Hyperlipoproteinemias (disorders of lipid metabolism) are divided into primary and secondary forms:
- Primary hyperlipoproteinemias are genetic (hereditary).
- Secondary hyperlipoproteinemias may occur in some diseases as a symptom of the disease (secondary phenomenon)
Primary hyperlipoproteinemias
Primary hyperlipoproteinemias are subdivided according to the WHO classification according to their lipoproteinemia pattern (typing according to Fredrickson/Fredrickson classification – see Table). Type II and type IV are particularly common, accounting for over 80% of primary hyperlipoproteinemias. Lipoproteinemia patterns can change due to external influences such as diet, or regular alcohol consumption, so this typing has limited diagnostic value. There is therefore no type constancy, so that type changes in the lipoproteinemia pattern are generally possible. Furthermore, this subdivision cannot be used to distinguish primary from secondary forms, so that a reliable etiological (causal) assignment is not possible with this typing. Nevertheless, one will have to continue working clinically with the Fredrickson scheme until an etiopathogenetically based classification of hyperlipoproteinemia has been made. Hyperlipoproteinemia types based on the Fredrickson classification.
| Type | Chol / TG | LDL / HDL | Lipid electrophoresis | CHD risk | Clinic | Other name(s) |
| I | Norm ↑ ↑ ↑ | ↓ ↓ | – | Pancreatitis,eruptive xanthomas,lipemia retinalis,hepatomegaly | Fam.Liopoprotein lipase deficiencyFam.Apo-C-II deficiency. | |
| IIa | ↑ ↑ norm | ↑ ↓ | α, pre-ß, ß | +++ | Xanthelasmata,tendon xanthoma | Fam. hypercholesterolemiaFam. apo B-100 defectFam. combined HLP |
| IIb | ↑ ↑ ↑ | ↑ ↓ | α | +++ | Xanthelasmata,tendon xanthoma | Fam. combined HLP |
| III | ↑ ↑ ↑ ↑ | ↑ ↓ | α, (ß) | +++ | Xanthomatosis,yellow hand lines,tuberous xanthomas,eruptive xanthomas,glucose intolerance,hyperuricemia | Fam. type-III-HLP(also called fam. dys-β-lipoproteinemia). |
| IV | ↑ ↑ ↑ | ↓ standard | α, ß | ++ | Glucose intolerance,hyperuricemia | Fam. hypertriglyceridemia(Fam. type V syndrome). |
| V | ↑ ↑ ↑ ↑ | ↓ ↓ | α, ß | + | Pancreatitis,eruptive xanthomas,lipemia retinalis,glucose intolerance,hyperuricemia,hepatomegaly | Fam. type V syndromeFam. apo-C-II deficiency(Fam. hypertriglyceridemia). |
Legend
- Chol: cholesterol
- TG: triglycerides
- LDL: low-density lipoprotein
- HDL: high-density lipoprotein
- CHD risk: coronary heart disease (CHD) risk.
Hyperchylomicronemia (hyperlipoproteinemia type I)
In hyperchylomicronemia (hyperlipoproteinemia type I), there is an autosomal recessive inherited defect of the postheparin lipoprotein lipase system (deficiency of lipoprotein lipase or the activator protein Apo-C-II). This leads to a strongly delayed degradation of chylomicrons (transport the dietary fats absorbed in the intestine bypassing the liver via the lymphatic system into the large bloodstream) and their accumulation (accumulation) in the blood predominantly after meals. Clinically, the often adolescent patients are conspicuous by eruptive xanthomas (orange-yellowish, nodular to plaque-like fatty deposits in the skin) predominantly on the trunk and buttocks, as well as by hepatosplenomegaly (enlargement of the liver and spleen) and seizure-like abdominal pain (abdominal pain). As a result of hyperchylomicronemia (an excess of chylomicrons), there is an increased risk of pancreatitis (risk of pancreatitis).
Hypercholesterolemia (hyperlipoproteinemia type II)
Hypercholesterolemia (hyperlipoproteinemia type II) is divided into:
- Type IIa → isolated increase in serum LDL and apo protein B concentrations.
- Type IIb → additionally increased VLDL concentration
Type IIa hyperlipoproteinemia
The cause of the polygenic form (form with involvement of several genes in the expression) of hypercholesterolemia (majority of type IIa cases) is dysfunction of lipoprotein receptors, which normally regulate the transport of cholesterol across the cell membrane as well as the synthesis of cholesterol. In this case, there is a marked reduction in activity of the LDL-specific apo-B/E receptor in response to diet-induced cholesterol accumulation in the liver. Monogenic form (about 5% of cases)Causes of autosomal-dominant inherited hypercholesterolemia (excessive blood cholesterol levels) are the marked or complete insufficiency (weakness) or dysfunction of the LDL receptor (apo-B/E receptor), which is due to a mutation (permanent change in the genetic material) of the receptor gene on chromosome 19, so that LDL can only be taken up by the liver or extrahepatic cells (cells outside the liver) via this receptor to a reduced extent. Complete receptor deficiency in homozygous trait carriers causes cholesterol levels between 600 and 1,000 mg/dl, so that patients are at risk of myocardial infarction (heart attacks) already in adolescence. The feedback inhibitory effect of high cholesterol on new synthesis of cholesterol is abolished. Without extracorporeal LDL elimination (LDL apheresis; blood purification procedure to remove cholesterol from whole blood), these patients are unlikely to reach the age of 20. Apolipoprotein E polymorphismPatients with apolipoprotein phenotype E 3/4 or 4/4 reabsorb cholesterol more rapidly and in greater amounts, resulting in LDL cholesterol elevation.
