CCCS3 Lipoproteins Dyslipidemia & Related Case Studies PDF

Clinical chemistry case study Plasma lipids and lipoproteins and three case studies on: “Familial Hypercholesterolemia”, “Abetalipoproteinemia”, and “Tangier Disease” Lipids Major lipids plasma are fatty acids, Triglycerides, cholesterol and pho...

Clinical chemistry case study Plasma lipids and lipoproteins and three case studies on: “Familial Hypercholesterolemia”, “Abetalipoproteinemia”, and “Tangier Disease” Lipids Major lipids plasma are fatty acids, Triglycerides, cholesterol and phospholipids. Other lipid-soluble substances, present in much smaller amounts(e.g. steroid hormones) Elevated plasma concentrations of lipids, particularly cholesterol, are related to the pathogenesis of atherosclerosis which is the leading cause of death worldwide. Cholesterol A sterol derivative that functions in: cell membranes steroid hormones bile acids Largely endogenous and synthesized in liver. Diet influences blood levels by 10 to 20%. 30 to 60% of cholesterol in diet is absorbed mixed with conjugated bile acids, phospholipids, fatty acids, and monoacylglycerides Triglycerides Most abundant dietary fat and compose 95% of all fat stored in adipose tissue. Primary function: furnish energy for the cell. In the intestines, in the presence of lipases and bile acids Triglycerides are hydrolyzed into fatty acids, glycerol and monoglycerides. After absorption, are reconstituted into chylomicrons. Triglycerides are also produced endogenously by the liver and are loaded Plasma lipoproteins The plasma lipoproteins are spherical macromolecular complexes of lipids and specific proteins (apolipoproteins). Lipoproteins are composed of a neutral lipid core (containing triacylglycerol [TAG] and cholesteryl esters) surrounded by a shell of Plasma lipoproteins Lipoprotein particles constantly interchange lipids and apolipoproteins with each other, the actual apolipoprotein and lipid content of each class of particles is somewhat variable. Lipoproteins function both to keep their component lipids soluble as they transport them in the plasma and to provide an efficient mechanism for transporting their lipid contents to (and from) the tissues. In humans, the transport system is less perfect than in other animals and, as a result, humans experience a gradual deposition of lipid (especially cholesterol) in tissues and vessels causing the narrowing of Plasma lipoproteins The lipoprotein particles include chylomicrons, very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). They differ in lipid and protein composition, size, density, and site of origin. Characteristics of major Lipoproteins (Density) The density of lipoproteins depend on protein to lipid ratio. HDL particles are the smallest and densest. Classes and Characteristics of major Lipoproteins Characteristics of major Lipoproteins (electrophoretic mobility) Electrophoretic pattern of serum Lipoproteins Density pattern Chylomicrons VLDL LDL HDL Chylomicrons (CM) Large particles produced by the intestines that are very rich in triglycerides (90%) of dietary origin, poor in cholesterol and phospholipids, and low in protein (1%) Less dense than water due to high lipid to protein ratio and floats. Cause of “milky” plasma. Due to action of lipoprotein lipase, CM becomes triglyceride-poor: CM REMNANTS which are taken by the liver (Apo E is required for the uptake) Very-low-density lipoproteins (VLDL) Like chylomicrons, are triglyceride-rich (55%), can float and make plasma turbid. Unlike chylomicrons, are endogenous (produced by liver). Contains cholesterol and phospholipids (25%), and protein (8 %). Action of Lipoprotein lipase gives rise to IDL (also known as VLDL remnant). The resulting IDL is either taken up directly by the liver (Apo E is required for liver uptake) or converted to LDL by hepatic triglycerol lipase (HL). Low-density lipoproteins (LDL) Make up 50% of total lipoproteins. Even when in high concentration, does not cause turbidity of plasma. Esterified cholesterol makes up 50% of mass. Produced from IDL (see previously) LDL is taken up by peripheral tissues via the LDL Receptor to meet local cholesterol needs (primary function). Any left over LDL particles are finally removed by the liver via the LDLR. When oxidized LDL cholesterol gets high, it is taken up (scavenger receptors) by macrophages which become foam cells and accumulate forming High-density lipoproteins (HDL) High-density lipoproteins Contain 50% protein, mostly apoA-I and II. Produced by liver and intestine in a discoidal