The focus will be on xanthomatosis, a tissue danger signal which needs to be recognized by the clinician, and its relationship with monogenetic lipoprotein disorders (cholesterol, triglycerides), bile acid and sterol metabolism, particularly on metabolic pathways and genetics as well as on musculoskeletal and cardiovascular involvement, and their implications for clinical management. The critical question is to assess coronary heart disease risk, requiring correct identification of the pattern of lipoprotein disorders and of the causes (primary or secondary). Familial hypercholesterolemia must be suspected in adults and children with raised total cholesterol, especially when there is a personal or a family history of premature coronary heart disease, usually requiring potent statins to achieve adequate LDL-cholesterol lowering, even if we do not know safety of long-term therapy and whether treatments of dyslipidemia early in life prevent cardiovascular diseases in adulthood. Cerebrotendinous xanthomatosis is a treatable disease and must be suspected if there is a history of infantile chronic diarrhea and/or juvenile cataracts, even in the absence of tendon xanthomas. Current evidence for the prevention and screening, diagnosis, and treatment of dyslipidemia are available for the clinicians.
Xanthomatosis is a condition marked by the development of widespread xanthomas, yellow tumour-like structures filled with lipid deposits. Xanthomas can be found in a variety of tissues including the skin, tendons, knee and elbow joints. Xanthomatosis is associated with disturbance of lipid metabolism and formation of foam cells (MeSH term). It is well known that plasma lipoprotein disorders are modifiable risk factors for atherosclerotic cardiovascular disease (CVD) which is a major cause of morbidity and mortality in developed countries. Then, if xanthomatosis can be sometimes a chance for the patient and the clinician to suspect lipoprotein disorders and/or lipid storage diseases, the critical question is to assess the coronary heart disease (CHD) risk in these patients, in order to prevent or to control atherosclerosis development. The problem is that the consequences of lipid metabolism disturbance are not similar in all patients, requiring correct identification of the pattern of lipoprotein disorders and of the causes (primary or secondary), in order to implement the best-treatment options , keeping in mind that neither the lipid and lipoprotein patterns in plasma nor the xanthomas associated with them are specific.
Methods
In this review, the main thread will be xanthomatosis and its relationship with monogenetic lipoprotein disorders (cholesterol (CT), triglycerides (TGYs)), bile acid and sterol metabolism. Secondary hyperlipidemias and lipid disturbances seen in lysosomal and peroxisomal disorders will be excluded. The focus will be on metabolic pathways and genetics as well as on musculoskeletal and cardiovascular involvement, and their implications for clinical management. An electronic search of the literature from January 1991 to August 2011 was conducted in Pubmed, Web of Knowledge and Cochrane Library by using Medical Subject Headings, Medline (MeSH), as well as free text words. The search included the terms ‘xanthomatosis’, ‘lipoproteins’, ‘hyperlipoproteinemias’, ‘cerebrotendinous xanthomatosis (CTX)’, ‘sitosterolemia’ matched with ‘metabolism’, ‘genetics’, ‘musculoskeletal disease’, ‘CVD’, ‘osteoporosis’, ‘arthritis’ and ‘treatment’. Both the French and English languages were used.
Is xanthomatosis specific?
Xanthomas can be observed or detected by careful palpation or imaging studies at the early stages of their formation in both primary (hereditary) and secondary hyperlipidemias. Because dyslipidemia may predispose patients to atherosclerosis and since efficacious therapy is currently available, physicians must be aware of the importance of recognising this clinical feature and the related diseases. Normal lipoprotein metabolism has to be understood to approach the diagnosis and differential diagnosis of xanthomas (for review, see Sullivan , Bakker ). Tendinous xanthomas are histologically characterised by accumulations of collagen and macrophages which contain CT esters (foam cells) and the other xanthomas by CT ester deposits in dermal foam cells .
Xanthomas can be classified as eruptive, tuberoeruptive, tuberous ( Fig. 1 ), tendon ( Fig. 2 ) or planar ( Fig. 3 ) according to clinical morphology, localisation and mode of development . Eruptive xanthomas can be considered as specific, occurring almost only in cases of hyperchylomicronemia due to either frequent secondary hyperlipidemia (poorly controlled diabetes mellitus, ethanol ingestion and exogenous estrogens) or genetic lipoprotein disorders, such as rare lipoprotein lipase deficiency in children and common familial hypertriglyceridemia (type V) in adults, sometimes associated with metabolic syndrome. Tuberous or tuberoeruptive xanthomas, usually located in the elbows, knees and buttocks can be suggestive of
- i)
familial dysbetalipoproteinaemia, particularly if associated with palmar crease xanthomas;
- ii)
homozygous familial hypercholesterolemia (FH) in association with intertriginous xanthomas in a child;
- iii)
CTX or sitosterolemia in association with tendon xanthomas in an adult with normal plasma CT and TGYs.
