Diagnosis

Due to its rarity and heterogenous clinical presentations, the diagnosis of lipodystrophy may be missed as most clinicians are not familiar with its diagnosis and management.1

  1. How can I detect lipodydstrophy
  2. What are the different forms of lipodydstrophy?
  3. Clinical characteristics of lipodydstrophy
  4. Differential Diagnosis

How can I detect Lipodystrophy?

Generalised and partial lipodystrophy may be hard to
detect. If you suspect your patient to have lipodystrophy,
several tools can assist you in determining a diagnosis.

Download the LipoDDx App
that can help in the diagnosis
of lipodystrophy

What are the different forms of
Lipodystrophy?

Lipodystrophies are potentially life threatening diseases,
heterogeneous in appearance, very rare, and characterised by a partial
or complete loss of subcutaneous fatty tissue. Symptoms manifest
differently in each patient and not all of these symptoms have to occur
in all patients.
The disease is subdivided according to four primary categories:
CGL, AGL, FPLD and APL.

Lipodystrophy is heterogenous in appearance – but it is always linked to a lack of subcutaneous adipose tissue.

Lipodystrophy is considered as a visual diagnosis, therefore the patient
must be examined unclothed. However, in addition to the unusual
appearance of a lipodystrophy patient, there are also other
conspicuous clinical symptoms.

For an overview of the clinical features for the different lipodystrophy subtypes please click the image

Clinical characteristics of Lipodystrophy

GENERALISED LIPODYSTROPHY

  1. Generalised absence of subcutaneous adipose tissue1-9
  2. Resulting deficiency in the hormone leptin1-6
  3. Metabolic abnormalities including1-6
    • Insulin resistance
    • Diabetes mellitus
    • Hypertriglyceridemia
  4. Ectopic fat deposition in the liver, muscle, and other organs which may cause serious organ damage1-6
  5. Estimated prevalence 0.23-0.96 in 1,000,000 population7
  6. May be Congenital – from birth or Acquired – usually presenting
    in childhood or adolescence1-5, 8,9

Congenital

Characteristics of Congenital Generalised Lipodystrophy1-5

Age of onset: Apparent at birth or early childhood
Male : Female ratio: 1 : 1 – 2
Essential characteristics:

  • Autosomal recessive (AR) inheritance in vast majority of cases,
  • Family history or consanguinity may present
  • Near-complete lack of adipose tissue

Possible clinical features of Congenital Generalised Lipodystrophy1-5,8

Not all of these features may be present in all patients:

  • Hyperphagia
  • Prominent muscles and veins
  • Hepatosplenomegaly
  • Hyperlipidemia
  • Acanthosis nigricans, signs of insulin resistance, diabetes
  • Hyperandrogenism in females
  • Acromegaloid features
  • Advanced bone age
  • Accelerated growth

Acquired

Characteristics of Acquired Generalised Lipodystrophy1-5,8-9

Age of onset: Variable, usually in childhood or adolescence
Male : Female ratio: 1 : 3
Essential characteristics:

  • Progressive loss of fat leading to near-complete lack of adipose tissue
  • No family history
  • Associated with autoimmune illness e.g. juvenile dermatomyositis, autoimmune hepatitis, type 1 diabetes or panniculitis

Possible clinical features of Acquired Generalised Lipodystrophy1-5,8-9

Not all of these features may be present in all patients:

  • Variable fat loss pattern (e.g. preserved intra-abdominal fat in some cases)
  • Hyperphagia
  • Prominent muscles and veins
  • Hepatosplenomegaly
  • Hyperlipidemia
  • Acanthosis nigricans, signs of insulin resistance, diabetes
  • Hyperandrogenism in females

PARTIAL LIPODYSTROPHY

  1. Partial absence of subcutaneous adipose tissue1-9
  2. Accumulation of fat in other parts of the body in some patients1-5
  3. Metabolic abnormalities including1-5
    • Insulin resistance
    • Diabetes mellitus
    • Hypertriglyceridemia
  4. Ectopic fat deposition in the liver, muscle, and other organs which may
    cause serious organ damage1-5
  5. Estimated prevalence 1.67 in 1,000,000 population7
  6. May be familial or aquired1-5, 8

Familial

Characteristics of Familial Partial Lipodystrophy1-5

Age of onset: Around puberty
Male : Female ratio: 1 : 4 – 5
Essential characteristics:

  • Regional loss of adipose tissue.
  • Fat accumulation may present resembling obesity or Cushing’s Syndrome
  • May present with hyperphagia
  • Variable degree of metabolic abnormalities