nascent HDL form which has low lipid content Subclasses: HDL2 and HDL3. Low levels of apoA-I related to Coronary Artery Disease. apoA-I is a cofactor for required for the activation of lecithin cholesterolacyltransferase (LCAT) enzyme which is responsible for the etabolism of high-density lipoprotein Metabolism of high-density lipoprotein (HDL) particles. Apo = apolipoprotein; ABCA1 = transport protein; C = cholesterol; CE = cholesteryl ester; LCAT = lecithin:cholesterol acyltransferase; VLDL = very-low-density lipoprotein; IDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; HDLs perform a number of important functions, including the following: 1.Apolipoprotein supply: HDL is a reservoir of apo C-II (transferred to VLDL and chylomicrons and is an activator of LPL) and apo E (required for the receptor-mediated endocytosis of IDLs and chylomicron remnants). 2.Uptake of unesterified cholesterol: Nascent HDLs containing primarily phospholipid (largely phosphatidylcholine) and apolipoproteins A, C, and E. They take up cholesterol from nonhepatic (peripheral) tissues and return it to the liver as cholesteryl esters (the high content of PC help in this function) HDLs perform a number of important functions, including the following: 3. Esterification of cholesterol: cholesterol taken up by HDL is immediately esterified by the plasma enzyme lecithin:cholesterol acyltransferase (LCAT is synthesized and secreted by the liver). LCAT binds to nascent HDL, and is activated by apo A-I. This esterification produces a hydrophobic cholesteryl ester, which is sequestered in the core of the HDL. Cholesteryl ester–rich HDL2 particles then carry these esters to the liver. HDLs perform a number of important functions, including the following: 4. Reverse cholesterol transport: The selective transfer of cholesterol from peripheral cells to HDL, from HDL to the liver for bile acid synthesis or disposal via the bile, and to steroidogenic cells for hormone synthesis, is a key component of cholesterol homeostasis. This process of reverse cholesterol transport is, in part, the basis for the inverse relationship seen between plasma HDL concentration and atherosclerosis and for HDL’s designation as the “good” cholesterol carrier. [Note: Exercise and estrogen raise HDL levels.] Lipoprotein metabolism summary Dyslipidemias Dyslipidemia is a medical condition that refers to an abnormal level of blood lipids. The most common type of dyslipidemia is hyperlipidemia or high lipid levels. Another, less common form of dyslipidemia, hypolipidemia, refers to lipid levels that are abnormally low.  Dyslipidemias Increases Decreases Hyperlipidemia Hypercholesterolemia: cholester Hypolipidemia ol Hypocholesterole Lipid Hyperglyceridemia: glycerides Hypertriglyceridemia: triglyc mia: cholesterol erides Hypolipoproteinemia: lipoproteins Hyperlipoproteinemia: lipoproteins Abetalipoproteine (usually LDL unless otherwise mia: Lipoprote specified) beta lipoproteins in Hyperchylomicronemia: chylomi Tangier crons disease: high density lipoprotein Combined hyperlipidemia: Both Primary hyperlipidemias Single or multiple gene mutations resulting in disturbance of LDL, HDL, and triglyceride production or clearance. Should be suspected in patients with premature heart disease family hx of atherosclerotic dx. serum cholesterol level >240mg/dl. Or physical signs of hyperlipidemia. Fredrickson’s classification of hyperlipidemias Chylomicron syndrome This can be due to familial lipoprotein lipase deficiency, an autosomal recessive disorder affecting about 1 in 1000000 people. Lipoprotein lipase is involved in the exogenous lipoprotein pathway by hydrolysing chylomicrons to form chylomicron remnants, and also in the endogenous pathway by converting VLDL to IDL particles. Presentation as a child with abdominal pain (often with acute pancreatitis) is typical. There is probably no increased risk of coronary artery disease. Gross elevation of plasma triglycerides due to the accumulation of uncleared Chylomicron syndrome Lipid stigmata include eruptive xanthomata, hepatosplenomegaly (due to the infiltration of macrophages in response to CM deposition) and lipaemia retinalis. Patients may show a type I or type V Fredrickson’s phenotype. Lipidemia retinalis: milky appearance of the veins and arteries of the retina, occurring when the lipids of the Familial hypercholesterolemia A codominant genetic disorder that is due to mutations in the gene for the LDL receptor which normally removes LDL from the circulation, The inheritance of one mutant