Hereditary and acquired lipodystrophies: molecular genetic and autoimmune mechanisms

Health status

Congenital generalized lipodystrophy

(also known as
Berardinelli–Sape lipodystrophy
) is an extremely rare autosomal recessive disorder characterized by an extreme lack of fat in the subcutaneous tissues. [2] This is a type of lipodystrophic disorder in which the amount of fat loss determines the severity of metabolic complications. [3] Only 250 cases of this condition have been reported and it is estimated to affect 1 in 10 million people worldwide. [4]

Presentation [edit]

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by insulin resistance, lack of subcutaneous fat, and muscle hypertrophy. [5] Homozygous or compound heterozygous mutations in four genes are associated with four subtypes of CGL. [3] The disease occurs in early childhood with accelerated linear growth, rapid bone aging, and increased appetite. As a child gets older, acanthosis nigricans (hyperpigmentation and thickening of the skin) begins to appear throughout the body - mainly in the neck, trunk and groin. [4] The disorder also has characteristic features such as hepatomegaly or liver enlargement, which occurs due to fatty liver and can lead to cirrhosis, muscle hypertrophy, lack of adipose tissue, splenomegaly, hirsutism (excessive hairiness) and hypertriglyceridemia. [6] Fatty liver and muscle hypertrophy occur because lipids accumulate in these areas instead; whereas in a healthy person, lipids are distributed more evenly throughout the body subcutaneously. The absence of fat tissue where it usually occurs causes the body to store fat in other areas. [7] Common cardiovascular problems associated with this syndrome are cardiac hypertrophy and hypertension (high blood pressure). [8] This disease can also cause metabolic syndrome. Most with this condition also have a bulging umbilical or umbilical hernia. Typically, patients also experience acromegaly with enlargement of the hands, feet, and jaw. After puberty, additional symptoms may develop. In women, clitoromegaly and polycystic ovary syndrome may develop. It impairs fertility in women, and there are only a few documented cases of successful pregnancies in women with CGP. However, the fertility of men with this condition will not be affected. [4]

Differences between type 1 and type 2[edit]

There are differences in how the disease affects patients with type 1 and type 2. Patients with type 1 still have mechanical fat tissue, but patients with type 2 have no fat tissue, including mechanical fat. [9] Patients with type 2 are more likely to have psychomotor retardation and intellectual impairment. [10]

Metabolic complications

Metabolic complications of lipodystrophy syndromes are a major cause of morbidity and mortality in these patients. Deficiency of adipose tissue leads to leptin deficiency, which provokes increased appetite and ectopic deposition of adipose tissue, which in turn contributes to insulin resistance associated with diabetes, hypertriglyceridemia, non-alcoholic fatty liver disease, PCOS, acanthosis nigricans and early atherosclerosis. For most forms of the disease, annual screening for diabetes, dyslipidemia, and liver, kidney, and heart disease should be performed. The main causes of mortality in patients with lipodystrophy syndromes are cardiovascular diseases (cardiomyopathy, heart failure, myocardial infarction, arrhythmia), liver diseases (liver failure, gastrointestinal bleeding, hepatocellular carcinoma), renal failure, acute pancreatitis and sepsis [2, 36].

Mechanism[edit]

Type 1[edit]

In people with CGL type 1, the disorder is caused by a mutation in the AGPAT2 gene, which encodes 1-acylglycerol-3-phosphate-O-acyltransferase 2 and is located at 9q34.3. This enzyme catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, which is very important in the biosynthesis of fats. This enzyme is highly expressed in adipose tissue, so it can be concluded that when the enzyme is defective in CGL, lipids cannot accumulate in adipose tissue. [eleven]

Type 2[edit]

Those with CGL type 2 have a mutation in the BSCL2 gene, which encodes the Seipin protein and is located on 11q13. This gene encodes the Seipin protein, whose function is unknown. Seipin protein mRNA expression is high in the brain but low in adipose tissue. In addition, patients who have mutations in this protein have a higher incidence of mental retardation and do not have the mechanically active adipose tissue that is present in patients with AGPAT2 mutations. [4]

Type 3[edit]

CGL type 3 involves a mutation in the CAV1 gene. This gene encodes the protein caveolin, which is a scaffolding membrane protein. This protein plays a role in lipid regulation. High levels of Cav1 are typically expressed in adipocytes. Thus, when the CAV1 gene is mutated, adipocytes lack Cav1 and cannot properly regulate lipid levels. [12]

Type 4[edit]

A mutation in the PTRF gene causes CGL type 4. This gene encodes a protein called polymerase I and a transcript release factor. One of the functions of the PTRF product is to stabilize and assist in the formation of caveolae. Thus, the mechanism is similar to type 3 in that caveolae fail to form properly and perform their role in lipid regulation in both. Types 3 and 4 are two different mutations, but they share a common defective pathway. [13]