Possible clinical features of Familial Partial Lipodystrophy (FPLD)1-5

FPLD more likely to present with:

  • Hyperphagia
  • Prominent muscles and veins
  • Acanthosis nigricans, signs of insulin resistance
  • Hyperandrogenism in females

*Not all of these features may be present in all patients

Acquired

Characteristics of Acquired Partial Lipodystrophy1-5,8,9

Age of onset: Child, adolescence or early adulthood
Male : Female ratio: 1 : 4
Essential characteristics:

  • Gradual loss of adipose tissue from head downwards
  • Fat can accumulate around the hips, buttocks, and legs in some patients
  • Metabolic abnormalities less common, but can vary in severity

Possible clinical features of Acquired Partial Lipodystrophy (APL)1-5,8,9

APLD more likely to present with:

  • No fat loss from lower extremities
  • Mild or no metabolic complications (but these may still be found)

*Not all of these features may be present in all patients

Differential Diagnosis

The path to diagnosis can be difficult and long. According to the subtype, onset of lipodystrophy symptoms may occur between infancy and adolescence.

Health complications associated with the disease can vary greatly. In particular, patients suffering from partial lipodystrophy do not necessarily display any symptoms until puberty.

Special attention should be paid to FPLD as this might be confused with truncal obesity, Cushing’s syndrome and multiple symmetric lipomatosis.

Download the diagnose leaflet
for Generalised lipodystrophy (GL)

Download the diagnose leaflet
for Partial lipodystrophy (PL)

Differential diagnosis of generalized lipodystrophy (GL)

Generalized Lipodystrophy

Key clinical features:
Near total fat loss, subtype specific features

Metabolic abnormalities:
Yes; may be absent in the early years of life

Appetite:
Increased

Adiponectin:
Low

Additional work-up:
Imaging, genetic testing, etc.

Adrenal insufficiency21,22

21,22

Key clinical features:
Symptoms of adrenal insufficiency

Metabolic abnormalities:
Hypoglycemia

Appetite:
Decreased

Adiponectin:
Normal in Addison’s disease, slightly low in SAI

Additional work-up:
Cortisol, ACTH, dynamic tests to evaluate the adrenal gland functions and HPA axis

Poorly controlled type 1 diabetes mellitus26-28

26-28

Key clinical features:
Insulin deficient diabetes

Metabolic abnormalities:
Hyperglycemia, ketoacidosis; hypertriglyceridemia possible

Appetite:
Variable

Adiponectin:
High

Additional work-up:
C-peptide, AntiGAD antibody

Diencephalic syndrome35

35

Key clinical features:
Headaches, abnormal progressive thinness and weakness, vomiting, vision abnormalities, nystagmus

Metabolic abnormalities:
Failure to gain weight and grow; hypoglycemia in some patients

Appetite:
Variable

Adiponectin:
Not studied

Additional work-up:
Imaging of tumor located in the diencephalon

Malnutrition/starvation11, Anorexia nervosa12, Tumor induced cachexia13, Severe chronic inflammation14,15

11,12,13,14,15

Key clinical features:
Poor growth in children with malnutrition, distorted body image in anorexia nervosa, elevated acute phase reactants in severe chronic inflammation

Metabolic abnormalities:
Hypoglycemia rather than hyperglycemia possible; glycogen deposition with elevated LFTs can be seen

Appetite:
Variable

Adiponectin:
Elevated

Additional work-up:
Albumin, or prealbumin, micronutrient levels; psychiatric counseling; tumor markers and imaging; work-up to diagnose chronic inflammatory diseases

HIV-associated wasting23,24

23,24

Key clinical features:
Chronic diarrhea and malabsorption, cytokine response to virus, hypogonadism, increased resting energy expenditure

Metabolic abnormalities:
Variable; insulin resistance; hypertriglyceridemia can be seen (at least partly associated with HIV treatment)

Appetite:
Decreased

Adiponectin:
Low

Additional work-up:
HIV Panel

Glycogenic hepatopathy29

Key clinical features:
Poorly controlled diabetes, hepatomegaly, elevated liver enzymes (usually higher than typical levels for NASH)

Metabolic abnormalities:
Ketoacidosis; most patients have type 1 diabetes; rarely reported in type 2 diabetes