gene that encodes for the LDL receptor affects about 1 in every 500 people (more common in certain groups such as Afrikaners and French Canadians), resulting in impaired LDL catabolism and hypercholesterolaemia Plasma LDL levels are elevated at birth and remain so throughout life, Plasma triglyceride levels are typically normal, and HDL cholesterol levels are normal or reduced Using the Fredrickson’s classification, this Familial hypercholesterolemia Heterozygotes, especially men, are prone to accelerated atherosclerosis and premature coronary artery disease (CAD). Homozygous may cause severe cardiovascular disease in childhood. Typically, patients manifest severe hypercholesterolaemia, with a relatively normal plasma triglyceride concentration in conjunction with xanthoma, which can affect the back of the hands, elbows, Achilles tendons. Premature cardiovascular disease is often observed, along with premature corneal arci. Xanthelasmas (cholesterol deposits on the eyelids) are also common. Case study A 23-year-old woman had her plasma lipids checked by her general practitioner because her father had died of a myocardial infarction aged 44 years. Her 24-year-old brother had hyperlipidaemia. Her renal, liver and thyroid function tests were normal, as was her blood glucose. On examination, she had tendon xanthomata on her Achilles tendons and bilateral corneal arci. Plasma (fasting): Cholesterol 11.4 mmol/L (3.5–5.0) Case study discussion Note the considerably raised plasma cholesterol concentration. The absence of an obvious secondary hyperlipidaemia (see secondary dyslipidemia later in this document), in conjunction with the family history of a first-degree relative with premature cardiovascular disease and hyperlipidaemia, suggests a genetic hyperlipidaemia. The presence of tendon xanthomata and premature corneal arci supports the diagnosis of familial hypercholesterolaemia. This is usually an autosomal dominant disorder and usually Familial defective apoB3500 This condition is due to a mutation in the apoB gene resulting in a substitution of arginine at the 3500 amino acid position for glutamine. Apolipoprotein B is the ligand upon the LDL particle for the LDL receptor. Thereby the mutation reduces the affinity of LDL for the LDL receptor, slowing LDL catabolism, It may be indistinguishable clinically from Familial Hypercholesterolemia (phenocopy of FH) and is also associated Familial hypertriglyceridaemia Familial hypertriglyceridaemia is often observed with low HDL cholesterol concentration. The condition usually develops after puberty and is rare in childhood. The exact metabolic defect is unclear, although overproduction of VLDL or a decrease in VLDL conversion to LDL is likely. There may be an increased risk of cardiovascular disease. Acute pancreatitis may also occur, and is more likely when the concentration of plasma triglycerides is more than 10 mmol/L (normal 0.7- 1.7 mmol/L) Some patients show hyperinsulinaemia and insulin resistance. Type III hyperlipoproteinaemia This condition is also called familial dysbetalipoproteinaemia or broad b- hyperlipidaemia. The underlying biochemical defect is one of a reduced clearance of chylomicron and VLDL remnants. The name broad b-hyperlipidaemia is sometimes used because of the characteristic plasma lipoprotein electrophoretic pattern that is often observed (the broad b-band that is seen being remnant particles). This rare disorder is associated with homozygosity for Apo E2. Apolipoprotein E shows three common alleles, E , E and E which Type III hyperlipoproteinaemia The mechanism for the disorder seems to be that apoE2-bearing particles have poor binding to the apoB/E (remnant) receptor and thus are not effectively cleared from the circulation. The development of disease requires additional factors that increase VLDL levels (A concurrent increase in plasma VLDL concentration seems necessary for the condition to be expressed, such as might occur in diabetes mellitus, hypothyroidism or obesity). Plasma cholesterol and triglycerides are increased (often in similar molar proportions with plasma concentrations of around 9–10 mmol/L) due to accumulation of chylomicron  Type III hyperlipoproteinaemia Plasma HDL is usually low. Plasma LDL may also be low due to the reduced conversion from IDL particles, although it may also be normal or elevated. Patients usually present in adulthood with xanthomas and premature coronary and peripheral vascular disease. Palmar xanthomata are considered pathognomonic for the disorder, but tubero- eruptive