Hypercholesterolemia: Causes

Pathogenesis (disease development)

There are several factors that can lead to polygenic hypercholesterolemia:

  • Genetic burden
  • Excessive exposure to lifestyle and diet
  • Diseases
  • Drug side effects

Depending on the limit, it affects about 20% of the population. In the familial form of hypercholesterolemia (FH) is a genetic disorder (autosomal dominant hypercholesterolemia):

  • Heterozygous form: with 1: 500; gene defect in the LDL receptor organ; LDL cholesterol: 190-450 ng/dl (4.9-11.6 mmol/l;affected are the following genes (indicating frequency as a percentage of cases): LDLR gene (74%), APOB gene (2-7%), PCSK9 gene (<3%), and STAP1 gene (percentage not known).
  • Homozygous form (HoFH): 1: 1,000,000); slow catabolism and a coexisting increased rate of synthesis of LDL; LDL cholesterol: > 400 mg/dL, 1,000 mg/dl (> 10.3 mmol/l, > 26 mmol/L) and more possible.

In another form of genetic hypercholesterolemia (autosomal recessive hypercholesterolemia), the disorder lies in mutations in the genes of LDL receptors; the two defect alleles of LDL-R adaptor protein 1 (LDLRAP1) are responsible. In rare cases, a familial ApoB-100 defect (according to Fredrickson classification: IIa) is present. In this case, defective ApoB-100 is present, resulting in LDL elevation (cholesterol: 250-600 mg/dl).

Etiology (Causes)

The following causative factors are known to be involved in hypercholesterolemia:

Biographic causes

  • Genetic burden from parents, grandparents
    • Genetic risk depending on gene polymorphisms:
      • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
        • Genes: APOB, LDLR, LDLRAP1, PCSK9, STAP1.
        • SNP: Since more than 100 SNPs are present, detailed enumeration is omitted.
    • Genetic diseases
      • Porphyria or acute intermittent porphyria (AIP); genetic disease with autosomal dominant inheritance; patients with this disease have a 50 percent reduction in the activity of the enzyme porphobilinogen deaminase (PBG-D), which is sufficient for porphyrin synthesis. Triggers of a porphyria attack, which can last a few days but also months, are infections, drugs or alcohol. The clinical picture of these attacks presents as acute abdomen or neurological deficits, which can take a lethal course. The leading symptoms of acute porphyria are intermittent neurologic and psychiatric disturbances. Autonomic neuropathy is often prominent, causing abdominal colic (acute abdomen), nausea (nausea), vomiting, or constipation (constipation), as well as tachycardia (heartbeats > 100 beats/min) and labile hypertension (high blood pressure).
  • Age of life – increasing age:
    • Hypercholesterolemia with values = 250 mg/100 ml and = 300 mg/100 ml occurs most frequently in women between 60 and 69 years of age
    • In men, the prevalence of hypercholesterolemia increases until the age of 80.
  • Hormonal factors – menopause (menopause in women): decrease in estrogen levels (→ LDL ↑ and HDL ↓).

Behavioral causes

  • Nutrition
    • Chronic overeating
      • High caloric intake
      • High intake of saturated fatty acids as well as cholesterol and trans fatty acids (10-20 g trans fatty acids/day; e.g., baked goods, chips, fast food products, convenience foods, fried foods such as French fries, breakfast cereals with added fat, snacks, confectionery, dry soups)
      • High sugar consumption
    • Too low a proportion of monounsaturated fatty acids
    • Too low a proportion of polyunsaturated fatty acids
    • Diet low in fiber
    • Micronutrient deficiency (vital substances) – see Prevention with micronutrients.
  • Consumption of stimulants
    • Alcohol (woman: > 20 g/day; man > 30 g/day).
    • Tobacco (smoking)
  • Physical activity
    • Physical inactivity
  • Psycho-social situation
    • Sleep deprivation
    • Stress
  • Overweight (BMI ≥ 25; obesity)? – DYSIS (Dyslipidemia International Study) studied more than 50,000 patients in 30 countries.The authors could not find a relationship between body mass index (BMI) and LDL cholesterol.

LDL elevation

Disease-related causes

  • Anorexia nervosa (anorexia nervosa)
  • Cholestasis (bile stasis)
  • Hepatitis (inflammation of the liver)
  • Hepatoma – malignant liver tumor
  • Hyperuricemia (increase in the level of uric acid in the blood).
  • Hypothyroidism (underactive thyroid gland)
  • Cushing’s disease – group of diseases leading to hypercortisolism (hypercortisolism; excess of cortisol).
  • Nephrotic syndrome – collective term for symptoms that occur in various diseases of the glomerulus (renal corpuscles); symptoms include: Proteinuria (increased excretion of protein in the urine) with protein loss of more than 1 g/m²/body surface per day; Hypoproteinemia, peripheral edema due to hypalbuminemia of < 2.5 g/dl in serum, hyperlipoproteinemia (lipid metabolism disorder) with LDL elevation.
  • Renal insufficiency – process leading to a slowly progressive reduction in renal function.
  • Porphyria or acute intermittent porphyria (AIP); patients with this disease have a 50 percent reduction in the activity of the enzyme porphobilinogen deaminase (PBG-D), which is sufficient for porphyrin synthesis. Triggers of a porphyria attack, which can last a few days but also months, are infections, drugs or alcohol.The clinical picture of these attacks presents as acute abdomen or neurological deficits, which can take a lethal course. The leading symptoms of acute porphyria are intermittent (occasionally or chronically) neurologic and psychiatric disturbances. Autonomic neuropathy is often in the foreground, causing abdominal colic (acute abdomen), nausea (nausea), vomiting or constipation (constipation), as well as tachycardia (heartbeat too fast: > 100 beats per minute) and labile hypertension (high blood pressure).
  • Growth hormone deficiency (hyposomatotropism, GHD, English growth hormone deficiency).

Medication

  • Anabolic steroids – LDL increase by up to 20% with consecutive 3- to 6-fold increased risk of CHD (coronary artery disease; coronary artery disease).
  • Carbamazepine (anti-epileptic drug)
  • Ciclosporin (cyclosporin A) (immunosuppressant).
  • Corticosteroids
  • Thiazides (diuretic)

Further

  • Gravidity (pregnancy) (LDL ↑)
  • Kidney transplantation

LDL lowering

Disease-related causes

  • Chronic infections
  • Gaucher disease – autosomal recessive hereditary sphingolipidosis as a storage disease based on deficiency of glucocerebrosidase with storage of cerebrosides in cells.
  • Hyperthyroidism (hyperthyroidism).
  • Liver cirrhosis – irreversible damage to the liver and a pronounced remodeling of liver tissue.
  • Malabsorption – disorder of food absorption.
  • Malnutrition (malnutrition)
  • Severe liver disease such as cirrhosis – nodular remodeling of the liver with loss of function.

Drugs that lower LDL

  • Niacin intoxication

Operations

  • Orchidectomy – removal of the testicles

Environmental pollution – intoxications (poisonings).

Further

Drugs that increase VLDL

  • Anion exchangers – drugs used to lower fat (lipid inhibitors), such as colestyramine; these bind bile acids in the intestine and increase their excretion; the body compensates for this resulting deficiency and requires cholesterol to do so
  • Antiretroviral therapy (ART) – for example, HIV protease inhibitors; drug treatment strategy for HIV patients.
  • Glucocorticoids – belong to the corticosteroids, a class of steroid hormones from the adrenal cortex; naturally occurring glucocorticoids include cortisol and corticosterone.
  • Retinoic acid (derivative / derivative of vitamin A).

Drugs that increase chylomicrons.