What is Lipodystrophy?

Lipodystrophy syndromes are extremely rare disorders. However, the core characteristic is complete (generalised) or partial absence of subcutaneous adipose tissue or unusual fat distribution. The loss of adipose tissue is frequently associated with serious metabolic complications and leptin deficiency.1

Pathophysiology of Lipodystrophy

Lipodystrophies can be characterised by the extent of the adipose tissue loss, generalised loss over the whole body or partial loss. They are also classified into whether they are inherited (congenital or familial) or acquired. This leads to four main types: congenital generalised lipodystrophy (CGL), acquired generalised lipodystrophy (AGL), familial partial lipodystrophy (FPLD) and acquired partial lipodystrophy (APL). Adipose tissue is important as an energy store, in maintaining energy homeostasis and secreting hormones such as leptin. A significant loss of adipose tissue can result in significant metabolic disruption and leptin deficiency.1,2

Generalised and partial lipodystrophy are always connected to a lack of subcutaneous adipose tissue. 
The extent and location of adipose tissue loss depends on the subtype of lipodystrophy.

How is Leptin related to Lipodystropy?

Leptin is an adipocyte-secreted hormone that regulates energy homeostasis as well as metabolic, reproductive, neuroendocrine, and immune functions.1 Normally, excess energy and fat is stored in adipose tissue. In lipodystrophy, adipose tissue is markedly reduced leading to leptin deficiency and adipose storage capacity is exceeded.1 Combined, these can cause ectopic fat deposition and metabolic complications.1,2

A leptin deficiency caused by the loss of adipose tissue makes a significant contribution to the metabolic complications seen in lipodystrophy patients and also leads, in particular, to insatiable hunger and excess food intake, which exacerbates the metabolic comorbidities further.

Premature Mortality

Patients with lipodystrophy may die prematurely. Major causes include: heart disease (cardiomyopathy, heart failure, myocardial infarction, arrhythmia), liver disease (liver failure, gastrointestinal haemorrhage, hepatocellular carcinoma), kidney failure, acute pancreatitis, sepsis.

Clinical consequences of Leptin Deficiency

Triglycerides

People living with lipodystrophy tend to experience moderate to extreme levels of hypertriglyceridaemia.2,12 Concerning this, our experts highlighted two key indicators to either initiate or change treatment for lipodystrophy patients:2

  1. Uncontrolled hypertriglyceridaemia despite lipid-lowering drugs
  2. Severely elevated levels of triglycerides (>500 mg/dL)

It is recommended that triglyceride levels are measured and monitored annually.2

Diabetes 

One of the severe metabolic abnormalities that is common among those living with lipodystrophy is diabetes mellitus.11 Persistently high blood glucose levels can, over time, cause some of the metabolic symptoms of lipodystrophy to worsen and so should be managed with urgency.2, 11, 17 Our experts highlighted two factors that should prompt further treatment among patients – diabetes that:2 

a. Requires high insulin doses 

b. Is poorly controlled 

Healthcare professionals managing those living with lipodystrophy should screen for diabetes on an annual basis. The guidelines of the American Diabetes Association (fasting plasma glucose, oral glucose tolerance test, or glycosylated haemoglobin [HbA1c]) can be helpful for this screening.2 Patients with acquired generalised lipodystrophy (AGL) may develop type 1 diabetes in addition to insulin resistance;11 measurement of autoantibodies may clarify the diagnosis. 

Cardiomyopathy 

Cardiomyopathy, demonstrated by echocardiography and electrocardiogram (ECG), is not rare among patients in lipodystrophy.17 Cardiomyopathy has multiple etiologies in lipodystrophy.18 Metabolic abnormalities (hyperglycemia, dyslipidemia, and hyperinsulinemia) due to leptin deficiency seem to play a role in cardiac hypertrophy.18 Cardiomyopathies and sudden cardiac death contribute to high risk of early mortality in patients with lipodystrophy.13, 19, 20 21 Patients diagnosed with lipodystrophy should be tested for cardiomyopathy using an echocardiogram and/or an ECG.11,13,20,21 

Chronic Kidney Disease  

Chronic kidney disease (CKD) and hyperphagia are listed by lipodystrophy treating clinicians as among the top triggers to treat.13, 23 CKD is a long-term condition defined by an abnormal structure or function of the kidney persisting for a number of months.23 This complication is frequent in patients with lipodystrophy as it can onset from an early age.23 Those with CKD may also go on to experience renal failure.23

Renal disease in lipodystrophy seems to be multifactorial and at least partly driven by poorly controlled diabetes and severe insulin resistance due to adipose tissue dysfunction and leptin deficiency.23 CKD can be confirmed by studying the level of proteinuria and the estimated glomerular filtration rate (eGFR) of patients.24 

Pancreatitis 

Some of the severe lipodystrophy symptoms, including high triglyceride levels, can have a knock-on effect on the pancreas and cause pancreatitis.15 Our experts identified the following two symptoms as important indicators of needing to actively treat lipodystrophy:15

a. History of acute pancreatitis 

b. Recurrent pancreatitis 

People experiencing episodes of acute pancreatitis may experience abdominal pain, nausea, vomiting and fever.16 Confirming these episodes can be done by testing levels of amylase and lipase in the patient’s blood.16

Atherosclerotic Cardiovascular Disease 

Atherosclerotic cardiovascular disease (ACVD) and cardiomyopathy are listed by lipodystrophy treating clinicians as among the top 10 triggers to treat.13 Due to the increased prevalence of dyslipidaemia and diabetes, patients with lipodystrophies appear to be at high risk of ACVD.14

Metabolic complications, i.e. dyslipidaemia and diabetes mellitus, should be managed to prevent the risk of ACVD.3, 11, 13, 14, 17 

Steatosis  

Steatosis, or fatty liver, is a common feature of lipodystrophy due to the ectopic deposition of fat due to the paucity of subcutaneous adipose tissue.11 Our experts highlighted both hepatic steatosis and non-alcoholic steatohepatitis (NASH) as symptoms that may support treatment decisions in patients with lipodystrophy.11 

The diagnosis of NASH is made by liver biopsy. Liver biopsy can also show how severe the liver disease is.22

Hyperphagia   

Many patients with lipodystrophy experience profound hyperphagia, which can be seen as one of the hallmark symptoms in this group of conditions.3,11 

As many metabolic complications associated with lipodystrophy require certain diets, it is important to work alongside patients to manage hyperphagia so that the treatment and approaches to managing these complications are as effective as possible.11

References

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    Syndromes: A Multi-Society Practice Guideline. J Clin Endocrinol Metab. 2016;101(12):4500-4511. 
  3. Adapted vom Akinci B, Meral R, Oral EA. Phenotopic and Genetic Characteristics of Lipodystrophy: Pathophysiology, Metabolic Abnormalities, and Comorbidities. Currently Diab Rep. 2018;18(12):143.
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