Metabolic Diseases

Jump to: navigation, search

Atherosclerosis is the cause of over 50% of deaths in western world. It is slowly progressive disease of arteries, with thickening of intima, fibrotic deposits which gradually narrow the lumen and simultaneously are the location of bleeding and thrombus development. Atheroma is the most frequent visible sign of atherosclerosis, i.e. a subendothelial accumulation of large lipid containing foam cells that later becomes a fibrous plaque. Clinical symptomatology is the result of endothel dysfunction, coagulation and fibrinolysis. Thrombus, responsible for acute symptoms, is usually triggered by a recent atheroma, without fibrous capsule, that obstructs the arterial lumen only 40% or less.

There are five risk factors that can be influenced, i.e. hyperlipidemia, smoking, hyperhomocysteinemia , hypertension, diabetes mellitus, and three that cannot: older age, male sex, genetic predisposition. There is some relationship with hyperfibrinogenemia, and gout.

Hyperhomocysteinemia is the sole independent risk factor for early, or ‘premature’, atherosclerosis. Homocystein is a highly reactive amino acid with both direct and indirect toxic effect upon endothel and subsequent thrombogenesis.

According to the hypothesis of a ‘response to injury’ in pathogenesis of arteriosclerosis the first step is an endothelial damage, and a reaction to it follows in the form of plaques developing on the spots with large mechanical demands, i.e. arterial branching.

Dietary fats, largely triacylglycerides, are hydrolyzed in the intestine by lipases from exocrine pancreas. The breakdown products of triacylglycerides are absorbed by the intestinal mucosal cells, which utilize energy of ATP to reassemble these into triacylglycerides again. Cholesterol from animal fat is absorbed as well and metabolized into cholesterol ester. Intestinal mucosal cells synthesize certain proteins at the same time, assemble large lipoprotein particles from these proteins and lipids, called chylomicrons. Chylomicrons are secreted by mucosal cells into blood. Another lipoprotein, VLDL, is assembled from lipids and proteins in the liver and released into blood.

Both VLDL’s and chylomicrons function as lipid transporters so that other cells in the body are provided with fuel molecules for metabolism, i.e. muscle cells, or for storage of fat for future needs, i.e. in fatty cells. Lipoproteins cannot unload triacylglycerides into cells directly, i.e. they are broken down by lipoprotein lipase, that acts on VLDL and chylomicrons in the blood, into smaller breakdown products, fatty acids. Fatty acids can be taken up by the cells in the vicinity of the breakdown. The VLDL lipoproteins decrease dramatically in size by this breakdown, and become smaller lipoproteins, i.e. LDL’s. (Note on terminology: the more fat there is in a lipoprotein, the lighter it is. Thus LDL is heavier than VLDL as it contains a higher percentage of protein and cholesterol and less triacylglycerides than VLDL.)

‘Bad’ cholesterol is associated with LDL, while ‘good’ cholesterol resides in HDL lipoprotein. HDL is the smallest of lipoproteins, made by the liver, initially rich in protein, with very little cholesterol ester. HDL picks up cholesterol from cells, converts it to cholesterol ester, carries it to the liver where it can be transferred to LDL or VLDL.

Cause of metabolic disorders is often faulty endocrine regulations, i.e. diabetes mellitus, defects of genes for enzymes, i.e. enzymopathies, or defects of transport proteins, i.e. mucoviscidosis, cystinosis.

Disorders of lipoprotein metabolism:

Lipids are transported in blood in the form of globoid molecular complexes, lipoproteins. The ‘wrapping’ of the globoid structures is by hydrophilic lipids, i.e. phospholipids, cholesterol, and the ‘nucleus’ is made of strongly hydrophobic lipids, i.e. triacylglycerols and cholesterol esters, that are the transport and storage form of cholesterol. Besides that lipoproteins contain some apolipoproteins. All metabolic abnormalities of lipoprotein concentration, and thereby the transport of lipids in blood are placed in this group.

Lipoproteins are recognized by their size, density, lipid composition, production locus, and their apolipoproteins, that serve as structural elements of lipoproteins.

Plasma lipoproteins are macromolecules which enable dissolution of normally water-insoluble cholesterol, triacylglycerol and phospholipids in water, and that takes place in plasma. They also transport such lipids from locations where they enter plasma, by absorption from intestines, or from their production in hepatocytes, to locations where they are catabolized.

