Hypocholesterolemia.

Hypocholesterolemia is defined as total cholesterol (TC) and low density cholesterol (LDL-C) levels below the 5(th) percentile of the general population adjusted for age, gender and race. Hypocholesterolemia may be attributed to inherited disorders or several secondary causes. Inherited forms of hypocholesterolemia consist of a group of rare diseases. The best studied are familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL). Clinical diagnosis rests on lipid levels and the pattern of inheritance after secondary causes are excluded. Patients with primary hypobetalipoproteinemias may manifest a variety of symptoms and signs affecting several organs (steatorrhea, neurological and ophalmological symptoms, non-alcoholic fatty liver disease) or be asymptomatic. Understanding hypocholesterolemia and the underlying molecular basis is of crucial importance since this may provide new insights in the treatment of hypercholesterolemia and cardiovascular disease.

[Hepatic steatosis associated with heterozygotic familial hypobetalipoproteinemia]. / Esteatosis hepática asociada a hipobetalipoproteinemia familiar heterocigótica. Presentación de un caso.

Fatty liver disease is now recognized as a major health burden, due to the greater number of cases that are being diagnosed. This trend could partly be explained by the increased use of liver ultrasonography in asymptomatic patients for various reasons, mainly persistent transaminase elevation. The most commonly reported risk factors associated with fatty liver disease are chronic alcohol intake, obesity, type 2 diabetes mellitus, hyperlipidemia, and some drugs. When these factors have been ruled out in a patient with a fatty liver, less frequent causes such as certain inherited metabolic disorders should be considered. Familial hypobetalipoproteinemia is characterized by an alteration of apolipoprotein B (apo B) synthesis, leading to the secretion of truncated forms of the protein, which in turn leads to a marked reduction in excretion of very low-density lipoproteins from the liver and consequently to lipid deposits, especially triglycerides, in the hepatocytes. We report the case of a 23-year-old man who met the diagnostic criteria for heterozygous familial hypobetalipoproteinemia. He presented with mild transaminase elevation and fatty liver. Total cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol and apo B were below normal limits, while levels of high-density lipoprotein cholesterol were normal. Lipid profile determination and liver ultrasonography of first and second-degree relatives were also performed. Molecular studies of the index case revealed an unaffected apo B gene.

Diffuse fatty liver in familial heterozygous hypobetalipoproteinemia.

A 34-year-old man had asymptomatic hepatomegaly, slightly increased serum alanine aminotransferase and gamma-glutamyl transpeptidase levels, and a sonographic pattern suggesting diffuse hepatic steatosis. Liver biopsy revealed fatty change in 25% to 50% of hepatocytes. The patient also had low serum levels of cholesterol and triglycerides and met clinical, biochemical, and familial diagnostic criteria of heterozygous hypobetalipoproteinemia. We could not relate his hepatic steatosis to any already known cause of fatty liver and could only attribute it to heterozygous hypobetalipoproteinemia. Familial heterozygous hypobetalipoproteinemia should be ruled out in patients with unexplained hepatic steatosis.

The hypobetalipoproteinemias.

The fifth- and ninety-fifth-percentile concentrations of low-density lipoprotein (LDL) cholesterol in most Western populations are approximately 90 and 200 mg/dl, respectively. Persons with LDL cholesterol levels equal to or less than the fifth percentile are defined as having hypobetalipoproteinemia. Epidemiologic studies show that such individuals have lower-than-average risk for atherosclerotic cardiovascular disease but higher risk for a variety of cancers, pulmonary, and gastrointestinal diseases than persons with higher levels of cholesterol. The reasons for this are not known, nor are the causes of most cases of hypobetalipoproteinemia. However, in some well-studied kindreds the hypobetalipoproteinemia phenotype is inherited as an autosomal dominant trait. Heterozygotes in such kindreds are usually healthy and have no difficulty absorbing dietary fat. In most kindreds, the molecular variants responsible for the hypobetalipoproteinemia are unknown, but a subset of kindreds have strong genetic linkages between the low-cholesterol phenotype and truncation-producing mutations of the apolipoprotein (apo) B-100 gene. The truncations of apoB are named according to a centile nomenclature. The full-length 4536-amino acid protein is called apoB-100, and the 25 truncations identified to date have been named apoB-2 to apoB-89. The mutations introduce premature termination codons resulting from frameshift-producing base additions or deletions. The mutations produce slowed rates of secretion of the truncated apoBs relative to the apoB-100s present in the heterozygotes. In addition, the apoB-100 molecules of the heterozygotes are also secreted at rates slower than those observed in closely matched normolipidemic controls. These physiologic results account for the hypobetalipoproteinemia of these subjects. The response of the plasma lipoproteins of heterozygotes to the manipulation of various dietary components remains to be determined. Additional low-cholesterol syndromes are autosomal recessive forms of hypobetalipoproteinemia, chylomicron retention disease, and abetalipoproteinemia. The molecular causes of the first two are unknown. Abetalipoproteinemia is an autosomal recessive condition resulting from mutations of the microsomal triglyceride transfer protein. All three conditions are characterized by vanishingly small concentrations of LDL, dietary fat malabsorption, and failure to thrive in infancy.

[Cryptogenetic liver cirrhosis with hypobetalipoproteinemia. Typing of the HLA histocompatibility system]. / Cirrosi epatiche criptogenetiche con ipobetalipoproteinemia. Tipizzazione del sistema di istocompatibilità HLA.

One hundred and forty-six patients with chronic liver disease have been studied. Some of them (15) showed a clinical picture characterized by cryptogenetic liver cirrhosis associated with hypotriglyceridemia and hypobetalipoproteinemia. These patients had compensated cirrhosis and no history of alcohol abuse; they did not suffer major illness in the past and had no signs of portosystemic encephalopathy. The pathogenetic mechanism of this association and the possible role of genetic factors are discussed. The HLA system has been studied and the A2 antigen found with high frequency, raising the possibility that patients with this syndrome may represent a particular subgroup among these with liver cirrhosis.

On the pathogenesis of acquired hypo-beta-lipoproteinemia. A case associated with sideroblastic anemia.

A 71-year-old previously hypercholesterolemic woman developed gradually severe hypocholesterolemia of 1.55 mmol/l. Simultaneously she developed progressive sideroblastic anemia, altered erythrocyte morphology and defective platelet function. Hypo-beta-lipoproteinemia was demonstrated with abnormal lipid composition of both very low density (VLDL), low density (LDL) and high density lipoprotein (HDL) fractions. Other plasma lipids, as well as erythrocyte lipids, were normal. The fractional catabolic rate of homologous 125I-LDL was increased to 4-5-fold, while its rate of synthesis was normal. The patient's serum contained autoantibodies directed against LDL. It is concluded that her hypo-beta-lipoproteinemia was due to autoantibodies towards LDL causing an increased catabolism without any concomitant effect on the rate of LDL synthesis. It is suggested that acquired hypo-beta-lipoproteinemia can be subdivided into two types, one in which the primary defect is an increased catabolism due to immunoelimination, and another in which the primary defect is a decreased rate of LDL synthesis.