xanthomata, typically Secondary dyslipidemia One should not forget that there are many secondary causes of hyperlipidaemia. These may present alone or sometimes concomitantly with a primary hyperlipidaemia. Most adult cases of dyslipidemia are secondary in nature in western civilizations Secondary Causes of Hyperlipidemia Most Commonly Encountered in Clinical Practice Secondary Elevated LDL-C$ Elevated Triglycerides Cause Saturated Weight gain, high intake of or trans fats, weight Diet refined carbohydrates, gain, anorexia excessive alcohol intake nervosa Oral estrogens, glucocorticoids, Diuretics, bile acid sequestrants, anabolic cyclosporine, Drugs steroids, tamoxifen, beta glucocorticoids, blockers (not carvedilol), amiodarone thiazides Biliary obstruction, Nephrotic syndrome, chronic Diseases nephrotic syndrome renal failure Disorders and Diabetes (poorly controlled), altered states Hypothyroidism, *ofCholesterol andobesity, triglycerides hypothyroidism, rise progressively obesity; throughout pregnancy* pregnancy; pregnancy* metabolismtreatment with statins, niacin, and ezetimibe are contraindicated during pregnancy and lactation. $ LDL-C indicates low-density lipoprotein cholesterol. Lipid profile Lipid profile or lipid panel is a panel of blood tests that serves as an initial screening tool for abnormalities in lipids, such as cholesterol and triglycerides. The lipid profile typically includes: Total cholesterol (This is a sum of blood's cholesterol content.) Triglycerides High density lipoprotein cholesterol (HDL-C) good cholesterol Low density lipoprotein cholesterol Fasting lipid profile A fasting blood sample is the “gold standard” for diagnosing dyslipidemia. The ideal is for the individual to forego anything by mouth except water and prescription medications for not less than 12 hours and not significantly longer than When 14 hours. to check lipid profile? According to Adult Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP) Beginning at age 20: obtain a fasting (12 to 14 hour) serum lipid profile consisting of total cholesterol, LDL, HDL and  Adult reference range for lipids TABLE from “Bishop Clinical chemistry, 6th edition” ANALYTE REFERENCE RANGE Total cholesterol 140–200 mg/dL (3.6-5.2 mmol/L) HDL cholesterol 40–75 mg/dL (1.0-2.0 mmol/L) LDL cholesterol 50–130 mg/dL (1.3-3.4 mmol/L)  Clinical chemistry case study A case of Abetalipoproteinemia  Case history and findings Age: 28-years Gender: male Chief complaint: mild recurrent abdominal discomfort and diarrhea History of present illness: symptoms occur periodically throughout his life symptoms had worsened since his arrival to the united stats (Immigrated to the United States a few years ago and not traveled since that) no association between his abdominal discomfort and specific food Numbness  Case history and findings Past medical history: benign except for “Occasional abdominal distress”, diarrhea, flatus and abdominal pain, greasy, pale and foul smelling stool diagnosed with celiac disease and treated with a gluten-free diet he was compliant with dietary instructions, symptoms continued for the next year No history drugs or alcohol abuses No history of any medication no pets or recent animal exposures Family history: Unremarkable: Both parents and three Clinical examination Physical examination healthy adult, height 1.8 m, weight 76.5 kg hemodynamically stable Noticeable Bruises on his thighs Mild peripheral neuropathy, decreased proprioception and dulled response to painful, vibratory stimuli in the extremities, decreased deep tendon reflex Muscle strength was preserved bilaterally Positive Romberg sign and slight ataxic gait Fundoscopic examination: Pigmented retinopathy. Clinical laboratory tests Blood and plasma tests findings : Hematocrit: 33% (normal is 38% - 45%). Reticulocyte count: 2.0% (normal is 0.5% – 1.5%). Normal mean corpuscular volume: 90 fL. Decreased erythrocyte sedimentation rate. Prothrombin time 15 s (normal 11-13 s). Normal complete blood cell count. Acanthocytes on a blood smear. Stool sample examination : Steatorrhea Negative for fecal occult blood, leukocytes, ova, parasites and cultures Clinical laboratory tests Endoscopic examination: The small intestine was atypically white\ yellow in appearance Jejunal biopsy findings : Normal villous architecture. High fat content in epithelial cell, and no inflammation, ulceration or parasites. Fasting lipid profile : Total cholesterol was 1 mmol/L (normal I 3.5- 5.0 mmol/L). Normal HDL. Postprandial electrophoresis : Presence of