Fats are transported in the bloodstream as lipoprotein particles composed of lipids (principally triglycerides, cholesterol and cholesterol esters), phospho-lipids and proteins (called apoproteins). These proteins exert a stabilizing function and allow the particles to be recognized by receptors in the liver and peripheral tissues.
There are five principal types of lipoprotein particles:
■ Chylomicrons are synthesized in the small intestine postprandially and serve to transport the digestion products of dietary fat (mainly triglycerides, small amounts of cholesterol) to the liver and peripheral tissues.
■ Very-low-density lipoproteins (VLDLs) are synthesized and secreted by the liver and transport endogenously synthesized triglycerides (formed in the liver from plasma free fatty acids) to the periphery. In fat and muscle, triglycerides are removed from chylomicrons and VLDLs by the tissue enzyme lipoprotein lipase and the essential cofactor apoprotein C-II.
■ Intermediate-densiy lipoproteins (IDLs), derived from the peripheral breakdown of VLDLs, are transported back to the liver and metabolized to yield the cholesterol-rich particles - low-density lipoproteins (LDLs).
■ Low-density lipoproteins (LDLs) deliver most cholesterol to the periphery and liver with subsequent binding to LDL receptors in these tissues.
■ High-density lipoproteins (HDLs) transport cholesterol from peripheral tissues to the liver. HDL particles carry 20-30% of the total quantity of cholesterol in the blood.
The major clinical significance of hypercholesterolaemia (both total plasma and LDL concentration) is as a risk factor for atheroma and hence ischaemic heart disease. The risk is greatest in those with other cardiovascular risk factors, e.g. smoking and hypertension. There is a weak independent link between raised concentrations of (triglyceride-rich) VLDL particles and car-diovascular risk. More than half of all patients aged under 60 with angio-graphically conữmed coronary heart disease have a lipoprotein disorder. Severe hypertriglyceridaemia (>6 mmol/L) is associated with a greatly increased risk of acute pancreatitis and retinal vein thrombosis. In contrast, HDL particles, which transport cholesterol away from the periphery, appear to protect against atheroma.
Measurement of plasma lipids
Most patients with hyperlipidaemia are asymptomatic, with no clinical signs, and they are discovered through routine screening (Table 15.10). A fasting
Table 15.10 Indications for measurement of plasma lipids |
Family history of coronary heart disease (especially below 50 years of age) First-degree relative with a lipid disorder Prospective partner of patients with heterozygous monogenic lipid disorder (because of the risk of producing children with the disorder Presence of a xanthoma Presence of xanthelasma or corneal arcus before age 40 years Obesity Diabetes mellitus Hypertension Acute pancreatitis Patients undergoing renal replacement therapy |
blood sample is necessary to test for hypertriglyceridaemia; random is suf-ficient for cholesterol. If the total cholesterol concentration is raised, HDL cholesterol, triglyceride and LDL cholesterol should be measured on a fasting sample. Specific diagnosis of the defect (see below) requires the measure-ment of individual lipoproteins by electrophoresis, but this is not usually necessary. If a lipid disorder has been detected it is vital to carry out a clinical history, examination and simple special investigations (i.e. plasma glucose, urea and electrolytes, liver biochemistry and thyroid function tests) to detect the causes of secondary hyperlipidaemia (Table 15.11).
The primary hyperlipidaemias
Disorders of VLDL and chylomicrons -hypertriglyceridaemia alone
■ Polygenic hypertriglyceridaemia accounts for most cases, in which there are many genes both acting together and interacting with environmental factors to produce a modest elevation in serum triglyceride levels.
■ Familial hypertriglyceridaemia is inherited in an autosomal dominant fashion. The exact defect is not known and the only clinical feature is a history of acute pancreatitis or retinal vein thrombosis in some individuals.
■ Lipoprotein lipase deficiency and apoprotein C-II deficiency are rare dis-eases which usually present in childhood with severe hypertriglycerid-aemia complicated by pancreatitis, retinal vein thrombosis and eruptive xanthomas - crops of small yellow lipid deposits in the skin.
Disorders of LDL - hypercholesterolaemia alone
■ Familial hypercholesterolaemia is the result of underproduction of the LDL cholesterol receptor in the liver, which results in high plasma concentra-tions of LDL cholesterol. Heterozygotes may be asymptomatic or develop coronary artery disease in their 40s. Typical clinical features include tendon xanthomas (lipid nodules in the tendons, especially the extensor
Table 15.11 Causes of secondary hyperlipidaemia |
Hypothyroidism Poorly controlled diabetes mellitus Obesity Renal impairment Nephrotic syndrome Dysglobulinaemia Hepatic dysfunction Drugs: oral contraceptives in susceptible individuals, retinoids, thiazide diuretics, corticosteroids diuretics, corticosteroids |
tendons of the fingers and the Achilles tendon) and xanthelasmas. Homozygotes have a total absence of LDL receptors in the liver. They have grossly elevated plasma cholesterol levels (>16 mmol/L) and, without treatment, die in their teens from coronary artery disease.
