Category Archives: Diameties Mellitus and Other Desorder of Metabolism

The Porphyrias

This heterogeneous group of rare inborn errors of metabolism is caused by abnormalities of enzymes involved in the biosynthesis of haem, resulting in overproduction of the intermediate compounds called porphyrins.

Structurally, porphyrins consist of four pyrrole rings. These pyrrole rings are formed from the precursors glycine and succinyl-CoA, which are converted to a-aminolaevulinic acid (a-ALA) in a reaction catalysed by the enzyme a-ALA synthetase. Two molecules of a-ALA condense to form a pyrrole ring.
Porphyrins can be divided into uroporphyrins, coproporphyrins or protoporphyrins depending on the structure of the side-chain. They are termed type I if the structure is symmetrical and type III if it is asymmetrical. Both uroporphyrins and coproporphyrins can be excreted in the urine.
The sequence of enzymatic changes in the production of haem. The chief rate-limiting step is the enzyme a-ALA synthetase, as an increase in this enzyme results in an overproduction of porphyrins. Haem provides a negative feedback mechanism on this enzyme.
In porphyria the excess production of porphyrins occurs either in the liver (hepatic porphyrias) or in the bone marrow (erythropoietic porphyria), but porphyrias can also be classified in terms of clinical presentation as acute or non-acute. Acute porphyrias usually produce neuropsychiatric problems and are associated with excess production and urinary excretion of a-ALA and porphobilinogen;
these metabolites are not increased in nonacute porphyrias. The second control mechanism is therefore porphobilinogen deaminase;
this is depressed or normal in the acute porphyrias and raised in non-acute cases.

Porphyrin metabolism. The numbers indicate the blocks occurring in forms of porphyria. 1, acute intermittent porphyria; 2, congenital (erythropoietic) porphyria; 3, porphyria cutanea tarda; 4, hereditary coproporphyria; 5, variegate porphyria; 6, erythropoietic protoporphyria.

Porphyrin metabolism. The numbers indicate the blocks occurring in forms of porphyria. 1, acute intermittent porphyria; 2, congenital (erythropoietic) porphyria;
3, porphyria cutanea tarda; 4, hereditary coproporphyria; 5, variegate porphyria; 6, erythropoietic protoporphyria.

Acute intermittent porphyria

This is an autosomal dominant disorder. Presentation is in early adult life, usually around the age of 30 years, and women are affected more than men. It may be precipitated by alcohol and drugs such as barbiturates and oral contraceptives, but a wide range of lipid-soluble drugs have also been incriminated. The abnormality lies at the level of porphobilinogen deaminase in the haem biosynthetic pathway.
Presentation is with:
• Abdominal pain, vomiting and constipation (90%)
• Polyneuropathy (motor, but occasionally sensory) (70%)
• Hypertension and tachycardia (70%)
• europsychiatric disorders (such as depression, anxiety and frank psychosis) (50%)
The diagnosis should be considered whenever there is a combination of these cardinal features or:

A FAMILY HISTORY of porphyria.
THE URINE TUR S RED-BROWN OR RED ON STANDING. A classic bedside test for excess porphobilinogen may be performed by adding one volume of urine to one volume of Ehrlich’s aldehyde, which produces a pink colour. If excess porphobilinogen is present, the pink colour persists when two volumes of chloroform are added.

Other investigations

NORMAL BLOOD COUNT; occasional neutrophil leucocytosis
ABNORMAL LIVER BIOCHEMICAL TESTs-elevated bilirubin and transferases
BLOOD UREA often raised
SCREENING. Family members should be screened to detect latent cases. Urinalysis is not adequate and measurement of erythrocyte porphobilinogen deaminase and ALA synthetase is extremely sensitive.

MANAGEMENT

Management of the acute episodes is largely supportive. A high carbohydrate intake is maintained (this has an indirect effect on porphyrin overproduction), and a narcotic may be given for pain. Intravenous haematin infusion also appears to be of benefit. Management in the remission period is by avoidance of possible precipitating factors, particularly drugs and alcohol.

The classification of porphyrias.

The classification of porphyrias.

Other acute porphyrias

Variegate porphyria

This combines many of the features of acute intermittent porphyria with those of a cutaneous porphyria. A bullous eruption develops on exposure to sunlight owing to the activation of porphyrins deposited in the skin. There is an increased production of protoporphyrinogens owing to an abnormality of protoporphyrinogen oxidase in the haem biosynthetic pathway.

Hereditary coproporphyria

This is extremely rare and broadly similar in presentation to variegate porphyria. The distinction is based on biochemical analysis.
Porphyria cutanea tarda (cutaneous hepatic porphyria) This condition, which has a genetic predisposition, presents with a bullous eruption on exposure to sunlight; the eruption heals with scarring. Alcohol is the most common aetiological agent. There is an abnormality in hepatic uroporphyrinogen decarboxylase. Evidence of biochemical or clinical liver disease may also be present. Polychlorinated hydrocarbons have been implicated and porphyria cutanea tarda has been seen in association with benign or malignant tumours of the liver.
The diagnosis depends on demonstration of increased levels of urinary uroporphyrin. Histology of the skin shows subepidermal blisters with perivascular deposition of periodic acid-Schiff-staining material. The serum iron and transferrin saturation are often raised. The liver biopsy shows mild iron overload as well as features of alcoholic liver disease.
Remission can be induced by venesection; this should be repeated if the urinary uroporphyrin rises in the remission phase. Chloroquine may also have a useful role in promoting urinary excretion of uroporphyrins.

Erythropoietic porphyrias

Congenital porphyria

This is extremely rare and is transmitted as an autosomal recessive trait. Its victims show extreme sensitivity to sunlight and develop disfiguring scars. Dystrophy of the nails, blindness due to lenticular scarring, and brownish discoloration of the teeth also occur.