HDL. Absence of chylomicrons , VLDL , and LDL. Clinical biochemistry tests Plasma levels of apolipoprotein: Absence of apolipoprotein B (apoB). Moderately reduced apoA1 Plasma proteins, enzymes, and vitamins: Normal total protein and albumin values. Normal ALT, AST, fasting glucose, HbA1c , amylase and lipase ranges Low vitamins A and K, near absence of vitamins E The lipids and lipoproteins test was the specialized biochemical test which help to reach diagnosis for this case Lipoprotein Assembly and Microsomal Triglyceride Transfer Protein (MTP) ApoB-100 expressed mainly in hepatocytes, (thus it becomes a structural component of VLDL, IDL, and LDL) The intestinal cells produce ApoB-48, the main lipoprotein in chylomicrons. ApoB-48 is a truncated form of ApoB-100 produced by the action of Apobec-1 (Apolipoprotein B mRNA editing enzyme) To assemble Apolipoprotein B containing lipoproteins lipid droplets are transferred to ApoB-100 in the liver and to ApoB-48 in the intestine. This process is mediated by microsomal triglyceride transfer protein (MTP) and results in  Allan D. Sniderman et al. JACC 2014;63:1935-1947 Lipoprotein Assembly and Secretion from Liver and Intestine Effects of lomitapide and mipomersen. (Top) see previous slide. (Bottom) Effects of the newly approved orphan drugs lomitapide and mipomersen. Lomitapide inhibits MTP activity in both liver and intestine, whereas mipomersen stops production of hepatic APOB-100 and has no effect on intestinal lipoprotein production. Abetalipoproteinemia A rare, autosomal recessive disease Characterized by: the absence of plasma apoB lipoproteins fat-soluble vitamin deficiencies (A, E, and K), the presence of acanthocytosis Pathogenesis: inability to assemble apoB into lipoproteins due to a defect in the mttp gene which codes for microsomal triglyceride transfer protein (MTP) ApoB synthesis from mRNA transcript occurs, but its not successfully assembled into the mature lipoprotein particle because of the defective MTP. The net result is near absence of all plasma apoB lipoproteins.  In ABL, an early step in apoB lipoprotein assembly shared by intestinal and liver cells is defective. Martine Paquette MSc et al., “A tale of 2 cousins: An atypical and a typical case of abetalipoproteinemia” Journal of Clinical Lipidology. Volume 10, Issue 4, July– August 2016, Pages 1030-1034  Findings in abetalipoproteinemia Signs and symptoms associated with abetalipoproteinemia Malabsorption syndrome (steatorrhea, diarrhea, flatus, failure to thrive) Spinocerebellar disease Ataxia, positive Romberg sign Decreased proprioception and vibratory senses Loss of deep tendon reflexes Night blindness Laboratory and other diagnostic findings: Low plasma cholesterol levels Absence of plasma apoB lipoproteins (chylomicrons, VLDL, and LDL) Fat-soluble vitamin (A, E, and K) deficiencies Pigmented retinopathy Findings in abetalipoproteinemia Acanthocytosis: dysmorphic,“starry-shaped” RBC, as a result of decreased cholesterol content. The RBCs are fragile and prone to increased destruction Acanthocytosis in a patient with Findings in Abetalipoproteinemia Laboratory and other diagnostic findings (contd.) Normocytic anemia with compensatory reticulocytosis Decreased erythrocyte sedimentation rate Hepatic steatosis Gelee blanche intestine (white frosting appearance, which reflects infiltration of the mucosa by lipids) by endoscopic evaluation Histological presentations: normal villi, absence of inflammation, accumulation of neutral lipids The key diagnostic feature is an extremely low plasma total cholesterol and the Patient Findings explanation Reappearance of diarrhea and overall discomfort after moving to the United States: introduction of high-fat Western diet No improvement on gluten-free diet rules out the celiac disease Endoscopic analysis and intestinal biopsies findings: useful to rule out other diseases of the intestine and to confirm ABL: White frothy appearance indicate massive accumulation of lipids supports ABL No inflammation and normal villi appearance rule out other malabsorption syndrome Low levels of vitamin K cause haemostatic abnormalities and hemorrhage (prolonged prothrombin time (PT)) Patient Findings explanation Neurological problems are consequences of prolonged vitamin E deficiency: The spinocerebellar degenerative symptoms observed in ABL are often confused with Friedreich ataxia, but the last one doesn't show malabsorption symptoms, so rule it out. Vitamin A deficiency presents as progressive night blindness: This could explain the bruises