and fatty liver disease (n
= 5). Additionally, levels of leptin and adiponectin were modestly decreased.
In 2017, one of us reported a case of adult lipodystrophy, which developed after early autologous BMT at the age of 2 years to treat acute myeloblastic leukemia (AML) followed by treatment with TBI and allogeneic BMT [20
]. Later, the patient received immunosuppressive treatment after developing GVHD. At the age of 13, the patient was diagnosed with severe dyslipidemia, and in the further course—at the age of 17—with T2DM and fatty liver disease. She presented with subcutaneous lipoatrophy in the limbs and gluteal region, while fat at the cheeks was preserved.
Another case developed acute as well as chronic GVHD after receiving HSCT at the age of 4 years to treat ALL [22
]. At the age of 10 years, she was diagnosed with hyperglycemia. CT imaging revealed abnormal body fat distribution and fatty liver, indicating acquired partial lipodystrophy.
Two more cases with partial LD after allogeneic HSCT/TBI were described in 2019 [23
]. The first case developed lipoatrophy in the upper and lower extremities and at the gluteal region at the age of 14 years after receiving HSCT in early childhood. The appearance of scleroderma-like skin suggested the suspicion of GVHD development in the patient. The second patient was diagnosed with ALL at the age of seven years and received HSCT, including TBI conditioning, one year later. Consequently, she developed chronic GVHD, which was treated with immunosuppressants, including prednisolone. At the age of 17 years, she presented with partial lipodystrophy affecting the extremities accompanied by diabetes mellitus, dyslipidemia, and fatty liver. The authors of this study speculated that this form of acquired lipodystrophy is a consequence of GVHD affecting the adipose tissue [23
From these ten cases, it becomes obvious that these patients share a common disease pattern, including partial lipodystrophy with fat loss in the extremities and preserved fat depots in the face, neck, and abdomen accompanied by metabolic disease. All patients described so far (n = 10) had a history of total body irradiation at a young age, and the majority (n = 9) received immunosuppressive therapy due to GVHD development. Endocrinopathies were also frequently found including growth hormone deficiency (n = 6), hypothyroidism (n = 5) and hypogonadism (n = 6).
A cross-sectional study in 2017 [19
] including n
= 65 pediatric patients who underwent HSCT for malignancies or hematological disorders brought further information about the frequency of HSCT-associated LD as well as common risk factors associated with this novel disease entity. Interestingly, almost 10% of the children developed partial LD in adolescence with gluteal lipoatrophy and facial lipohypertrophy. The authors found that compared to patients who did not develop LD, patients with LD were older at diagnosis, had a longer elapsed time following HSCT, had more frequently a history of disease recurrence, and were more likely to have undergone multiple HSCTs. In addition, they had higher blood pressure and exhibited higher levels of low-density lipoprotein-cholesterol and triglycerides, whereas their adiponectin levels were significantly lower.
4. Treatment Strategies for Metabolic Derangements in HSCT-Associated LD
The present international guidelines for follow-up of survivors of childhood and adolescent cancer or stem cell transplantation consider the importance of early detection of obesity and associated cardiovascular risk factors. Indications, scope, and frequency of clinical investigations vary among guidelines [31
]. For example, the Scottish SIGN guidelines recommend annual monitoring of weight, height, and BMI in long-term survivors of childhood cancer [33
]; similarly, the Center for International Blood and Marrow Transplant Research (CIBMTR) / European Society for Blood and Marrow Transplantation (EBMT) [34
] and US COG guidelines [35
] recommend this for long-term survivors after stem cell transplantation. At a minimum, blood pressure should be measured annually in long-term survivors [33
], and lipid status and fasting glucose or HbA1c should be determined every two years in overweight or obese and every five years in normal-weight survivors of childhood cancer according to Scottish Intercollegiate Guidelines Network (SIGN) recommendations [33
], and every five years in “standard risk” stem cell transplant survivors [34
]. Increased frequency of serum lipid and glucose homeostasis (fasting glucose or HbA1c) testing is indicated in survivors treated with TBI or abdominal radiation (every two years [35
] or mediastinal radiation every three to five years [31
]), and at three- to six-month intervals after HCT in high-risk patients treated with corticosteroids, or other immunomodulatory therapies [34
Metabolic disorders developing after BMT are not easy to treat. Generally, lifestyle changes are recommended first, with changes in food choices and an increase in physical activity to influence the underlying insulin resistance [36
]. In advanced stages of metabolic disorders such as manifest diabetes mellitus, hypertriglyceridemia, and also arterial hypertension, pharmacological therapy with gradual adjustment is required.