■ Mutations in the apoprotein B-100 gene result in a clinical picture resem-bling heterozygous familial hypercholesterolaemia. LDL particles nor-mally bind to their clearance receptor in the liver through apoprotein B-100, and the mutation results in high LDL concentrations in the blood.
■ Polygenic hypercholesterolaemia accounts for those patients with a raised serum cholesterol concentration, but without one of the monogenic disorders above. The precise nature of the polygenic variation in plasma cholesterol remains unknown.
Combined hyperlipidaemia (hypercholesterolaemia and hyperlipidaemia)
Polygenic combined hyperlipidaemia and familial combined hyperlipidaemia account for the vast majority of patients in this group. A small minority is the result of the rare condition, remnant hyperlipidaemia.
Management of hyperlipidaemia
Guidelines to therapy
The initial treatment in all cases of hyperlipidaemia is dietary modification, but additional measures are usually necessary. Patients with familial hyper-cholesterolaemia will need drug treatment. Secondary hyperlipidaemia should be managed by treatment of the underlying condition wherever pos-sible. In all patients, other treatable cardiovascular risk factors, including smoking, hypertension and excess weight should also be addressed in tandem with treatment of hyperlipidaemia.
Lipid-lowering diet
■ Dairy products and meat are the principal sources of fat in the diet. Chicken and poultry should be substituted for red meats and the food grilled rather than fried. Low-fat cheeses and skimmed milk should be substituted for the full-fat varieties.
■ Polyunsaturated fats, e.g. corn and soya oil, should be used instead of saturated fats.
■ Reduction of cholesterol intake from liver, offal and fish roe.
■ Increased intake of soluble fibres, e.g. pulses and legumes, which reduce circulating cholesterol.
■ Avoid excess alcohol and obesity, both causes of secondary hyperlipidaemias.
Lipid-lowering drugs (Table 15.12)
■ HMG-CoA reductase inhibitors (statins), e.g. atorvastatin, pravastatin, simvastatin, inhibit the enzyme hydroxymethylglutaryl-coenzyme A
Table 15.12 Drugs used in the management of hyperlipidaemias (listed in the order in which they are usually selected for treatment) |
||
Hypertriglyceridaemia |
Hypercholesterolaemia |
Combined |
Fibrates |
Statins |
Fibrates |
Nicotinic acid |
Ezetimi be/fi b rates |
Nicotinic acid |
Fish oil capsules |
Bile acid-binding resins (ω-3 marine triglycerides) |
(HMG-CoA) reductase, an enzyme involved in cholesterol synthesis in the liver. They are the most potent of the lipid lowering drug classes for lowering total cholesterol and LDL-cholesterol and they also raise HDL-cholesterol and lower triglycerides to some extent. Side-effects of statins include hepatitis, muscle injury and gastrointestinal problems (p. 700).
■ Cholesterol absorption inhibitors, e.g. ezetimibe, inhibit gut absorption of cholesterol from food and also from bile. The mechanism of this inhibition is unclear. They mostly act in the gut and little is absorbed. Thus short-term safety is good. They are used when a second drug in addition to a statin is required.
■ Fibrates, e.g. gemfibrozil and bezafibrate, activate peroxisome proliferator-activated nuclear receptors (esp, PPAR-alpha) and are broad-spectrum lipid-modulating agents. They decrease serum triglycerides, raise HDL cholesterol and reduce LDL cholesterol concentrations. They are the drugs of first choice for treating isolated hypertriglyceridaemia and are used in combination with other treatments (statins, ezetimibe, fish oils) for patients with mixed dyslipidaemias. A rare but serious side-effect is myositis.
■ Bile acid-binding resins, e.g. colestyramine and colestipol, bind bile acids in the intestine, preventing their reabsorption and thus lowering the cholesterol pool. They reduce LDL cholesterol and have a synergistic effect when given with a statin.
■ Fish-oils, rich in omega-3 marine triglycerides, reduce plasma triglycerides.
■ Nicotinic acid reduces total and LDL cholesterol levels and can reduce triglyceride levels. It is not widely used because of side-effects.
Whom to treat
Primary prevention for people at risk of cardiovascular disease Lipid-lowering therapy using a statin, or alternatives as above, should be given to the following asymptomatic individuals irrespective of the total or LDL cho- lesterol level:
■ Diabetes mellitus > 40 years of age or irrespective of age with retinopathy or persistent microalbuminuria
■ A total cardiovascular disease risk of > 20% over 10 years
■ Two or more of: positive family history of cardiovascular disease, albu-minuria, hypertension, smoking
■ Men with LDL cholesterol persistently > 6.5 mmol/L despite dietary change. The situation for women is less clear
■ Familial hypercholesterolaemia.
Secondary prevention Statin treatment is also indicated for any patient with known macrovascular disease (coronary artery disease, TIA or stroke, periph-eral artery disease), irrespective of the total or LDL cholesterol level. Aterna-tive and combination agents are ezetimibe, bile acid binding agents or fibrates (avoid with statins due too overlapping side-effects).
Aims of treatment
Statins reduce cardiovascular events and all-cause mortality. Treatment should be adjusted to achieve a target total cholesterol of less than 4 mmol/L or a LDL-cholesterol concentration of less than 2.0 mmol/L.