on the patient’s thighs Pigmented retinopathy is also associated with vitamin A deficiency but is not specific to ABL. Acanthocytosis and associated abnormalities are believed to result from Biochemical explanation for symptoms Why are plasma vitamin E levels more severely affected than those of vitamins A or K? Vitamin E, requires apoB lipoproteins at every stage of its transport. Thus, mobilization of vitamin E from intestinal and liver cells is critically dependent on apoB lipoprotein assembly and secretion. In contrast, apoB lipoprotein assembly is required only for the mobilization of dietary vitamin A by the intestinal cells. Unlike vitamins E and A, dietary vitamin K may only partially depend on apoB lipoproteins for its transport across the Clinical Biochemistry Case Study Tangier Disease: A Disorder in the Reverse Cholesterol Transport Pathway This case was the first case that led to the discovery of Tangier disease by Donald S. Fredrickson & colleagues in 1961! Case history and findings Patient Age: a 5-year-old Gender: male patient Chief complaint : enlarged and lobulated tonsils ,with a distinctive yellow-orange color causing an oropharyngeal obstruction. History of present illness: tonsillar honeycomb-like appearance, with many septa running through abnormal lobulated regions. Case history and findings Past medical history: recurrent tonsillitis and oropharyngeal obstruction No medications Past surgical history (PSHx): no PSHx Family history: the patient’s sister and mother had the same manifestations of the child A partial pedigree of the children in this family indicated consanguinity in their grandparent’s (both maternal and paternal) and parent’s generations. Since the disease is autosomal recessive one, both maternal and paternal copies of gene Case history and findings General examination: normal except for enlarged and lobulated tonsils with a distinctive yellow-orange color causing him unable to breathe well. Systems examination : Systemic evaluation revealed the following: Moderate hepatosplenomegaly (liver and spleen enlargement). Scattered enlarged lymph nodes. Clinical examination Systems examination (contd.): Neurological examination was unremarkable in this patient A common finding in Tangier Disease is the presence of Peripheral neuropathy. (Abnormal lipid deposition in Schwann cells is proposed to be responsible for the neuropathy. ) About 30% of adult patients develop this symptoms. The onset of it usually takes place after 10 years of age. These symptoms include absent deep- tendon reflexes, ptosis, weakness and ocular muscle palsies. inical Biochemistry lab test Notes! Tangier disease is an extremely rare genetic disease , the definitive diagnosis is made by detecting a nonsense mutation within exon 12 of ATP-binding cassette transporter A1(ABCA1) gene responsible for the efflux of cholesterol and phospholipids from cells The most important biochemical lab for the diagnosis of are the Lipid Profile and levels of apoA-I used. These will be discussed later in this presentation Tangier disease (TD) A rare inherited disorder (autosomal recessive) Approximately 100 cases identified worldwide. More cases are likely undiagnosed. Named after an island off the coast of Virginia where the first affected individuals were identified. Individuals with TD are unable to eliminate cholesterol from cells, leading to its accumulation in the tonsils and other organs Caused by mutations in the ABCA1 (ATP- binding cassette) gene which hogenesis of Tangier disease (TD Mutations to ABCA1 gene lead to a defective ABCA1 transporter. These mutations prevent the ABCA1 protein from effectively transporting cholesterol and phospholipids out of cells for pickup by ApoA1 in the bloodstream. This inability to transport cholesterol out of cells leads to a deficiency of high-density lipoproteins in the circulation. Additionally, the buildup of cholesterol in cells can be toxic, causing cell death or impaired function. These combined factors lead to the signs and al findings of the Tangier disease The major clinical signs are: Hepatosplenomegaly (Thrombocytopenia due to sequestration of platelets in enlarged spleen is an important manifestation of Tangier disease) Peripheral neuropathy Hyperplastic orange-yellow tonsils and to accumulation adenoidal tissue.of fatcolor is attributed The soluble vitamin E, retinyl esters (yellow) and carotenoids (orange) bound to cholesteryl esters. agnosis of Tangier disease (TD) The lipid profile in TD patients shows: low serum total cholesterol, (