Type IIb Hypercholesterolemia
The cause of type IIb hypercholesterolemia is thought to be an overproduction of apo-B-100. Electrophoretically, the ß-lipoprotein (IIa) and preß-lipoprotein (IIb) fractions are broadened. As a result of severely elevated cholesterol levels, the risk of atherosclerosis (risk of hardening of the arteries) is increased in those with the disease.
Familial Dys-ß Lipoproteinemia (Type III)
Familial dys-β-lipoproteinemia (type III) is an autosomal-dominant inherited disorder. Here, there is a degradation disorder of pre-ß lipoproteins with accumulation of cholesterol-rich IDL and chylomicron remnants. The cause is abnormality of apolipoprotein E, where binding to the apolipoprotein E2 (remnant) receptor appears to be impaired. This results in incomplete degradation of chylomicrons and VLDL particles to chylomicron remnants (degradation stages of chylomicrons) and LDL particles, respectively. In electrophoresis (laboratory test in which electrically charged particles of blood travel in an electric field), a broad ß-band and a moderately pronounced increase in triglycerides, cholesterol and phosphatides can be detected. This results in a high risk of atherosclerosis (risk of hardening of the arteries), usually with obesity, decreased glucose tolerance (ability of the body to break down a large amount of glucose without the development of pathological blood glucose or urine sugar levels), steatosis hepatis (fatty liver), hyperuricemia (elevation of uric acid levels in the blood; gout) as well as characteristic yellow planar xanthomas (flat, orange-yellowish, nodular to plaque-like fatty deposits in the skin) along the palmar lines. There is also usually an arcus lipoides corneae (synonyms: Arcus senilis, gerontoxon, Greisenbogen, Greisenring; annular opacity of the corneal periphery), along with peripheral arterial circulatory disorders (e.g., of the legs).
Familial hypertriglyceridemia (hyperlipoproteinemia type IV)
Familial hypertriglyceridemia (hyperlipoproteinemia type IV) is the most common hyperlipoproteinemia of adults.The hereditary form (inherited form) is based on an autosomal dominant inheritance with incomplete penetrance (percentage probability with which a certain genotype/genotype leads to the formation of the associated phenotype/appearance).The pathogenesis (development of the disease) is not yet fully understood. There is an increase in pre-ß-lipoproteins (VLDL), which are mainly transported by endogenously (within the body) produced triglycerides. An overproduction of endogenous triglycerides or an impaired utilization of triglyceride-rich lipoproteins may be present.Accordingly, hypertriglyceridemia (type IV; dyslipidemia with elevation of triglycerides) may be carbohydrate-inducible and, in combination with low HDL cholesterol levels, is one of the basic components of the metabolic syndrome. These patients are mostly obese, have decreased glucose tolerance or diabetes mellitus – type 2, and present with fatty liver with hepatosplenomegaly, hyperuricemia, eruptive xanthomas, and upper abdominal colic (pancreatitis) in the presence of severely elevated triglycerides. There is progressive (advancing) atherosclerosis.
Apolipoproteinopathies
The apolipoproteinopathies are divided into:
- Familial a-β-lipoproteinemia is due to an autosomal recessive inherited absence of the structural apolipoprotein of chylomicrons, resulting in a severe lipid assimilation disorder.
- Hereditary (inherited) deficiency of activator apolipoprotein C-II, (co-factor of adipose tissue lipoprotein lipase) leads to hyperchylomicronemia.
- Structural defects of apolipoprotein A I lead to hypercholesterolemia.
- An-α-lipoproteinemia leads to the deposition of cholesterol esters in the tissues (orange-red discolored tonsils / tonsils).
- Hypo-α-lipoproteinemia (autosomal dominant inheritance) is associated with low cholesterol levels (HDL cholesterol < 35 mg/dI).
