Acquired generalised lipodystrophy and type 1 diabetes mellitus in a child: a rare and implacable association

Abstract

Lipodystrophy syndromes are frequently associated with marked degree of insulin resistance and lipoatrophic diabetes. Although acquired generalised lipodystrophy (AGL) has been known to be associated with various autoimmune disorders, type 1 diabetes mellitus (T1DM) is very rarely reported to occur with AGL. Combination of AGL and T1DM can lead to a totally different phenotype with very difficult-to-treat diabetes and progressive complications of both the conditions. We report a case of AGL with T1DM with poor diabetes control despite high doses of insulin, metformin and pioglitazone. Our case further progressed to develop complication of retroperitoneal fibrosis, not hitherto reported with AGL.

Background

Lipodystrophy syndromes are a group of rare heterogenous disorders with common features of partial or generalised loss of adipose tissue resulting in abnormal body shape, insulin resistance, steatohepatitis and hypertriglyceridaemia. Lipodystrophies can be congenital and acquired; localised and generalised. Acquired generalised lipodystrophy (AGL) usually occurs in later part of first decade or early part of second decade, although it can occur later in adulthood as well. It is further classified into three types including panniculitis associated AGL, AGL with autoimmune disorders and idiopathic AGL.¹ Various autoimmune conditions have been described in patients with AGL, common being Sjogren’s syndrome, juvenile idiopathic arthritis, Hashimoto’s thyroiditis, autoimmune haemolytic anaemia and autoimmune thrombocytopenia. Type 1 diabetes mellitus (T1DM) with glutamic acid decarboxylase (GAD) antibody positivity in children with AGL has been reported only in two patients so far.² In AGL with T1DM, the presence of insulin resistance and insulin deficiency at the same time results into very difficult-to-treat diabetes phenotype. Our patient also had very poor diabetes control despite multidrug regimen including high-dose insulin, metformin and pioglitazone. Our patient also had some other unusual features including antinuclear antibody (ANA) positivity and retroperitoneal fibrosis.

Case presentation

An 8-year-old boy presented to our hospital with complaints of frequent passage of greasy stools and abdominal distension for 1.5 months. There was history of jaundice lasting for few days 1 year back. There was history of progressive loss of body fat, muscular appearance and prominent veins all over the body for the last 2 years. There was no history of polyuria or polydipsia. Child had achieved developmental milestones at appropriate age and had average performance at school. In family history, grandfather had type 2 diabetes mellitus and mother had hypothyroidism and chronic kidney disease. On examination, he had anaemia, acanthosis nigricans, hepatosplenomegaly, abdominal distension, pseudohypertrophy of all muscles, phlebomegaly with generalised loss of subcutaneous fat (figure 1). Initial clinical possibility considered at this stage was generalised lipodystrophy with insulin resistance and chronic liver disease. Liver functions were normal except for raised transaminases. Serum tissue transglutaminase antibody and ceruloplasmin levels were normal. Markers for autoimmune hepatitis were negative. Hepatitis B virus surface antigen, antihepatitis C virus and HIV serology was negative. Plasma fasting insulin levels and C-peptide were high. Glycated haemoglobin (HbA1c) was in prediabetic range; however, 2 hour oral glucose tolerance test (fasting plasma sugar 92; 1 hour 167; 2 hour 148 mg/dL) and lipid profile were normal (table 1). No specific therapy could be advised and the patient was lost to follow-up for nearly 2 years.

Figure 1.

Panels (A) and (B) showing facial appearance at age4 and 7 years. Panels (C)–(F) are the clinical photographs at 13 years of age showing front and lateral aspect, pseudohypertrophy of all muscles, phlebomegaly with generalised loss of subcutaneous fat.

Table 1.

Summary of clinical and laboratory parameters at diagnosis and various ages till last follow-up

Parameters	At first presentation (8 years)	10 years (T1DM diagnosed)	12 years	13.5 year	Last follow-up (13.8 years)
Weight (kg)/height (cm)	27.8/125	27.8/136	32.3/142.8	35.2/144.4	34.4/144.9
SMR staging	G1	G1	G2 P2 Bilateral TV 3–4 cc	G3 P3 TV 5cc	G3 P3 TV 5cc
Total bilirubin (mg/dL)	0.8	1.52	1.59/0.16	ND	1.9
AST/ALT (U/L)	298/376	236/369	117/151		103/111
Total protein/albumin (g/dL)	8.6/4.1	8.2/4.0	8.8/3.3		9.8/4.3
RBS (mg/dL)	102	580	370		ND
Urine for ketones	ND	3+	+		ND
Urine sugar	Nil	2+	4+sugar		ND
Plasma HbA1c (%)	5.8	10.2%	14.4	8.7	10.4
Fasting serum C-peptide (1.1–4.4 ng/mL)	7.550	0.092	0.054		0.010
Serum insulin (2.00–25.00 μU/mL)	50.40	2.87	ND	ND	ND
Serum GAD 65	ND	Positive	ND	ND	ND
Fasting serum lipids (mg/dL)	108	145	143	362	377
Cholesterol	108	122	278	1460	1745
Triglycerides	41.6	37	18	21	14.8
HDL	20.1	24.4	56
VLDL	45.0	83.6	16
LDL
Serum T3 (ng/mL)/T4 (μg/dL)/TSH (IU/L)	ND	1.21/11.61/2.28	1.0/8.19/3.44		1.01/9.34/3.34
Serum TTG IgA	Negative	Negative	ND	ND	Negative
Serum antinuclear antibody	ND	Negative	Positive (3+fine speckled)	ND	ND
Serum anti-ds-DNA	ND	ND	Negative	ND	ND
Insulin and other drug regimen		Aspart+glargine+ metformin	Added acarbose and pioglitazone	Lifestyle modification	Added atrovastatin (20 mg), ezetimibe (10 mg), fenofibrate (40 mg)