Erythropoietic protoporphyria

This is commoner than congenital porphyria and is inherited as an autosomal dominant trait. It presents with irritation and burning pain in the skin on exposure to sunlight. Hepatic involvement may also occur. Diagnosis is made by fluorescence of the peripheral red blood cells and by increased protoporphyrin in the red cells and stools. Oral J3-carotene provides effective protection against solar sensitivity; the reason for this is not known.

Further reading

The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. New England Journal of Medicine 329: 977- 986.
Ferner RE, Alberti KGMM (1989) Sulphonylureas in the treatment of non-insulin dependent diabetes. Quarterly Journal of Medicine 73, 987-995.
Galton DJ, Krone W (1991) Hyperlipidaemia in Practice. London: Gower Medical Publishing. Kohner EM (1989) Diabetic retinopathy. British Medical Bulletin 45: 148-173.
Scriver CR, Beaudet AL, Sly WS & Valle D (1989) The Metabolic Basis of Inherited Disease, 6th edn. New York: McGraw-Hill. Tattersall RB, Gale EAM (eds) (1990) Diabetes Clinical Management. Edinburgh: Churchill Livingstone. Ward JD (1989) Diabetic neuropathy. British Medical Bulletin 45: 111-126.

Amyloidosis

This is a disorder of protein metabolism in which there is extracellular deposition of insoluble fibrillar protein, either localized or widely distributed throughout the body.
Characteristically the amyloid protein consists of f3- pleated sheets that are responsible for the insolubility and resistance to proteolysis. A smaller part of the protein is the amyloid P component (AP), which is derived from normal circulatory glycoprotein and is related to the acute-phase reactant, C-reactive protein (CRP). Amyloid in tissues appears as an amorphous, homogeneous substance that stains pink with haematoxylin and eosin and stains red with Congo red, which also shows a green fluorescence in polarized light.

Hereditary systemic amyloidosis

In the Portuguese type I neuropathic amyloidosis, fibrils composed of prealbumin formed into f3 sheets are found, producing a polyneuropathy. In familial Mediterranean fever, renal amyloidosis is a common serious complication. Deposition of amyloid A (AA) fibrils occurs.

Local amyloidosis

Deposits of amyloid fibrils of various types can be localized to various organs or tissues, e.g. skin, heart and brain. An amyloid syndrome due to f32-microglobulin deposition as amyloid fibrils is seen in patients on chronic dialysis.

Senile amyloid

Amyloid deposits are frequently found in the elderly. In particular, cerebral deposits of the A4 protein are found, and this protein is also seen in the brains of patients with Down’s syndrome and Alzheimer’s disease. Apoprotein E (involved in LDL transport, interacts directly with f3-A4 protein in senile plaques and neurofibrillary tangles in the brain. The gene for apoprotein E is on chromosome 19 and may be an important susceptibility factor in the aetiology of Alzheimer’s disease.

Immunocyte-related amyloidosis

In this variety, the deposits consist of amyloid light (AL) chain fragments. The molecular weights of these fragments range from 5000 to 25000. The amyloidosis is usually associated with lymphoproliferative diseases of the Bcell lineage, e.g. myeloma, Waldenstrom’s macroglobulinaemia or non-Hodgkin’s lymphoma.

CLINICAL FEATURES

The clinical features are related to the organs involved, patients presenting with heart failure, nephrotic syndrome, purpura or bleeding, peripheral neuropathy or weight loss. Weakness and paraesthesia of the hand may occur due to the carpal tunnel syndrome. On examination, a characteristic feature is macroglossia, which only occurs in this form of amyloidosis. Hepatomegaly and occasionally splenomegaly are seen.

INVESTIGATION

The diagnosis is made on the presence of the characteristic histological features mentioned above in a biopsy of the rectum or gums. The bone marrow may show plasma cells in primary amyloidosis or a lymphoproliferative disorder. A paraproteinaemia and light chains in the urine may be seen as a result of associated conditions.

TREATMENT

Treatment is symptomatic or of the associated cause. Reactive systemic amyloidosis In reactive systemic amyloidosis, the amyloid (AA) is composed of protein A (molecular weight 8500), which is a precursor of the normal serum component serum amyloid A (SAA), an acute-phase reactant. Overproduction of SAA as well as its degradation to AA determines whether amyloidosis occurs. This type of amyloidosis, which used to be known as secondary amyloidosis, involves the spleen, liver, kidney and adrenal glands. It is associated with long-standing chronic infections (e.g. tuberculosis), inflammation (e.g. rheumatoid arthritis), malignancy (e.g. Hodgkin’s disease), and also occurs in familial Mediterranean fever.
Clinically there is hepatosplenomegaly. Hepatic failure and renal failure with renal-vein thrombosis or the nephrotic syndrome may develop,

Cystinosis

In cystinosis, cystine accumulates in the reticuloendothelial cells. It is inherited in an autosomal recessive manner. The exact mechanism is unknown but it is thought to be a defect of cystine transport across the lysosomal membrane. Three forms are recognized: the infantile form is usually fatal in the first year owing to renal failure; the intermediate form presents in early/young adult life with fever and renal problems; and the adult form is benign. The generalized aminoaciduria seen in these patients often causes confusion with the Fanconi syndrome. Corneal deposits of cystine are seen.

Lysosomal Storage Diseases

Lysosomal storage diseases are due to inborn errors of metabolism which are mainly inherited in an autosomal recessive manner. Glucosylceramide lipidoses:

Gaucher’s disease

This is the most prevalent lysosomal storage disease and is due to a deficiency in glucocerebrosidase, a specialized lysosomal acid l3-glucosidase. This results in accumulation of glucosylceramide in the lysosomes of the reticuloendothelial system, particularly the liver, bone marrow and spleen. Several mutations have been characterized in the glucocerebrosidase gene, the commonest being a single base change causing the substitution of arginine to serine; this is seen in 70% of Jewish patients. The typical Gaucher cell, a glucocerebroside-containing reticuloendothelial histiocyte, is found in the bone marrow. There are three clinical types, the commonest presenting in adult life with an insidious onset of hepatosplenomegaly.