By ultracentrifuge lipoproteins can be divided into:

- chylomicrones

- VLDL, very low density lipoproteins

- LDL, low density lipoproteins

- HDL, high density lipoproteins.

If only main lipids are taken into consideration, then disturbances of lipid metabolism can be divided into two main groups:

1/ Hyperlipidemias, i.e. hypercholesterolemias and hypertriacylglycerolemias,

2/ Dyslipidemias, where the ratios of levels of various types of lipoproteins are abnormal, i.e. higher level of LDL, lower level of HDL, etc.

Plasma levels of two classes of lipoproteins have a significant relationship to the development of premature atherosclerosis in individuals under 50 years of age: higher concentration of LDL and lower concentration of HDL. In individuals over 60 years of age the prognostic value of high LDL is of lesser importance, but lower concentration of HDL is highly significant. The main risk factor for development of atherosclerosis of coronary vessels, the lowered concentration of HDL-cholesterol in blood serum, is associated with mutation of gene for lipoprotein lipase.

The second componentt of lipoproteins are proteins, called apolipoproteins, very important for transport and metabolism of lipids:

Apolipoprotein A-I is the main protein component of HDL, that plays a very important role in reversed transport of cholesterol from tissues back to the liver;

Apolipoprotein A-II is the 2nd most important protein of HDL;

Apolipoprotein B is the basic component of LDL: it is 90% of its molecule, and it is the main apolipoprotein of VLDL and chylomicrons;

Apolipoprotein C-II is important for creation of VLDL and HDL;

Apolipoprotein E plays the main role in metabolism of cholesterol and triacylglycerides.

Lipoproteins, especially Lp(a), are the link between atherogenic process and processes of coagulation and fibrinolysis. At least 17 – 25% of all patients with myocardial infarction have abnormalities of Lp(a), very similar to LDL.

Lipoprotein lipase (LPL) is a multifunctional protein. Besides catalysis of breakdown of triacylglycerides there are additional structural domains for binding on endothelial cells, chylomicrons, VLDL, proteoglycans, etc., and for that reason the phenotypic expressions of mutation of LPL gene could vary, especially when they are in another domain,i.e. not in the same domain where they were originally created as a result of mutation of LPL gene.

Chylomicrons transport lipids from the intestine via intestinal lymph throughout the body, i.e. skeletal muscles, fatty tissue, where their apolipoproteins activate endothelial lipoproteinlipase that splits off free fatty acids which are then taken up by myocytes and fatty cells. Remnants of chylomicrons are bound in the liver to the receptors, engulfed by endocytosis, and pass on their triacylglycerides, cholesterol and cholesterol esthers. Liver exports imported as well as newly synthetized triacylglycerides and cholesterol in the form of VLDL to the periphery, where lipoproteinlipase, activated by its ApoCII, releases again free fatty acids.

HDL picks up extra cholesterol from extrahepatic cells and blood, and carries it, and cholesterol esters, to the liver and steroid hormones producing endocrine glands, i.e. ovaries, testes, adrenal cortex.

Atherogenic lipoprotein phenotype is in 95% of cases caused by genetic metabolic malfunctions, i.e. familial hyperlipoproteinemias and dyslipoproteinemias. A specific patient can be found to have one or more of the following laboratory findings: hypercholesterolemia, hypertriacylglycerolemia, higher level of LDL-cholesterol, of apolipoprotein B and lipoprotein(a), or lower level of HDL-cholesterol and apolipoprotein A-I.

Increased level of lipids in blood applies to cholesterol, triacylglycerides, or both. In majority of patients with hypercholesterolemia the real cause is not known even though it often runs in some families, but obesity and improper nutrition play a role.

In familial hypercholesterolemia with incidence in homozygotes 1:1,000,000, and in heterozygotes of 1:500, due to genetic defects of LDL-receptor, and thereby a blockage of intake of LDL by the cell, plasma cholesterol level is higher since birth, and that causes myocardial infarction already in teens. Serum cholesterol rises, because cells do not accept cholesterol-rich LDL, and there is an increased synthesis of cholesterol in extrahepatic tissues. Treatment in heterozygotes is by ion changer Cholestyramin that binds biliary acids in the intestine, and blocks enterohepatic re-circulation, thereby triggering a new production of biliary acids from cholesterol, so that intracellular concentration of cholesterol decreases. In homozygotes only plasmapheresis is of value.

In combined hyperlipidemia, another genetic disease, besides cholesterol also levels of triacylglycerides are higher. There is an increased synthesis of VLDL, and thereby also of LDL.