Tendon xanthomas often involve the Achilles tendons, finger extensor tendons, the patellar tendon and may be associated with periosteal xanthomas in sites exposed to trauma (elbows, tibial tuberosities and ankle malleoli) . Tendon xanthomas, rare in young children, have been considered as essentially pathognomonic of FH , since Achilles tendon xanthomas associated with tendinitis occur about 6 times more frequently among individuals with FH than among those in the general population . However, tendon xanthomas may present in familial dysbetalipoproteinaemia (type III) and states with no demonstrable lipoprotein abnormalities, such as monoclonal gammopathy or normolipidemic xanthomatosis, such as CTX and sitosterolemia . Planar xanthomas, diffuse or well circumscribed, encompass several types: intertriginous xanthomas, which are pathognomonic of homozygous FH, palmar crease xanthomas, which are pathognomonic of familial dysbetalipoproteinaemia (type III), planar xanthomas of cholestasis, diffuse plan xanthomas suggestive of dysglobulinemia or paraproteinemia, and xanthelasmas the most common and least specific of all xanthomas. Xanthomas can be occasionally seen in familial high-density-lipoprotein (HDL)-deficiency syndromes , such as apolipoprotein AI deficiency and lecithin cholesterol acyltransferase (LCAT) deficiency . The involvement of bone in xanthoma is uncommon .
Is xanthomatosis specific?
Xanthomas can be observed or detected by careful palpation or imaging studies at the early stages of their formation in both primary (hereditary) and secondary hyperlipidemias. Because dyslipidemia may predispose patients to atherosclerosis and since efficacious therapy is currently available, physicians must be aware of the importance of recognising this clinical feature and the related diseases. Normal lipoprotein metabolism has to be understood to approach the diagnosis and differential diagnosis of xanthomas (for review, see Sullivan , Bakker ). Tendinous xanthomas are histologically characterised by accumulations of collagen and macrophages which contain CT esters (foam cells) and the other xanthomas by CT ester deposits in dermal foam cells .
Xanthomas can be classified as eruptive, tuberoeruptive, tuberous ( Fig. 1 ), tendon ( Fig. 2 ) or planar ( Fig. 3 ) according to clinical morphology, localisation and mode of development . Eruptive xanthomas can be considered as specific, occurring almost only in cases of hyperchylomicronemia due to either frequent secondary hyperlipidemia (poorly controlled diabetes mellitus, ethanol ingestion and exogenous estrogens) or genetic lipoprotein disorders, such as rare lipoprotein lipase deficiency in children and common familial hypertriglyceridemia (type V) in adults, sometimes associated with metabolic syndrome. Tuberous or tuberoeruptive xanthomas, usually located in the elbows, knees and buttocks can be suggestive of
- i)
familial dysbetalipoproteinaemia, particularly if associated with palmar crease xanthomas;
- ii)
homozygous familial hypercholesterolemia (FH) in association with intertriginous xanthomas in a child;
- iii)
CTX or sitosterolemia in association with tendon xanthomas in an adult with normal plasma CT and TGYs.
Tendon xanthomas often involve the Achilles tendons, finger extensor tendons, the patellar tendon and may be associated with periosteal xanthomas in sites exposed to trauma (elbows, tibial tuberosities and ankle malleoli) . Tendon xanthomas, rare in young children, have been considered as essentially pathognomonic of FH , since Achilles tendon xanthomas associated with tendinitis occur about 6 times more frequently among individuals with FH than among those in the general population . However, tendon xanthomas may present in familial dysbetalipoproteinaemia (type III) and states with no demonstrable lipoprotein abnormalities, such as monoclonal gammopathy or normolipidemic xanthomatosis, such as CTX and sitosterolemia . Planar xanthomas, diffuse or well circumscribed, encompass several types: intertriginous xanthomas, which are pathognomonic of homozygous FH, palmar crease xanthomas, which are pathognomonic of familial dysbetalipoproteinaemia (type III), planar xanthomas of cholestasis, diffuse plan xanthomas suggestive of dysglobulinemia or paraproteinemia, and xanthelasmas the most common and least specific of all xanthomas. Xanthomas can be occasionally seen in familial high-density-lipoprotein (HDL)-deficiency syndromes , such as apolipoprotein AI deficiency and lecithin cholesterol acyltransferase (LCAT) deficiency . The involvement of bone in xanthoma is uncommon .