There is a high incidence in Ashkenazi

Jews (1 in 3000 births), and patients have a characteristic pigmentation on exposed parts, particularly the forehead and hands. The clinical spectrum is variable with patients developing anaemia, evidence of hypersplenism and pathological fractures due to bone involvement. Nevertheless, many have a normal life-span.
Acute Gaucher’s disease presents in infancy or childhood with rapid onset of hepatosplenomegaly with neurological involvement due to Gaucher cells in the brain. The outlook is poor.
Some patients with non-neuropathic Gaucher’s disease show considerable improvement with infusion of L-glucerase (mannose-terminated placental glucocerebrosidase).
Sphingomyelin cholesterol lipidoses:

Niemann-Pick disease

The disease is due to a deficiency of lysosomal sphingomyelinase which results in the accumulation of sphingo myelin cholesterol and glycosphingolipids in the reticuloendothelial macrophages and many organs, particularly the liver, spleen, bone marrow and lymph nodes. The disease usually presents within the first 6 months of life with mental retardation and hepatosplenomegaly. Typical foam cells are found in the marrow, lymph nodes, liver and spleen.

The mucopolysaccharidoses (MPS)

These are a group of disorders caused by the deficiency of lysosomal enzymes required for the catabolism of glycosaminoglycans (rn ucopolysaccharides). The catabolism of dermatan sulphate, heparan sulphate, keratin sulphate or chondroitin sulphate may be affected either singularly or together. Accumulation of glycosaminoglycans in the lysosomes of various tissues results in the disease. Ten forms ofMPS have been described; all are chronic but progressive and a wide spectrum of clinical severity can be seen within a single enzyme defect. The MPS types show many clinical features though in variable amounts with dysostosis, abnormal facies, poor vision and hearing and joint dysmobility (either stiff or hypermobile) being frequently seen. Mental retardation is present in, for example, Hurler (MPS IH) and San Filippo A (MPS IlIA) types, but normal intelligence and life-span are seen in Scheie (MPS IS).

The GM2 gangliosidoses

In these conditions there is accumulation of GM2 gangliosides in the central nervous system and peripheral nerves. It is particularly common (1 : 2000) in Ashkenazi Jews. Tay-Sachs disease is the severest form where there is a progressive degeneration of all cerebral function, with fits, epilepsy, dementia and blindness and death usually occurs before 2 years of age. The macula has a characteristic cherry spot appearance.

Fabry’s disease

This X-linked recessive condition is due to a deficiency of the lysosomal hydrolase a-galactosidase, causing an accumulation of glycosphingolipids with terminal a-galactosyl moieties in the lysosomes of various tissues including the liver, kidney, blood vessels and the ganglion cells of the nervous system. The patients present with peripheral nerve involvement, but eventually most patients develop renal problems in adult life.

Diagnosis

Many of the sphingolipidoses can be diagnosed by demonstrating the enzyme deficiency in the appropriate tissue.
Prenatal diagnosis is becoming possible in a number of the conditions by obtaining specimens of amniotic cells. Carrier states can also be identified, so that sensible genetic counselling can be given.

Inborn Errors of Amino Acid Metabolism

Inborn errors of amino acid metabolism are chiefly inherited as autosomal recessive conditions.

Amino acid transport defects

Amino acids are filtered by the glomerulus but 95% of the filtered load is reabsorbed in the proximal convoluted tubule by an active transport mechanism. Aminoaciduria results from:
• Abnormally high plasma amino acid levels (e.g. phenylketonuria)
• Any inherited disorder that damages the tubules secondarily (e.g. galactosaemia)
• Tubular reabsorptive defects, either generalized (e.g. Fanconi syndrome) or specific (e.g. cystinuria)
• Amino acid transport defects can be congenital or acquired.

GENERALIZED AMINOACIDURIAS

Fanconi syndrome

This occurs in a juvenile form (De Toni-Fanconi-Debre syndrome); in adult life it is often acquired due to, for .example, heavy metal poisoning, drugs or some renal diseases. There is defective tubular reabsorption of:
• Most amino acids
• Glucose
• Urate
• Phosphate, resulting in hypophosphataemic rickets
• Bicarbonate, with failure to transport hydrogen ions, causing a renal tubular acidosis that then produces a hyperchloraemic acidosis

Other abnormalities include:
• Potassium depletion, primary or secondary to the acidosis
• Polyuria
• Increased excretion of immunoglobulins and other low-molecular-weight proteins
Various combinations of the above abnormalities have been described.
The juvenile form begins at the age of 6-9 months, with failure to thrive, vomiting and thirst. There is also acidosis, dehydration and vitamin D-resistant rickets. In the adult, the disease is similar to the juvenile form, but osteomalacia is a major feature.
Treatment is with large doses of vitamin D (e.g. 1-2 J.Lg of l o-hydroxycholecalciferol with regular blood calcium monitoring).

Lowe’s syndrome (oculocerebrorenal dystrophy)

In this syndrome there is generalized aminoaciduria combinedwith mental retardation, hypotonia, congenital cataracts  and an abnormal skull shape.

SPECIFIC AMINOACIDURIAS

Cystinuria

There is defective tubular reabsorption and jejunal absorption of cystine and the dibasic amino acids lysine, ornithine and arginine. Inheritance is either completely or incompletely recessive, so that heterozygotes who have increased excretion of lysine and cystine only can occur. Cystine absorption from the jejunum is impaired but, nevertheless, cystine in peptide form can be absorbed. Cystinuria leads to urinary stones and is responsible for approximately 1-2% of all urinary calculi. The disease often starts in childhood, although most cases present in adult life.