Fat loss in lipodystrophy is often associated with a decrease in leptin production and circulating leptin levels [14
]. Leptin deficiency results in hyperphagia and can lead to severe hypertriglyceridemia, fatty liver disease, and diabetes, as well as to several other metabolic and endocrine comorbidities [14
]. The use of metreleptin to treat hyperglycemia and hypertriglyceridemia in patients with generalized and partial lipodystrophy has been approved first in Japan [37
] and later in the European Union [38
] and in the UK [39
]. In the United States, the FDA has approved the use of metreleptin in generalized LD only [37
So far, two cases with HSCT-associated lipodystrophy have been reported who were treated with metreleptin to overcome metabolic disease [24
]. In the first report, a 28-year old female who developed partial lipoatrophy after receiving allogeneic BMT at the age of four years was treated with metreleptin due to poorly controlled hyperglycemia [24
]. The patient showed lipoatrophy at the lower extremities accompanied by an accumulation of visceral adipose tissue and fatty liver disease. Treatment with high-dose anti-diabetic combination treatment did not sufficiently improve hyperglycemia in the patient. The authors reported that upon daily administration of metreleptin, the metabolic profile of the patient returned to normal levels. However, the exact treatment regimen and metabolic data after treatment were not presented in this case report.
In the second study, a 17-year old woman with HSCT-associated LD who developed diabetes, dyslipidemia, fatty liver, and marked insulin resistance was treated with metreleptin for a period of 28 months [25
]. Within the treatment period, her blood glucose and lipid parameters, as well as liver function, improved, while there was no significant change in physical activity or food intake.
Thus, the data from the aforementioned studies demonstrate that metreleptin is a useful drug for the treatment of metabolic disturbances in HSCT-associated LD and further supports that metabolic disease upon HSCT is based on adipose tissue dysfunction.
6. Potential Mechanism
The molecular mechanisms of pathogenesis in HSCT-associated LD are not well understood. From the above-mentioned risk factors potentially causing the development of HSCT-associated lipodystrophies, we would like to expand the current view on the underlying mechanisms [25
] by the hypothesis that transplanted donor cells contribute to adipose tissue mass and function (Figure 1
). The major prerequisite for the development of the disease seems to be a damaging effect of TBI on adipose tissue. Although not shown directly in vivo in affected patients, the inhibition of adipocyte progenitor cell expansion by radiation seems to be a major contributor to this damage. Pharmacologic treatment during conditioning and GVHD treatment and GVHD itself may further accelerate the disease, as the use of glucocorticoids is associated with similar phenotypes as seen in the patient cohorts. Lipodystrophy often occurs more than 10 years after therapy, indicative of long-term development for the disease. It has been shown that donor-derived adipocytes accumulate over time in the adipose tissue [64
], indicating that the BM is a reservoir of adipocyte progenitor cells. Replacing patient adipocytes with donor BM-derived cells might have a detrimental impact on adipose tissue homeostasis and metabolism. Higher infiltration rates of BM-derived adipocyte progenitor cells into visceral compared to subcutaneous adipose tissue have been shown in mice [65
]. Although not shown in humans so far, this could also contribute to the alteration in body fat distribution. The functional properties of donor-derived adipocytes have not been investigated so far. Thus, further studies are warranted to investigate if donor-derived adipocytes are commonly detected in patients with HSCT-associated LD if tissue-preferential infiltration exists, and if donor-derived adipocytes are metabolically divergent from host adipocytes.
Taken together, we have reviewed the novel disease entity of HSCT-associated lipodystrophy and describe possible underlying mechanisms in the pathology of the disease. As this is an extremely rare disorder, one has to take into consideration that the disease is often overlooked upon patient follow-up. Implementation of the disease into registries such as the ECLip database will facilitate documentation and further research of this rare condition.