ALT, alanine transaminase; AST, aspartate transaminase; GAD, glutamic acid decarboxylase; HbA1C, glycated haemoglobin; HDL, high-density lipoprotein; Ig, immunoglobulin; LDL, low-density lipoprotein; ND, not done; RBS, random glucose test; SMR, sexual maturity rating; TSH, thyroid-stimulating hormone; TTG, tissue transglutaminase; VLDL, very low-density lipoprotein.

Two years later, at nearly 10 years of age, the child was hospitalised with features of mild diabetic ketoacidosis (DKA). At this time, he was presented with history of excessive weight loss for 2 months along with polyuria, polydipsia and polyphagia for 1 week. He had excessive wasting in the form of thinning of fingers, hollowing of cheeks and supraclavicular fossa with more prominent veins and muscles of whole body. He did not gain significant weight over the last 2 years but gained height at 5.5 cm/year. His body mass index was 15.0 kg/m² (−0.78 Z score; WHO standards) at 10 years. On examination, his vital signs were within normal limits except for mild tachycardia. Abdominal examination revealed palpable firm liver 7 cm below the right costal margin with span of 13 cm; firm spleen was palpable 3 cm below left costal margin, and there was no free fluid. Other system screen examination was normal. Laboratory investigations revealed the presence of mild DKA with random blood sugar of 583 mg/dL and HbA1c of 10.2%. Urine examination showed 3+ ketones and sugar. Plasma insulin level was 2.87 μU/mL (reference 2–25); C-peptide level was 2.5 ng/mL (reference 1.1–4 ng/mL), and GAD 65 was positive. The serum adiponectin level was low at 1.7 μg/mL (reference 4–26). The lipid profile and triglyceride level were again within normal limits. Thyroid function test and coeliac screen were normal. Ultrasound of the abdomen showed hepatosplenomegaly. Genetic study using targeted next-generation sequencing for common gene mutations associated with congenital liposdystrophy and insulin resistance (LMNA, AGPAT2, BSCL2, PPARG, INSR, ZMPSTE 24) was performed and was found negative. In view of the above clinical and laboratory profiles, diagnosis of T1DM with acquired generalised lipodystrophy was considered and the patient was discharged on metformin, acarbose and insulin analogues including glargine and aspart (total dose of 3.5 U/kg/day).

During further follow-up, over the next 2 years, his triglyceride levels increased and diabetes control worsened (with some initial improvement after starting treatment for T1DM) even with high doses of insulin and metformin. At 12 years, his HbA1c increased to 14.4% despite very high doses of insulin (5.7 units/kg/day). At this stage, he was again hospitalised for left-sided pyonephrosis with rupture which required drainage. The pus grew methicillin-sensitive Staphylococcus aureus on culture for which intravenous antibiotics were given for nearly 3 weeks. During this hospitalisation, contrast-enhanced CT abdomen showed large hepatosplenomegaly with chronic liver disease, bilateral renomegaly with ruptured left renal abscess with retroperitoneal fibrosis (RPF). RPF was also confirmed on MRI abdomen (figure 2). Positron emission tomography-CT showed non-F-18 fluorodeoxyglucose avid retroperitoneal density (Hounsfield units approximately 44–64) in the retroperitoneum extending from the level of D12 vertebra to sacrum. RPF was seen to encase the abdominal aorta and its branches and bilateral common iliac vessels (figure 2). Further workup for other common causes of RPF showed positive ANA 3+ speckled with negative double stranded DNA (dsDNA) titre and normal serum immunoglobulin G4 subclass level. By this time, his hepatosplenomegaly, abdominal distension, loss of fat and triglyceridaemia had also further progressed. The lipid profile showed serum high-density lipoprotein of 21 mg%, serum cholesterol 362 mg% and serum triglycerides 1460 mg%. An echocardiogram revealed mild left ventricular hypertrophy, and ultrasound of the abdomen showed hepatosplenomegaly with diffuse fatty infiltration of the liver with liver parenchymal disease and portal hypertension. He was continued on insulin basal-bolus regimen, metformin and started on pioglitazone. Further follow-up, 1.5 years after starting pioglitazone, showed significant reduction in HbA1c to 8.7% (although it rose to 10.7% at last follow-up), some improvement in liver transaminases but hyperlipidaemia progressed further. Dual-energy X-ray absorptiometry scan for total body fat estimation by whole body fan beam (Model: Hologic Discovery) showed total body fat being very low at 13.2%. At this stage, he qualified for intervention for hyperlipidaemia. He was advised lifestyle changes for 3 months followed by addition of atorvastatin 20 mg, ezetemibe 10 mg and fenofibrate 40 mg daily.