ALTERNATION OF INJECTION AREAS

Multiple studies have shown that in order to protect normal tissue, it is necessary to correctly and consistently alternate injection sites. One regimen with proven effectiveness divides the injection area into four quadrants (or sections in the case of the thighs or buttocks), using only one quadrant each week and then the next one in a clockwise rotation, as shown below ( Fig. 3 Scheme of rotation at insulin injection sites). Injections into any quadrant or part should be spaced at least 1 cm apart to avoid re-traumatization of the tissue.

rice. 3 Rotation scheme at insulin injection sites

Finally, I would like to once again emphasize the importance of learning the correct insulin injection technique. Remember that how you inject insulin is just as important as what you inject.

Diagnosis[edit]

A medical diagnosis of CGL can be made after observing the physical symptoms of the disease: lipoatrophy (loss of fatty tissue) of the trunk, limbs and face; hepatomegaly; acromegaly; insulin resistance; and high serum triglyceride levels. Genetic testing can also confirm the disease, as mutations in the AGPAT2 gene indicate CGL1, mutations in the BSCL2 gene indicate CGL2, and mutations in the CAV1 and PTRF genes indicate CGL3 and CGL4, respectively. [10] Physical diagnosis of CGL is easier, as patients with CGL are recognized from birth due to their extremely muscular shape, which is caused by a lack of subcutaneous fat. [9]

In patients with CGL3, serum creatine kinase concentrations are much higher than normal (2.5 to 10 times normal). This can be used to diagnose patients with type 3 and differentiate them from CGL 1 and 2 without mapping their genes. Additionally, patients with CGL3 have low muscle tone compared to other patients with CGL. [14]

Arterial hypertension

How often: Very often. For example, the US Department of Veterans Affairs reports that 45% of patients with HIV are diagnosed with hypertension. However, scientists are not entirely sure whether this may be due only to HIV infection or treatment with antiretroviral drugs, or a combination of these factors.

Treatment: Stop smoking, weight loss, salt restriction. Vasodilators (for example, hydralazine), antihypertensive drugs (see above), diuretics (hypothiazide, etc.) are used.

Translation by Evgeniy Ignatov

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Treatment[edit]

Metformin is the main drug used for treatment as it is commonly used in patients with hyperglycemia. [15] Metformin reduces appetite and improves symptoms of hepatic steatosis and polycystic ovary syndrome. [4] Leptin can also be used to reverse insulin resistance and hepatic steatosis, reduce food intake, and lower blood glucose levels. [16]

Diet[edit]

Patients with CHF must follow a strict diet for life, as their excess appetite will cause them to overeat. In such patients, carbohydrate intake should be limited. To avoid chylomicronemia, CGL patients with hypertriglyceridemia should follow a very low-fat diet. Patients with CHF also need to avoid common proteins, trans fats, and eat plenty of soluble fiber to avoid high cholesterol levels in the blood. [17]

Diarrhea

How often: Occurs very often. Diarrhea is believed to be one of the most common reasons why people living with HIV stop treatment or change their treatment regimen.

Treatment: Use of antidiarrheals that slow down intestinal motility. These include Imodium (loperamide), Lomotil (diphenoxylate and atropine). These drugs should be used only as prescribed by a doctor, since their uncontrolled use can pose a threat to life and health.

Mytesi is the only drug for the relief of diarrhea in people living with HIV and the second herbal drug to be approved by the FDA. It is obtained from the sap of the Croton lechleri ​​plant.

In some situations, ART adjustment is required.

History[edit]

Congenital generalized lipodystrophy, also known as Berardinelli-Seip lipodystrophy, was first described in 1954 by Berardinelli [18] and then by Seip in 1959. [19] The CGL type 1 gene was identified as AGPAT2 on chromosome 9q34, [20] and Later. the CGL type 2 gene was identified as BSCL2 on chromosome 11q13. [21] More recently, CGL type 3 has been identified as a distinct type of CGL, which has been identified as a mutation in the CAV1 gene. A distinct type 4 CGL was then identified as a mutation in the PTRF gene. [22]

Diseases of the cardiovascular system

How often: It is the second leading cause of death among people living with HIV.

Treatment: A comprehensive approach is required, which includes various types of treatment. There are drugs that lower cholesterol levels, such as Crestor (rosuvastatin) and others. Programs that help you quit smoking, lose weight, and exercise are helpful. It is necessary to reduce the consumption of alcohol and salt. If your blood pressure is not at normal levels, your doctor will help prescribe the necessary medications. Options include: ACE inhibitors, angiotensin II receptor blockers, beta blockers, calcium channel blockers.

Links[edit]

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