Treatment is with a high fluid intake in order to keep the urinary cystine concentration low. Patients are encouraged to drink up to 3 litres over 24 hours and to drink even at night. Penicillamine should be used for patients who cannot keep the cystine concentration of their urine low.
The condition cystinosis must not be confused with cystinuria.

Hartnup’s disease

There is defective tubular reabsorption and jejunal absorption of most neutral amino acids but not their peptides. The resulting tryptophan malabsorption produces nicotinamide deficiency. Patients can be asymptomatic, but others develop evidence of pellagra, with cerebellar ataxia, psychiatric disorders and skin lesions. Treatment is with nicotinamide and often brings about considerable improvement.

Tryptophan malabsorption syndrome (blue diaper syndrome)

This is due to an isolated transport defect for tryptophan; the tryptophan excreted oxidizes to a blue colour on the baby’s diaper.

Familial iminoglycinuria

This occurs when there is defective tubular reabsorption of glycine, proline and hydroxyproline. It seems to have few clinical effects.

Methionine malabsorption

syndrome

This is due to failure to absorb and excrete methionine, and results in diarrhoea, vomiting and mental retardation. Patients characteristically have an oast-house smell.

Inborn Errors of Carbohydrate Metabolism

Glycogen storage disease

All mammalian cells can manufacture glycogen, but the main sites of its production are the liver and muscle. Glycogen is a high-molecular-weight glucose polymer. In glycogen storage disease there is either an abnormality in the molecular structure or an increase in glycogen concentration owing to a specific enzyme defect. Almost all these conditions are autosomal recessive in inheritance and present in infancy, except for McArdle’s disease, which presents in adults .The classification and clinical features of some of these diseases. New specific enzyme defects, e.g. liver phosphorylase, phosphorylase kinase, are being recognized.

Galactosaemia

Galactose is normally converted to glucose. However, a deficiency of the enzyme galactose-j-phosphate uridyltransferase results in accumulation of galactose-I-phosphate in the blood. This deficiency, inherited as an autosomal recessive, results in hypoglycaemia and acidosis in the neonate. Progressive hepatosplenomegaly, cataracts,
renal tubular defects and mental retardation occur. Treatment is with a galactose-free diet, which, if started early, results in normal development. Untreated patients die within a few days. Prenatal diagnosis and diagnosis of the carrier state are possible by measurement of the level of galactose-I-phosphate in the blood.
Galactokinase deficiency also results in galactosaemia and early cataract formation.

Defects of fructose metabolism

Absorbed fructose is chiefly metabolised in the liver to lactic acid or glucose. Three defects of metabolism occur;all are inherited as autosomal recessive traits:
FRUCTOSURIA is due to fructokinase deficiency. It is a benign condition.
FRUCTOSE INTOLERANCE is due to fructose-lphosphate aldolase deficiency. Fructose-J-phosphate accumulates after fructose ingestion, resulting in symptoms of hypoglycaemia. Hepatomegaly and renal tubular defects occur but are reversible on a fructose-free diet. Intelligence is normal and there is an absence of dental caries.
FRUCTOSE-l ,6-DIPHOSPHATE DEFICIENCY leads to a failure of gluconeogenesis, and to hepatomegaly.

Pentosuria

Pentosuria is due to L-xylulose reductase deficiency. It has no clinical significance.

Prevention Trials

Since relatively few deaths will occur in a group of middle-aged subjects, approximately 20000 high-risk patients need to be studied for at least 5 years in a prevention trial to demonstrate whether treating hypercholesterolaemia produces a reduction in death rate. No such large well-designed trial has been performed. During a 5-10 year period of follow-up many more middle-aged subjects will develop non-fatal cardiovascular disease than will die. Thus if cardiovascular endpoints, and not death, are used in cholesterol-lowering trials, much smaller numbers of patients (approximately 4000) need be recruited to have a reasonable chance of showing a real effect if one exists. The two best controlled primary intervention studies (the Helsinki Heart Study and the Lipid Research Clinics Trial) each used different drug therapies in 4000 patients in two different countries and both demonstrated a significant improvement in cardiovascular risk with treatment of hypercholesterolaemia. Furthermore the improvement in cardiovascular risk increased progressively year by year. These two well-designed trials provide the strongest evidence that cholesterol-lowering therapy is worthwhile. Both these studies were of insufficient size to examine mortality as an end-point, and this was appreciated when they were designed. Despite this limitation some critics erroneously state that ‘the trials showed that treating hypercholesterolaemia has no effect on mortality’! Unfortunately, although well-designed trials have been undertaken, many poorly constructed trials with inconclusiveresults litter the literature and some hint at an increase in  mortality due to violent death and suicide in treated patients. Overall, however, the weight of evidence favouring the judicious treatment of lipid disorders is great.

Drugs used in the management of hyperlipidaemia.

Drugs used in the management of hyperlipidaemia.

Drugs used in the management of hyperlipidaemia.

Drugs used in the management of hyperlipidaemia.

Follow-up study of coronary events in controls and patients treated for hypercholesterolaemia in two study groups: (a) Lipid Research Clinics Study; (b) Helsinki Heart Study.

Follow-up study of coronaryevents in controls and patients treated for hypercholesterolaemia in two study groups: (a) Lipid Research Clinics Study; (b) Helsinki Heart Study.

OTHER LIPID DISORDERS

Hypolipidaemia

Low lipid levels can be found in severe protein-energy malnutrition. They are also seen occasionally with severe malabsorption and in intestinal lymphangiectasia.