Primary “familial hyperlipoproteinemias” divided by characteristics
Three clinically relevant groups of hyperlipoproteinemias can be distinguished ethiologically by the determination of cholesterol and triglycerides:
- Hypercholesterolemia
- Hypertriglyceridemia
- Combined forms
Primary “Familial hyperlipoproteinemias, (FH)” divided by characteristics.
| Classification(Frederickson) | Defect | Lipoprotein elevation | typical values (mg/dl) | |
| Hypercholesterolemia | ||||
| Familial hypercholesterolemia | Ila | LDL receptor | LDL | Chol 350-600 |
| Familial ApoB-100 defect | Ila | defective ApoB-100 | LDL | Chol 250-600 |
| Hypertriglyceridemia | ||||
| Familial hypertriglyceridemia | IV(V) | multiple defects | VLDL (Chylo) | TG 500 Chol 200 |
| Familial lipoprotein lipase deficiency | I | lack of LPL | Chylo | TG > 1.000 Chol 500 |
| Familial apo C-II deficiency | I, V | Deficiency of apoprotein C-II | VLDL | |
| Familial type V syndrome | V (IV) | multiple defects | Chylo (VLDL) | TG 2,000 |
| Combined hyperlipidemia | ||||
| Familial type III HLP | III | Apo E 2/2 | Remnants | TG 350 Chol 400 |
| Familial combined HLP | Ila, Ilb, IV | multiple defects(VLDL production increased) | VLDL/LDL | TG 100-500Chol 250-400 |
Legend
- Chol: cholesterol
- TG: triglycerides
- Chylo: chylomicrons
- VLDL: very-low-density lipoprotein,
- LDL = low-density lipoprotein, Apo = apoprotein.
Secondary hyperprolactinemias
Secondary hyperlipoproteinemias are a consequence of other underlying diseases that are not due to a disorder of lipid metabolism, so that after treatment of the underlying disease it can be assumed that lipid metabolism returns to normal.Likewise, some medications may cause a derailment of lipid metabolism, but in most cases this regresses after discontinuation of the inducing (triggering) drug. Frequently, medications merely manifest or exacerbate a pre-existing primary but subclinical predisposition to hyperlipoproteinemia. Causes of secondary hyperlipoproteinemia may include:
- Diet
- Fasting
- “Zero diet”
- Lipid-rich (high fat) diet
- Stimulant
- Alcohol (alcohol excess)
- Hepatopathies (liver diseases), eg.
- Hepatitis (liver inflammation)
- Zieve syndrome (symptom triad of: Hyperlipidemia, hemolytic anemia (anemia in which red blood cells break down prematurely), and alcohol toxic liver damage with icterus/ jaundice).
- Metabolic syndrome (abdominal obesity, insulin resistance (decreased response of the body’s cells to the hormone insulin), hyperinsulinemia (condition with an increased concentration of the hormone insulin in the blood above normal levels), impaired glucose tolerance, dyslipoproteinemia (lipid metabolism disorder), albuminuria (appearance of albumin in the urine), hypertension/high blood pressure).
- Nephropathies (kidney diseases)
- Renal insufficiency (kidney weakness; increase in concentration of urinary substances).
- Condition after kidney transplantation
- Nephrotic syndrome – collective term for symptoms that occur in various diseases of the glomerulus (renal corpuscles); symptoms include: Proteinuria (increased excretion of protein in urine) with protein loss greater than 1 g/m²/body surface area per day; hypoproteinemia, peripheral edema (water retention) due to serum hypalbuminemia of < 2.5 g/dL, hyperlipoproteinemia (dyslipidemia) with LDL elevation.
- Endocrinopathies (clinical pictures caused by impaired function of the endocrine glands or the defective action of hormones).
- Acromegaly – disease characterized by overproduction of the growth hormone somatotropin (STH) in the anterior pituitary lobe (HVL); is accompanied by an increase in the size of the body limbs or acras.
- Diabetes mellitus type 1 + 2
- Hyperparathyroidism (parathyroid hyperfunction).
- Hyperuricemia (gout)
- Hypothyroidism (hypothyroidism)
- Hypopituitarism, anterior pituitary insufficiency (HVL insufficiency).
- Cushing’s disease – group of disorders leading to hypercortisolism (hypercortisolism; excess of cortisol).
- Polycystic ovary syndrome (PCO syndrome, Stein-Leventhal syndrome) – symptom complex characterized by hormonal dysfunction of the ovaries (ovaries).
- Dysproteinemias (disorder of protein distribution in the blood).
- Amyloidosis – systemic disease with deposition of proteins (albumen) in various organ systems.
- Dysglobulinemia (malformation of globulins / blood protein).
- Lupus erythematosus → autoimmune hyperlipidemia.
- Plasmocytoma (synonym: multiple myeloma); belongs to the non-Hodgkin’s lymphomas of B lymphocytes.
- Multiple myeloma is associated with malignant neoplasia (new formation) of plasma cells and the formation of paraproteins) → macroglobulinemia.
- Other diseases
- Anorexia nervosa (anorexia)
- Idiopathic hypercalcemia (calcium excess).
- Glycogenoses (e.g., glycogenosis type I) – group of storage diseases.
- Hepatoma (neoplasm of the liver; malignant and benign adenomas of the liver).
- Malignancies/malignant tumors
- Pancreatitis (inflammation of the pancreas)
- 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).
- Medication
- Pregnancy