Appetite:
Variable

Adiponectin:
Not studied, more likely elevated

Additional work-up:
Liver biopsy

Thyrotoxicosis16-20

16-20

Key clinical features:
Symptoms of thyrotoxicosis

Metabolic abnormalities:
Mild hyperglycemia/insulin resistance; triglycerides usually normal; elevated LFTs possible

Appetite:
Normal/Increased

Adiponectin:
Normal

Additional work-up:
Thyroid functions

Insulin receptor mutations (INSR)25

Key clinical features:
Extreme insulin resistance, hyperandrogenism in females, prepubertal linear growth acceleration, pseudoacromegaly

Metabolic abnormalities:
Extreme hyperinsulinemia but normal lipid profile; relative lack of fatty liver; acanthosis nigricans 

Appetite:
Normal/Increased

Adiponectin:
Very high

Additional work-up:
Elevated SHBG and IGFBP1

Acromegaly/gigantism30-34

30-34

Key clinical features:
Symptoms of acromegaly, no actual generalized fat loss

Metabolic abnormalities:
Yes; but usually moderate (unless there is a preexisting underlying metabolic disorder)

Appetite:
Usually increased

Adiponectin:
Low

Additional work-up:
IGF-1, GH, OGTT

ACTH, Adrenocorticotropic hormone; GH, Growth hormone; GAD, Glutamic acid decarboxylase; HIV, Human immunodeficiency virus; HPA, Hypothalamic-pituitary-adrenal; IGF, Insulin growth factor; IGFBP1, IGF binding protein- 1; LFTs, Liver function tests; NASH, Nonalcoholic steatohepatitis; OGTT, Oral glucose tolerance test; SAI, Secondary adrenal insufficiency; SHBG, Sex Hormone Binding Globulin.

Differential diagnosis of generalized lipodystrophy (PL)

FPLD36,37

36,37

Family History:
Likely

Key clinical features:
Loss of fat in the limbs predominantly affecting the lower part of the body Increased fat in face, neck and genital area (FPLD2)

Metabolic abnormalities:
Yes. Heart disease (structural, ischemic or arrhythmogenic disorders reported)

Leptin:
Normal or low

Adiponectin:
Normal or low, but lower than truncal obesity

Additional work-up:
DEXA and/or MRI Anthropometric measurements Genetic testing

Barraquer-Simons43,44

43,44

Family History:
No

Key clinical features:
Central obesity

Metabolic abnormalities:
Less frequent

Leptin:
Likely normal

Adiponectin:
Likely normal

Additional work-up:
Serum C3 complement Urinary protein excretion Retina exam

HIV-associated lipodystrophy51,52

51,52

Family History:
No

Key clinical features:
Fat redistribution, central obesity

Metabolic abnormalities:
Yes

Leptin:
Normal or high

Adiponectin:
Usually in the normal range

Additional work-up:
HIV test
Lymphocyte subpopulations

Cushing syndrome38,39

38,39

Family History:
No

Key clinical features:
Muscle weakness, stretch marks, central obesity, round face, buffalo hump, osteoporosis

Metabolic abnormalities:
Yes

Leptin:
Usually high, although conflicting reports are present

Adiponectin:
Normal or high, although conflicting reports are present

Additional work-up:
Serum cortisol levels Cortisol suppression test

Progeroid syndromes* 45,46

45,46

Family History:
Likely in some but most cases are de novo.

Key clinical features:
Progressive fat loss (GL or PL), progeroid features, cardiac abnormalities, renal involvement likely

Metabolic abnormalities:
Metabolic abnormalities develop later, and are usually progressive.

Leptin:
Usually low

Adiponectin:
Usually low

Additional work-up:
Genetic testing
Subtype specific work-up

Truncal obesity40-42

40-42

Family History:
Likely in some

Key clinical features:
Central obesity

Metabolic abnormalities:
Yes

Leptin:
Normal or high

Adiponectin:
Normal or low

Additional work-up:
Rule out secondary obesity

Myeloablative therapy induced lipodystrophy47-50

47-50

Family History:
No

Key clinical features:
Loss of fat in limbs and trunk, increased fat in face and neck (some cases)

Metabolic abnormalities:
Yes

Leptin:
Not reported

Adiponectin:
Not reported

Additional work-up:
Not specific

*Progeroid syndromes are their own category, but need to be separated from APL due to the development of fat loss later in life and FPLD due to genetic etiology.
Progeroid features include micrognathia, mottled skin, atrophic skin, beaked nose, thin lips and receding hairline, hair loss, skeletal abnormalities such as mandibular and clavicular hypoplasia, scoliosis, acroosteolysis, etc.

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