Lipoprotein metabolism
Briefly (for review see reference ), CT and TGYs are transported in complexes called lipoproteins, which include specific apolipoproteins, the latter serving as ligands for binding to specific receptors. These proteins facilitate transmembrane transport and regulate enzymatic activity. Lipoproteins can be classified according to their density, as follows: chylomicrons (CMs), very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and HDLs. The first two categories are TGY-rich particles; the latter three are CT-rich particles. Lipoproteins can be separated by electrophoresis into beta (LDL), pre-beta (VLDL) and alpha (HDL) lipoproteins. Beta-VLDL (IDL) can be determined by ultracentrifugation and electrophoresis; the resultant phenotypes were groups categorised by Fredrickson into five major variants .
However, this classification does not include LDL-C and HDL-C whose abnormalities are of major importance in the assessment of CVD risk, and it cannot differentiate severe monogenic lipoprotein disorders from the more common polygenic disorders . Non-HDL-C can be calculated by subtracting HDL-C from total cholesterol (TC). Non-HDL-C produces a measure of all apolipoprotein B (apoB)-containing lipoproteins, including VLDL, IDL, LDL (including small, dense LDL) and lipoprotein (a) (Lp(a)), all of which having the capability to transport CT into the arterial wall. This measure is thought to indicate the atherogenic risk not captured by LDL-C measurement alone, particularly in the context of elevated TGYs in which there are elevated levels of VLDL and atherogenic VLDL remnants .
The liver and the intestine are the most important sources of lipoproteins. The metabolic pathways of lipoproteins can be divided into (1) exogenous lipoprotein pathway referring to the metabolism of intestinal lipoproteins, the TGY-rich CMs, primarily formed in response to dietary fat; (2) endogenous lipoprotein pathway referring to lipoproteins and apoproteins synthesised predominantly in the liver that secretes the TGY-rich VLDL, containing apoproteins B 100, C-II and E into the circulation .
Primary hypercholesterolemia (genetic causes of elevated LDL-C levels)
Monogenic hypercholesterolemia , such as autosomal-dominant hypercholesterolemia (ADHs) or autosomal recessive hypercholesterolemia (ARH), involves mutations that inhibit cellular CT uptake via the LDL receptor (LDLR) pathway; defective LDLRs are not able to remove CT-carrying LDLs from plasma, leading to an increase in plasma LDL . The mutant gene products of the main four monogenic diseases are shown in Fig 4 .
FH (OMIM#143890)
Most data derive from clinical guidance from the American National Lipid Association expert panel on FH .
Definition
FH is a group of inherited genetic defects leading to severe elevated LDL cholesterol (LDL-C) and TC. The focus in this review is on the autosomal dominant forms of severe hypercholesterolemia (ADH), due to defects in the genes for LDL receptor (LDLR) (ADH1), apolipoprotein (Apo) B ( ApoB ) (ADH2) and proprotein convertase subtilisin/kexin type 9 (PCSK9) (ADH3), leading to xanthomatosis and premature CHD with a predilection for the coronary ostia and valvular disease due to xanthoma-like lesions . According to the Fredrickson classification, FH patients are most often type IIa, sometimes types IIb and III . Increased levels of TC and LDL-C in children and adolescents persist in childhood, in contrast to hypercholesterolemia associated with polygenic disorders where CT levels vary with the exposure of patients to environment .
Prevalence
The prevalence of the major disorder underlying ADH, namely FH, has been estimated to be 1 in 300 to 500 (heterozygous form) in many populations . Homozygosity is rare, affecting 1 in 1 million of the general population, leading to greater elevations of LDL-C and earlier CHD onset than individuals who are heterozygotes . Higher prevalence is observed in the Afrikaner population in South Africa (introduction of at least three founder mutations by European settlers) and in the Quebec and Lebanese populations. In European countries, the distribution of mutations is variable, more heterogeneous in France and Italy . In France , the respective contribution of each known gene to ADH (French ADH Research Network, molecular data from 1003 probands from 11 regions) is: LDRL 73.9%, APOB 6.6%, PCSK9 0.9%, with no mutation found in 19% of the probands. In the Netherlands, 3000 cases have been characterised (77% carrying causative mutations) .