Abetalipoproteinaemia

Familial a-lipoprotein deficiency (Tangier disease)

One of the two HDL apoproteins, apoprotein A-I, is deficient in homozygotes with this very rare disease, so that there is little HDL in plasma. Tangier disease is inherited as an autosomal recessive. The serum cholesterol is low, but serum triglycerides are normal or high. Cholesterol accumulates in reticuloendothelial tissue, although the mechanism is uncertain, producing enlarged and orange-coloured tonsils and hepatosplenomegaly. There are also corneal opacities and a polyneuropathy.

Some glycogen storage diseases.

Some glycogen storage diseases.

MANAGEMENT OF HYPERLIPIDAEMIA

Hypertriglyceridaemia (without hypercholesterolaemia)

A serum triglyceride concentration below 2.0 mmol litre-I is normal. In the range 2.0-6.0 mmol litre-I no specific intervention will be needed unless there are many coincident cardiovascular risk factors, and in particular a strong family history of early cardiovascular death. In general, patients should be advised that they have a minor lipid problem, offered advice on weight reduction if obese, and advice on correcting other cardiovascular risk factors.

The graded management for hypercholesterolaemia.

The graded management for hypercholesterolaemia.

If the triglyceride concentration is above 6.0 mmol litre-I there is a risk of pancreatitis and retinal vein thrombosis. Patients should be advised to reduce their weight if overweight and start a formal lipid-lowering diet. A proportion of individuals with hypertriglyceridaemia have livers which respond to even moderate degrees of alcohol intake by allowing accumulation or excess production of VLDL particles. If hypertriglyceridaemiapersists lipid measurements should be repeated  before and after a 6 week interval of complete abstinence from alcohol. If a considerable improvement results, lifelong abstinence may prove necessary. Other drugs, including thiazides, oestrogens and glucocorticoids, can have a similar effect to alcohol in susceptible patients. If the triglyceride concentration remains elevated above  6.0 mmol litre “, despite the above measures, drug therapy is warranted. A fibric acid derivative is the agent of first choice. icotinic acid may be used in addition but its side-effects are often a problem. Fish oil capsules (Maxepa) which contain w-3 (n-3) long-chain fatty acids are also effective in lowering triglyceride concentrations.
The severe hypertriglyceridaemia associated with the rare disorders of lipoprotein lipase deficiency and apoprotein C-IJ deficiency may require restriction of dietary fat to 10-20% of total energy intake and the introduction of medium-chain triglycerides, which are not absorbed via chylomicrons.

Hypercholesterolaemia (without hypertrig Iyceridaem ia)

Individuals with polygenic hypercholesterolaemia require a graded approach and most will not need drug therapy. Perimenopausal women with hypercholesterolaemia should be offered female hormone replacement therapy as the risk of cardiovascular disease rises sharply after the menopause and hormone replacement therapy reduces this risk even in normocholesterolaemic women. A small number of women respond adversely to exogenous oestrogens with a rise in lipids and, therefore, measurement of the fasting lipids is necessary shortly after starting treatment. Individuals with familial hypercholesterolaemia will require treatment with both diet and drugs. FIBRATES raise HDL concentrations (beneficial) and reduce LDL cholesterol concentrations by 10-15% and are useful in patients with modest hypercholesterolaemia. Gemfibrozil has been demonstrated to reduce the incidence of cardiovascular events in a carefully performed large randomized double-blind placebo-controlled trial (Helsinki Heart Study) of patients with moderate hypercholesterolaemia,
whereas the benefit of the other fibrates on outcome has not been investigated.
BILE ACID BINDING RESINS produce an 8-15% reduction in LDL cholesterol concentration. Cholestyramine has been shown to reduce the incidence of cardiovascular events in hypercholesterolaemic patients in a carefully performed randomized double-blind placebocontrolled trial (Lipid Research Clinics Trial). The safety profile of these drugs is good and their long-term safety is established. They are particularly useful when a lipidlowering agent needs to be given to women of childbearing age. They have a synergistic effect when given with an HMG-CoA reductase inhibitor. This combination can reduce LDL cholesterol concentrations by 50-60%.
HMG-CoA REDUCTASE INHIBITORS reduce LDL cholesterol concentrations by 30-40%. There are no trial data showing an influence on outcome. In severe hypercholesterolaemia it is often combined with a bile acid binding resin (see above). Concurrent therapy with HMG-CoA reductase inhibitors and fibrates is usually avoided, in view of their overlapping side-effects, but in very severe cases such mixed therapy has been undertaken under very close supervision.
PROBUCOL is now used only rarely as a fourth-line agent.

Combined hyperlipidaemia (hypercholesterolaemia and hypertrig Iyceridaem ia)
Treatment is the same for all varieties of combined hyperlipidaemia.
For any given cholesterol concentration the hypertriglyceridaemia found in the combined hyperlipidaemias increases the cardiovascular risk considerably. Treatment is aimed to reduce serum cholesterol below 6.5 mmol litre ” and triglycerides below 2.0 mmollitre-I. Therapy is with diet in the first instance and with drugs if an adequate response has not occurred. Fibric acid derivatives are the treatment of choice since these reduce both cholesterol and triglyceride concentrations, and also have the benefit of raising cardioprotective HDL concentrations. The combination of fibric acid derivative and  bile acid binding resin is of considerable use when a fibrate alone produces an insufficient reduction in LDL cholesterol. Nicotinic acid can be used in addition, although its unwanted effects render it a third-line agent.