Figure 2.

(A) CT axial image showing sheet like hypodense soft tissue in the retroperitonium encasing the aorta, inferior vena cava and bilateral renal vessels (white arrow). (B) MR axial image showing the hyperintense soft tissue in the retroperitoneum.

Discussion

Our patient had AGL associated with autoimmune type 1 diabetes with all typical features of generalised lipodystrophies including insulin resistance (acanthosis nigricans), hypertriglyceridaemia, steatohepatitis, hepatosplenomegaly, phlebomegaly and generalised loss of subcutaneous fat starting at around 7 years of age. In addition, our patient developed marked RPF encasing large part of abdominal aorta and its main branches. Our patient also had GAD antibody and ANA positivity. There was poor response to high-dose insulin and metformin but some improvement on addition of pioglitazone. Diagnosis was further substantiated by normal fat on the face in serial photographs taken before the onset of symptoms (figure 1) and negative genetic mutation studies for common type of congenital generalised lipodystrophies. Late presentation of congenital generalised lipodystrophy was considered as a possibility, and genetic tests were done for the same as a part of academic collaboration.

AGL is 2–3 times more common in females like most autoimmune disorders.^{1 3} Association with autoimmune disorders is known to be a common feature of acquired generalised or localised lipodystrophy as per the largest recent review of 1141 children (less than 18 years) with congenital or acquired type of lipodystrophy excluding secondary lipodystrophies.³ Also, recent guidelines on diagnosis of various types of lipodystrophies suggest to pursue diagnosis of acquired lipodystrophies in patients with autoimmune disorders along with lipodystrophy.⁴

Park et al reported two patients with AGL associated with type 1 diabetes and insulin resistance as in our case. One patient reported by the authors had T1DM diagnosed at the age of 8 years followed by onset of generalised lipodystrophy at 11 years of age, although our patient had lipodystrophy apparent before the onset of T1DM. This patient also had hypertriglyceridaemia, raised liver transaminases, poor glucose control on high-dose insulin (up to 5 U/kg/day) as in our case. Second case reported by the authors had concurrent onset of T1DM and generalised lipodystrophy at 6 years of age, more like our patient but had very high triglyceride levels (2984 mg/dL) and insulin requirement (32 U/kg/day) along with elevated transaminases and steatohepatitis. Both patients responded well to the addition of leptin therapy with significant improvement in glycaemic control, decreased triglyceride levels and insulin dose. One of these patients was briefly given pioglitazone and then stopped due to persisting hypertriglyceridaemia and worsening transaminases. In a recent report of metreleptin (recombinant leptin) treatment of 51 children with lipodystrophies with low leptin levels, a significant improvement was noted in all glycaemic control, triglyceride levels, steatohaepatitis markers, etc, over 1-year treatment period and effects of treatment continued over 5 years of therapy.⁵ Our patient could not avail benefit of leptin therapy (not available in India), so we had option of only insulin, metformin and pioglitazone to treat our patient. Addition of pioglitazone did show some improvement in glycaemic control and transaminase levels in our patient but no improvement (rather worsening) in triglyceride levels.

Association of T1DM and AGL can be explained by the autoimmune basis of both the disorders. The specific type of AGL associated with autoimmune disorders is categorised as type 2 or autoimmune AGL.¹ Our patient also had positive ANA on two occasions, although dsDNA was negative and patient does not have any specific clinical features of systemic lupus erythematosus at present.

RPF seen in our patient has not been previously reported in AGL, although idiopathic RPF has been reported to be associated with long-standing T1DM. RPF could be a result of excess fat accumulation in the retroperitoneum which has undergone necrosis and fibrosis overtime. It is also hypothesised that antigens in atherosclerotic plaques in the aortic lumen could initiate allergic reaction around the abdominal aorta (autoallergic aortitis) and lead on to extensive RPF.⁶ RPF encasing abdominal aorta and its branches could have led to left ventricular hypertrophy due to back pressure effect in our patient as there is no hypertension noted in our patient as yet. We would like to follow our child for other complications of RPF including obstructive uropathy and renal hypertension.

Progressive dyslipidaemia in our child (as seen in recent two most recent lipid profiles in table 1) has crossed the threshold for treatment with drugs (statins and fibrates) as per the existing guidelines for hyperlipidaemia in children⁷ and thus been started on therapy for the same with lowest recommended doses. We plan to monitor liver functions closely for any side effects and dose adjustments needed as per response to therapy.

Learning points.

• Acquired generalised lipodystrophy (AGL) can be associated with various autoimmune disorders.

• Coexistence of AGL and type 1 diabetes mellitus, although very rare, presents as a totally different disease phenotype.

• Two conditions in combination can pose significant treatment challenge with regard to both the glycaemic control and the dyslipidaemia.

• In the absence of metreleptin therapy, a combination of drugs including insulin, metformin, pioglitazone, statins and fibrates would be required at various stages of disease course.