Familial dys-beta-lipoproteinemia with disturbed pick-up of chylomicron remnants in the liver, so that their plasma concentration rises, and thereby a high risk of atherosclerosis.

Primary hypertriacylglycerolemia with an increased synthesis of triacylglycerides in the liver, low HDL, and thereby higher risk of atherosclerosis, and a predisposition toward pancreatitis.

Hypo-lipo-proteinemias are also pathological. In Hypo-beta-lipoproteinemia, or Tangier disease, there is a defect of ApoA-liproteins, causing low HDL, and thereby high risk of atherosclerosis, and ataxia and neuropathy.

In A-beta-lipoproteinemia there is a lack of LDL in plasma so that chylomicrons cannot be exported from intestinal mucosa, and LDL from the liver, with resulting steatosis of liver. Fetal precursor cell transplantation of liver, placenta, stomach/intestine, is advised.

Hyperlipoproteinemia type 1, a rare AR disorder, caused by deficit of Apolipoprotein C-II and of lipoprotein lipase, is characterized by triacylglycerolemia, massive fasting chylomicronemia, and recurrent severe pancreatitis.

Familial hyperchylomicronemia is caused by mutations of LPL gene, and causes very high levels of triacylglycerol, and a risk of severe pancreatitis already in childhood.

Familial hypercholesterolemia, AD disorder, has been found in 5 - 10% of population in U.S. and U.K., characterized by high levels of LDL cholesterol and premature onset of atherosclerosis. It is the best studied cause of hyperlipidemia. In heterozygotes, with incidence 1:500, the first MI takes place in males before the age of 40, in females before the age of 60, and the level of LDL-cholesterol is twice the norm. In homozygotes, with incidence 1:1000000, there is a complete clinical picture with corneal arcus juvenilis, xanthelasma palpebrarum, extensive tuberous xanthomatosis in tendons and skin, extremely high LDL-cholesterol, already in childhood.

Familial combined hyperlipoproteinemia is the most frequent genetic metabolic disorder, with incidence of mutant genes 1:300, with high levels of cholesterol and triacylglycerides. Phenotypically, hypercholesterolemia, combined hyperlipidemia or atherogenic dyslipidemia, are present, along with obesity, hypertension, and insulin-resistance.

Familial dyslipidemia, AD disorder, with higher levels of triacylglycerides, and low levels of HDL-cholesterol, and insulin-resistance.

Familial hypo-a-lipoproteinemia, with android obesity associated with hypersecretion of lipoproteins containing apolipoprotein B and increased catabolism of apolipoprotein A-I containing lipoproteins.

Familial dys-ß-lipoproteinemia, AD disorder, with high risk of atherosclerosis, where the first clinical finding is peripheral arterial disease appearing at the age of 30, and palmar xanthomas.

Familial excess of lipoprotein(a), AD disorder, leads to premature atherosclerosis, frequently already in children. Lipoprotein(a) is a risk factor of atherosclerosis with the highest inheritance in population.

Family history with presence of risk factors for development of premature atherosclerosis, and presence of any of the just described genetic disorders of lipoproteins and lipoprotein lipase, are an important indication for fetal precursor cell transplantation of placenta, heart, liver, artery, gonads, mesenchyme. The success rate is high providing the patient is willing to eliminate the external risk factors.


Gout is the result of increased concentration of uric acid and urates in plasma. Uric acid is the final product of purine metabolism. Normally, 90% of all metabolites of nucleotides adenine, guanine, hypoxanthine, are re-used after being turned by respective enzymes into AMP, IMP or GMP. Only the remaining 10% is via xanthineoxidase converted into xanthine and finally uric acid. Uric acid dissolves minimally, particularly in cold environment, and at low pH, and that is the basis for gout. Since urates dissolve in synovial fluid, but poorly, especially so at low temperature, and the most distal parts of the body have lower temperature than the trunk, crystals of urates accumulate frequently in distal joints of foot. Alcohol ingestion, obesity, some drugs and presence of lead in the body, contribute to the crystallization process.

Hyperuricemia occurs in 10% of western population, and in 90% of instances it is ‘primary gout’ with genetic predisposition.

Gout attack develops when a part of microtophi releases some part of crystals that act as foreign body triggering aseptic arthritis. Sudden increase of uric acid level in plasma can cause massive precipitation of urates in collecting tubules of kidneys, which can lead to kidney failure.