The lipid-lowering diet

Studies have shown that dietitians helping patients adjust their own diet to meet the nutritional targets set out below produce a better lipid-lowering effect than issuing of standard diet sheets and advice from a doctor. The main elements of a lipid-lowering diet are:
REDUCTION OF TOTAL FAT INTAKE. Dairy products and meat are the principal sources of saturated fat in the diet. Intake of these products should therefore be reduced, and fish and poultry should be substituted. Visible fat and skin should be removed before cooking and preparing meat dishes. Meat products including pates, sausages and reconstituted meats (such as luncheon meat) should be avoided since the concentration of fat is unknown and often high. Baking and grilling of meats reduces the fat content and is preferred to frying. Low-fat or cottage cheese and skimmed or semi-skimmed milk should be substituted for the standard full-fat varieties. Pastries and cakes contain large quantities of fat and should be avoided. The overall aim should be to decrease fat intake such that it is providing approximately 30% of the total energy intake in the diet. Further reduction in fat intake is unacceptable to many patients.
SUBSTITUTION OF MONOUNSATURATES AND POLYUNSATURATES. Monounsaturated oils, particularly olive oil, and polyunsaturated oils such as sunflower, safflower, corn and soya oil should be used in cooking instead of saturated fat-rich alternatives.
REDUCTION IN DIETARY CHOLESTEROL INTAKE.
Liver, offal and fish roes should be avoided. Although eggs and prawns are rich in cholesterol their total contribution to the body’s cholesterol pool is small and they can still be part of a balanced lipid-lowering diet.
INCREASE FIBRE (non-starch polysaccharides, NSPs) content. Food high in soluble fibre, such as pulses, legumes, root vegetables, leafy vegetables, and unprocessed cereals, help reduce circulating lipid concentrations, and should be substituted in the diet in the place of higher fat alternatives.
REDUCE ALCOHOL CONSUMPTION. Excess alcohol is an important cause of secondary hyperlipidaemia, and may worsen primary lipid disorders.
ACHIEVE IDEAL BODY WEIGHT. Treatment of obesity is particularly important in the management of hyperlipidaemia both because it will exacerbate the lipid disorder itself, and also because obesity is an independent cardiovascular risk factor.

Screening

Most patients with hyperlipidaemia are asymptomatic and have no clinical signs. Many are discovered whilst screening high-risk individuals.

Whose lipids should be measured?

There are great doubts as to whether blanket screening of plasma lipids is warranted. Selective screening of people at high risk of cardiovascular disease should be undertaken including those with:
• Family history of coronary hear  disease (especially below 50 years of age)
• Family history of lipid disorders
• Presence of a xanthoma
• Presence of xanthelasma or corneal arcus before the age of 40 years
• Obesity
• Diabetes mellitus
• Hypertension
• Acute pancreatitis
• Those undergoing renal replacement therapy
Where one family member is known to have a monogenic disorder such as familial hypercholesterolaemia (1 in 500 of the population), siblings and children must have their plasma lipid concentrations measured. It is also worth screening the prospective partners of any patients with  this heterozygous monogenic lipid disorder because of the small risk of producing children homozygous for the condition.
Acute severe illnesses such as myocardial infarction can derange plasma lipid concentrations for up to 3 months. Plasma lipid concentrations should be measured either within 48 hours of an acute myocardial infarction (before derangement has had time to occur) or 3 months later.  Serum cholesterol concentration does not change significantly after a meal and as a screening test a random blood sample is sufficient. If the total cholesterol concentration is raised above 6.5 mmol litre “, HDL cholesterol, triglyceride, and LDL cholesterol concentrations should be quantitated on a fasting sample. If a test for hypertriglyceridaemia is needed, a fasting blood sample is mandatory.

SECONDARY HYPERLIPIDAEMIA

If a lipid disorder has been detected it is vital to carry out a clinical history, examination and simple special investigations to detect causes of secondary hyperlipidaemia , which may need treatment in their own right. The biochemical tests needed are for thyroid stimulating hormone, fasting blood glucose concentration, urea and electrolyte concentrations and liver biochemistry.

CLASSIFICATION, CLINICAL FEATURES AND INVESTIGATION OF PRIMARY HYPERLIPIDAEMIAS

As the genetic basis of lipid disorders becomes clearer the genetic classification of Goldstein and colleagues is proving of greater clinical relevance than the Fredrickson (WHO) classification (based on the pattern of lipoproteins found in plasma). The lack of direct correspondence between these two systems of classification can be confusing. For clarity we have used the genetic classification and not the Fredrickson classification. This has the advantage that the genetic disorders may be grouped by the results of simple lipid biochemistry into causes of hypertriglyceridaemia alone, hypercholesterolaemia alone or of combined hyperlipidaemia.

Hypertriglyceridaemia alone (without hypercholesterolaemia)

The majority of cases will be due to multiple genes acting together to produce a modest excess circulating concentration of VLOL particles, such cases being termed polygenic hypertriglyceridaemia. In a proportion of cases there will be a family history of a lipid disorder or its effects (pancreatitis). Such cases are often classified as familial hypertriglyceridaemia. The defect underlying the vast majority of such cases is not understood. The only clinical feature is a history of attacks of pancreatitis or retinal vein thrombosis in some individuals.
LIPOPROTEIN LIPASE DEFICIENCY AND APOPROTEIN C-II DEFICIENCY are rare diseases which produce greatly elevated triglyceride concentrations due to the persistence of chylomicrons (and not VLOL particles) in the circulation. The chylomicrons persist because the triglyceride within cannot be metabolized if the enzyme lipoprotein lipase is defective or because they cannot gain access to the normal enzyme due to deficiency of the apoprotein C-II on the surface of the chylomicron particles. The disorder is unlikely to be confused clinically with cases of polygenic or familial hypertriglyceridaemia as the patients present in childhood with eruptive xanthomas, lipaemia retinalis and retinal vein thrombosis, pancreatitis  and hepatosplenomegaly. If the disorder is not identified in childhood it can present in adults with gross  hypertriglyceridaemia resistant to simple measures. The most important test is to confirm the presence of chylomicrons in fasting plasma stored overnight (chylomicrons float like cream). This is confirmed by plasma electrophoresis or ultracentrifugation. An abnormality of apoprotein C can be deduced if the hypertriglyceridaemia improves temporarily after infusing fresh frozen plasma, and lipoprotein lipase deficiency is likely if it does not.

