Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort

Abstract

Context: Partial lipodystrophy (PL) is associated with metabolic co-morbidities but may go undiagnosed as the disease spectrum is not fully described.

Objective: The objective of the study was to define disease spectrum in PL using genetic, clinical (historical, morphometric) and laboratory characteristics.

Design: Cross-sectional evaluation.

Participants: Twenty-three patients (22 with familial, one acquired, 78·3% female, aged 12-64 years) with PL and non-alcoholic fatty liver disease (NAFLD).

Measurements: Genetic, clinical and laboratory characteristics, body composition indices, liver fat content by magnetic resonance imaging (MRI), histopathological and immunofluorescence examinations of liver biopsies.

Results: Seven patients displayed heterozygous pathogenic variants in LMNA. Two related patients had a heterozygous, likely pathogenic novel variant of POLD1 (NM002691·3: c.3199 G>A; p.E1067K). Most patients had high ratios (>1·5) of percentage fat trunk to percentage fat legs (FMR) when compared to reference normals. Liver fat quantified using MR Dixon method was high (11·3 ± 6·3%) and correlated positively with haemoglobin A1c and triglycerides while leg fat by dual-energy X-ray absorptiometry (DEXA) correlated negatively with triglycerides. In addition to known metabolic comorbidities; chronic pain (78·3%), hypertension (56·5%) and mood disorders (52·2%) were highly prevalent. Mean NAFLD Activity Score (NAS) was 5 ± 1 and 78·3% had fibrosis. LMNA-immunofluorescence staining from select patients (including one with the novel POLD1 variant) showed a high degree of nuclear atypia and disorganization.

Conclusions: Partial lipodystrophy is a complex multi-system disorder. Metabolic parameters correlate negatively with extremity fat and positively with liver fat. DEXA-based FMR may prove useful as a diagnostic tool. Nuclear disorganization and atypia may be a common biomarker even in the absence of pathogenic variants in LMNA.

Figure 1

A. Comparison of %fat trunk / %fat legs (fat mass ratio, FMR) in 23 patients with partial lipodystrophy, one of whom has acquired partial lipodystrophy (patient 4) to age, gender and ethnic group matched reference values (median with 95% confidence interval) from NHANES data⁽¹⁵⁾. Reference data was not available for pediatric patients (patients 7, 15, 23). B. Picture of patient 22 who presented with a very high fat mass ratio harboring a possibly pathogenic variant at position 349 (R349W). Patient displayed loss of fat from face, extremities, including loss of supportive fat from hands and feet, but with excessive fat deposition in the back displaying an exaggerated buffalo hump. Other clinical features included ischemic and non-ischemic cardiac disease, PCO-S with severe hyper-androgenism and infertility, alopecia, hematuria (due to thin basement membrane disease on kidney biopsy). Laboratory features included a high testosterone level and a very low alkaline phosphatase level typically associated with progeroid disorders. (C, D Pictures of patient 7 with a possibly pathogenic POLD1 variant. This patient and her mother displayed very severe insulin resistance, preservation of subcutaneous fat around the face and neck and even in the abdominal wall. There was a paucity of fat in the extremities. Patients also demonstrated stiffness in joints, elevated CK levels (mother displaying muscle weakness), proteinuria (massive in one leading to kidney biopsy showing membranoproliferative glomerulonephritis). The patient and her mother did not have deafness. E. X-ray of the narrow mandible for patient 6 with possibly pathogenic POLD1 variant.

Figure 2

Correlation was noted between metabolic parameters of hemoglobin A1c and liver fat % (A) as well as log transformed triglycerides and liver fat % (B). Hemoglobin A1c was not significantly correlated with leg fat mass (C). A significant correlation was seen between log transformed triglycerides and leg fat mass (D). Leg fat mass and liver fat % did not correlate (data not shown).

Figure 3

A. Frequency of medication use for diabetes, dyslipidemia, hypertension and mood disorders. B. Co-morbidity frequency among 23 patients with partial lipodystrophy.

Figure 4

A. Frequency distribution of NASH scores of liver biopsy specimens. B. H&E and C. Trichrome staining of liver biopsy sample in patient 15 (a 12-year-old with atypical PL) showing hepatic injury and steatosis (B) stage 4 fibrosis (C).

Figure 5

Abnormal nuclear morphology and lamin distribution in livers from patients with LMNA mutations. Lamin A/C distribution (red) and nuclei (blue) were visualized by immunofluorescence staining of frozen liver sections from patients with familial partial lipodystrophy (D-O). Liver biopsy specimens from two patients with nonalcoholic steatohepatitis but no history of PL and no pathogenic variants in LMNA were used as controls; representative images from one of these patients are shown (A-C). Dysmorphic nuclei and lamin disorganization are indicated by arrows in high magnification images (right column). Scale bars 20 μm (left and middle column), 10 μm (right column). Right panels show quantification of abnormal nuclear shape (upper right) and abnormal lamin distribution (lower right) in control NASH livers versus those from patients with LMNA and POLD1 variants. For each group, 3–4 randomly selected high-power fields were scored for each patient liver section (>150 nuclei per field, >700 nuclei per patient). Statistical significance was determined by one-way ANOVA followed by Tukey post-hoc test at a threshold of P < 0.05. Error bars represent the standard error of the mean.