1. Ethics and communication
2. Infectious diseases
3. Gastroenterology and nutrition
Gastroenterology and nutrition
4. Liver, biliary tract and pancreatic disease
Liver, biliary tract and pancreatic disease
LIVER BIOCHEMISTRY AND LIVER FUNCTION TESTS
SYMPTOMS AND SIGNS OF LIVER DISEASE
JAUNDICE
HEPATITIS
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
CIRRHOSIS
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
LIVER TRANSPLANTATION
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER ABSCESS
LIVER DISEASE IN PREGNANCY
LIVER TUMOURS
GALLSTONES
THE PANCREAS
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS
5. Haematological disease
Haematological disease
ANAEMIA
Assessment and treatment of suspected neutropenic sepsis
HAEMOLYTIC ANAEMIA
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
MYELOPROLIFERATIVE DISORDERS
THE SPLEEN
BLOOD TRANSFUSION
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
THROMBOSIS
THERAPEUTICS
6. Malignant disease
Malignant disease
MYELOABLATIVE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION
THE LYMPHOMAS
THE PARAPROTEINAEMIAS
PALLIATIVE MEDICINE AND SYMPTOM CONTROL
7. Rheumatology
Rheumatology
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
BACK PAIN
OSTEOARTHRITIS
INFLAMMATORY ARTHRITIS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
THERAPEUTICS
8. Water, electrolytes and acid–base balance
WATER AND ELECTROLYTE REQUIREMENTS
BODY FLUID COMPARTMENTS
REGULATION OF BODY FLUID HOMEOSTASIS
PLASMA OSMOLALITY AND DISORDERS OF SODIUM REGULATION
DISORDERS OF POTASSIUM REGULATION
DISORDERS OF MAGNESIUM REGULATION
DISORDERS OF ACID - BASE BALANCE
THERAPEUTICS
9. Renal disease
Renal disease
INVESTIGATION OF RENAL DISEASE
GLOMERULAR DISEASES
NEPHROTIC SYNDROME
URINARY TRACT INFECTION
TUBULOINTERSTITIAL NEPHRITIS
HYPERTENSION AND THE KIDNEY
RENAL CALCULI AND NEPHROCALCINOSIS
URINARY TRACT OBSTRUCTION
ACUTE RENAL FAILURE/ACUTE KIDNEY INJURY
CHRONIC KIDNEY DISEASE
RENAL REPLACEMENT THERAPY
CYSTIC RENAL DISEASE
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
DISEASES OF THE PROSTATE GLAND
TESTICULAR TUMOUR
URINARY INCONTINENCE
10. Cardiovascular disease
COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
CARDIAC ARRHYTHMIAS
HEART FAILURE
ISCHAEMIC HEART DISEASE
RHEUMATIC FEVER
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
MYOCARDIAL DISEASE
CARDIOMYOPATHY
PERICARDIAL DISEASE
SYSTEMIC HYPERTENSION
ARTERIAL AND VENOUS DISEASE
ELECTRICAL CARDIOVERSION
DRUGS FOR ARRHYTHMIAS
DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS
11. Respiratory disease
Respiratory disease
TUBERCULOSISnd
DIFFUSE DISEASES OF THE LUNG PARENCHYMA
OCCUPATIONAL LUNG DISEASE
CARCINOMA OF THE LUNG
DISEASES OF THE CHEST WALL AND PLEURA
DISORDERS OF THE DIAPHRAGM
12. Intensive care medicine
13. Drug therapy, poisoning, and alcohol misuse
Drug therapy, poisoning, and alcohol misuse
14. Endocrine disease
Endocrine disease
PITUITARY HYPERSECRETION SYNDROMES
THE THYROID AXIS
MALE REPRODUCTION AND SEX
FEMALE REPRODUCTION AND SEX
THE GLUCOCORTICOID AXIS
THE THIRST AXIS
DISORDERS OF CALCIUM METABOLISM
DISORDERS OF PHOSPHATE CONCENTRATION
ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL
DISORDERS OF TEMPERATURE REGULATION
THERAPEUTICS
15. Diabetes mellitus and other disorders of metabolism
DIABETES MELLITUS
DIABETIC METABOLIC EMERGENCIES
COMPLICATIONS OF DIABETES
SPECIAL SITUATIONS
HYPOGLYCAEMIA IN THE NON - DIABETIC
DISORDERS OF LIPID METABOLISM
THE PORPHYRIAS
16. The special senses
THE EAR
THE NOSE AND NASAL CAVITY
THE THROAT
THE EYE
17. Neurology
COMMON NEUROLOGICAL SYMPTOMS
COORDINATION OF MOVEMENT
THE CRANIAL NERVES
COMMON INVESTIGATIONS IN NEUROLOGICAL DISEASE
UNCONSCIOUSNESS AND COMA
STROKE AND CEREBROVASCULAR DISEASE
EPILEPSY AND LOSS OF CONSCIOUSNESS
NERVOUS SYSTEM INFECTION AND INFLAMMATION
HYDROCEPHALUS
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES
MUSCLE DISEASES
MYOTONIAS
DELIRIUM
THERAPEUTICS
18. Dermatology