Hypothyroidism

Diabetes mellitus (when poorly controlled)
Obesity
Renal impairment
Nephrotic syndrome
Dysglobulinaemia
Hepatic dysfunction
Drugs: oral contraceptives in susceptible individuals, retinoids, thiazide diuretics, corticosteroids, opDDD (used in the treatment of Cushing’s syndrome) Hypercholesterolaemia (without hypertrig Iyceridaem ia).

The monogenic disorder of heterozygous familial hypercholesterolaemia is present in 1 in 500 of the normal population. The average general practitioner would therefore be expected to have four such patients on his or her list, but because of clustering within families the prevalence is lower in some general practice lists and much higher in others. Surprisingly, most individuals with this disorder remain undetected. Patients may have no physical signs, in which case the diagnosis is made on the presence of very high plasma cholesterol concentrations which are unresponsive to dietary modification and are associated with a typical family history. Diagnosis can be more easily made if typical clinical features are present. These include xanthomatous thickening of the Achilles tendons and xanthomas over the extensor tendons of the fingers. Xanthelasma may be present, but is not diagnostic  of familial hypercholesterolaemia. The genetic defect of this disorder is the underproduction or malproduction of the LOL cholesterol receptor in the liver. Many different monogenic lesions producing various abnormalities of the receptor have been described in different families.  Homozygous familial hypercholesterolaemia is very rare indeed. Affected children have no LOL receptors in the liver. They have a hugely elevated LOL cholesterol concentration, and massive deposition of lipid in arterial walls, the aorta and the skin. The natural history is for death from ischaemic heart disease in late childhood or adolescence. Plasmapheresis has been used to regularly remove LOL cholesterol with some success in these patients. Liver transplantation offers the possibility of cure, but the numbers of patients having undergone this procedure is small. The possibility of gene therapy offers a glimmer of hope on the horizon for affected individuals. Patients who have raised serum cholesterol concentrations, but do not have familial hypercholesterolaemia exist in the right  hand tail of the normal distribution of cholesterol concentration, and are deemed to have polygenic hypercholesterolaemia. The precise nature of the polygenic variation in plasma cholesterol concentration remains unknown.

Combined hyperlipidaemia (hypercholesterolaemia and hypertrig Iyceridaem ia) The most common patient group IS a polygenic combined hyperlipidaemia.
FAMILIAL COMBINED HYPERLIPIDAEMIA is relatively common affecting 1 in 200 of the general population. The genetic basis for the disorder has not yet been characterized. It is diagnosed by finding raised cholesterol and triglyceride concentrations in association with a typical family history.
REM ANT HYPERLIPIDAEMIA is a rare cause of combined hyperlipidaemia. It is due to accumulation of LDL remnant particles and is associated with an extremely high risk of cardiovascular disease. It may be suspected in a patient with raised total cholesterol and triglyceride concentrations by finding xanthomas in the palmar creases (diagnostic) and the presence of tuberous xanthomas typically over the knees and elbows. Remnant hyperlipidaemia is almost always due to the inheritance of a variant of the apoprotein E allele (apoprotein E2) together with an aggravating factor such as another primary hyperlipidaemia. When suspected clinically the diagnosis can be confirmed using ultracentrifugation of plasma, or phenotyping apoprotein E.

Disorders of Lipid Metabolism

PHYSIOLOGY

Lipids are insoluble in water, and are transported in the bloodstream as macromolecular complexes. In these complexes, lipids (principally triglyceride, cholesterol and cholesterol esters) are surrounded by a stabilizing coat of phospholipid. Proteins (called apoproteins) embedded into the surface of these ‘lipoprotein’ particles exert both a stabilizing function and allow the particles to be recognized by receptors in the liver and the peripheral tissues. The structure of a chylomicron (one type of lipoprotein particle) is illustrated.
The genes for all the major apoproteins and that for the low-density lipoprotein (LDL) receptor have been isolated, sequenced and their chromosomal sites mapped. Production of abnormal apoproteins is known to produce,  or predispose to, several types of lipid disorder, and it is likely that others will be discovered. Genetic abnormalities which affect the LDL receptor cause familial hyper cholesterolaemia.
Five principal types of lipoprotein particles are found in the blood . They are structurally different and can be separated in the laboratory by their density and electrophoretic mobility. The larger particles give postprandial plasma its cloudy appearance.

Schematic diagram of the surface of a chylomicron particle (75-1200 nm) showing the apoprotein lying in the membrane.

Schematic diagram of the surface of a chylomicron
particle (75-1200 nm) showing the apoprotein lying in the membrane.

Chylomicrons

Chylomicrons are synthesized in the small intestine postprandially. They contain triglyceride and a small amount of cholesterol, and provide the main mechanism for transporting the digestion products of dietary fat to the liver and peripheral tissues. Each newly formed chylomicron contains several different apoproteins (B-48, A-I, AIr),  and acquires apoproteins C-II and E by transfer from high-density lipoprotein (HDL) particles in the bloodstream. Apoprotein C- II binds to specific receptors in the peripheral tissues and the liver and allows the endothelial enzyme, lipoprotein lipase, to remove triglyceride from the particle. The remaining chylomicron remnant particle, which contains most of the original cholesterol, is taken up by the liver by mechanisms which are still not fully understood, possibly mediated by apoprotein E. Very low density lipoprotein (VLDL) particles These are synthesized and secreted by the liver and contain most of the endogenously synthesized triglyceride and a smaller quantity of cholesterol. Apoprotein B-I00 is an essential component. Apoproteins C and E are later incorporated into VLOL by transfer from HOL particles. As they pass round the circulation VLOL particles bind  through apoprotein C allowing triglyceride to be progressively removed by lipoprotein lipase. This leaves a particle, now depleted of triglyceride and apoprotein C, called an intermediate-density lipoprotein (IDL) particle.

Schematic representation of the sites of origin, interaction between and fate of the major lipoprotein particles.

Schematic representation of the sites of origin,interaction between and fate of the major lipoprotein particles.

Intermediate-density lipoprotein particles

These also contain apoprotein B-lOO and can bind to the hepatocyte through apoprotein E. Once bound, IDL particles can be catabolized, or have further triglyceride removed (by the enzyme hepatic lipase) producing LOL particles.

Low-density lipoprotein particles

LOL particles are the main carrier of cholesterol, anddeliver it both to the liver and to peripheral cells. The  surface of the LOL particle contains a single apoprotein B-lOO, and also apoprotein E. The apoprotein B-lOO is the principal ligand for the LOL receptor. This receptor lies within coated pits on the surface of the hepatocyte. Once bound to the receptor, the coated pit invaginates and fuses with Iiposomes which destroy the LOL particle . The number of hepatic LOL receptors regulates the circulating LOL concentration. The circulating LOL concentration is also regulated by controlling the activity of the rate-limiting enzyme in the cholesterol synthetic pathway, hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase. Not all the cholesterol synthesized by the liver is packaged immediately into lipoprotein particles. Some is converted into bile salts. Both bile salts and cholesterol are excreted in the bile: both are then reabsorbed through the terminal ileum and recirculated (enterohepatic circulation).

Receptor-mediated endocytosis. lDL receptors are formed in the endoplasmic reticulum and transported via the Golgi apparatus to the cell surface.

Receptor-mediated endocytosis. lDL receptors areformed in the endoplasmic reticulum and transported via the Golgi apparatus to the cell surface.

High-density lipoprotein particles

HOL particles are produced in both the liver and intestine.The nascent particles are disc shaped, seemingly  inert and contain E apoproteins. They are modified by acquiring some surface components of chylomicron and VLOL particles as these are broken down into smaller particles. The materials gained by the nascent HOL  particles include phospholipids, and the A and C apoproteins. The more mature HOL particles take up cholesterol from cell membranes in the peripheral tissues. As it is taken up the enzyme lecithin-cholesterol acyltransferase (LeA T), activated by the apoprotein A on the particle’s surface, esterifies the sequestered cholesterol. The HOL particle is then capable of transporting this cholesterol away from the periphery to the liver (reverse cholesterol transport) where it binds through apoprotein E.
HOL particles carry 20-30% of the total quantity of cholesterol in the blood.
When a laboratory measures fasting serum lipids, the majority of the total cholesterol concentration consists of LOL particles with a 20-30% contribution from HOL particles. The triglyceride concentration largely reflects  the circulating number of VLOL particles, since chylomicrons are not normally present in the fasted state. If the patient is not fasted the total triglyceride concentration will be raised due to the presence of triglyceriderich chylomicrons as well as VLOL particles.

EVIDENCE FOR A RELATIONSHIP

BETWEEN LIPOPROTEIN

CONCENTRATIONS, ATHEROMA AND CARDIOVASCULAR RISK
LDL cholesterol.
EPIDEMIOLOGICAL LINKS BETWEEN CHOLESTEROL AND CORONARY HEART DISEASE. Population studies have repeatedly demonstrated a strong association between both total and LOL cholesterol concentration and coronary heart risk. There is a strong link between  mean fat consumption, mean serum cholesterol concentration and the prevalence of coronary heart disease between countries. The exception is France where the cardiovascular risk is only moderate-perhaps due to high alcohol consumption. Studies of migrants, particularly of Japanese men migrating to Hawaii, have shown that as diet changes, and cholesterol concentrations rise, so does the cardiovascular risk. Such studies show the importance of the environment rather than the genetic make-up of a population.

The Multiple Risk Factor Intervention Trial (MRFIT) screened one-third of a million American men for various cardiovascular risk factors and then followed them for 6 years. Data from this study have shown that although  cardiovascular risk rises progressively as total cholesterol concentration increases, the risk increase is modest for individuals with no other cardiovascular risk factors. With each additional risk factor, the effect produced by the same difference in cholesterol  concentration becomes greatly magnified. The Framingham Study has reproduced these findings in a separate population.
ANIMAL AND BIOCHEMICAL STUDIES. Diverse laboratory studies have shown a strong link between dietary fat intake, resultant elevation of LDL cholesterol concentrations and the development of atheroma .
PATIENTS WITH MONOGENIC INHERITED LIPID DISORDERS.
Young men with the monogenic disorder familial hypercholesterolaemia are normal apart from considerably
elevated LDL cholesterol concentrations, yet they die of premature cardiovascular disease, and only 20-30% reach retirement age.
PREVENTION TRIALS. Two large well-controlled primary prevention studies (the Lipid Research Clinics Trial and the Helsinki Heart Study) have shown an increasing improvement in cardiovascular risk with increasing duration of treatment for hyperlipidaemia. (Intervention trials).

The Multiple Risk Factor Intervention Trial:

The Multiple Risk Factor Intervention Trial:

HDL cholesterol

Epidemiological studies have shown that HDL particlesappear to protect against atheroma. This effect may be  due to the ability of the particle to transport cholesterol from the peripheral tissues to the liver. HDL particles have important effects on the function of platelets and of the haemostatic cascade. These properties may favourably influence thrombogenesis.

VLDL particles

There is a weaker independent link between raised concentrations of (triglyceride-rich) VLDL particles and cardiovascular risk. The evidence is only epidemiological so there is a weaker case for the treatment of hypertriglyceridaemia when it occurs alone.

Chylomicrons

Excess chylomicrons do not confer an excess cardiovascular risk, but raise the total plasma triglyceride concentration.