Genetics
The majority of FH cases is caused by mutations in the LDLR gene (chromosome 19p13), resulting in LDLR dysfunction (partial to complete) in clearing LDL-C from the circulation; CT synthesis is stimulated by the decrease in the hepatic CT pool; it results in the increased production of VLDL which further increases LDL levels. Over 1600 mutations have been described, mainly point mutations (91%), representing 85–90% of FH cases .
Similar phenotypes of ADH can be observed by deficiency in the apolipoprotein (Apo) B 100 due to mutations in the ApoB gene (Arg3500Gln) encoding the ligand for the LDLR protein (familial-defective Apo B: FDB or ADH2), leading to decreased clearance of circulating LDL , representing 5–10% of FH cases in Northern European populations or rare ‘gain-of-function’ mutation in PCSK9 that increases LDLR degradation and decreases clearance of plasma LDL (ADH3).
These mutations were studied in a cohort of 1430 children, aged 4–18 years, with ADH characterised by an LDL-C level 95th percentile for age and sex and an autosomal-dominant inheritance pattern of hypercholesterolemia, defined as at least one biological parent on treatment for hypercholesterolemia and a family history of hypercholesterolemia and CVD . Of the 269 children who remained after applying the exclusion criteria, 255 (95%) carried a functional mutation (LDLR 95%; ApoB 5%). No mutations in PCSK9 were detected. The authors concluded that a causative mutation can be identified in the vast majority of children with the ADH phenotype . This was not in line with the disappointing success rates of finding a pathogenic mutation in genetic screening (30–85%), linked to genetic heterogeneity or gene rearrangements .
Clinical and musculoskeletal features
Deposition or accumulation of CT in arterial walls and tissues results in the clinical features of FH: premature CHD, tendon xanthomas at any age (Achilles and finger extensor tendons palpable or observed), xanthelasma or tuberous xanthomas, corneal arcus (under age 45) and articular pain .
Age at the onset of CHD must be noted in the family history; the risk of premature CHD is being increased about 20-fold without treatment and usually heterozygotes are present in the third to fourth decades with premature CHD. CVD occurs before 50 and 60 years of age in respectively 50% of male and 30% of female heterozygous FH patients (LDL-C two- to threefold normal levels) ; there is a prevalence of CVD in middle-aged individuals with FH ranging from 22% to 39%, with a 24-fold increase in the risk of myocardial infarction by age of 40 . CVD occurs before 20 years of age in homozygous patients (LDL-C levels six- to10-fold normal levels). CVD is rare in children; endothelial dysfunction can be observed, as well as increased carotid intima-media thickness detected by ultrasonography .
Achilles tendon xanthomas are associated with a threefold greater risk of CVD but most FH patients do not have xanthomas, xanthelasma or corneal arcus . Tendinous and tuberous xanthomas, xanthelasma and corneal arcus are all commonly present in childhood in homozygous FH patients. Cutaneous xanthomas (often at the site of trauma and on the palms) involving the knees, elbows, hands and buttocks can be seen at birth or in the first years of life .
Corneal arcus is rare before 30 years of age (10% of heterozygotes) but frequent after age 30 (50% of heterozygotes), occurring before age 10 in homozygotes; it can be seen in subjects with normal lipid levels .
Even if the association of articular disease with FH has been considered as controversial , articular pain was reported in 40% of adult heterozygotes, Achilles pain or tendinitis in 29%, oligoarthritis in 7%, polyarticular or rheumatic fever-like arthritis in 4% . The most frequently involved joints are the knees, proximal interphalangeals, ankles, wrists, elbows, shoulders and hip joints . The typical attack is similar to acute gout or rheumatic fever but is not influenced by anti-inflammatory drugs, with (homozygotes) or without (heterozygotes) articular damage such as erosive arthropathy . Migratory polyarthritis was described in 10 young patients out of 18 homozygous FH (55%) . Elevated erythrocyte sedimentation rate is thought to be linked to increased serum LDL and does not normalise after an attack of polyarthritis . The pathogenesis of arthritis in FH remains unknown and there are no CT crystals in the synovial fluid from FH patients with arthritis .
Diagnosis
The majority of FH cases are either underdiagnosed or diagnosed only after the first coronary event . Physical signs are not sensitive but can be specific. Three validated tools are currently used for the clinical diagnosis of FH : the Simon Broome Register criteria (UK) ( Table 1 ), the Dutch Lipid Clinic Network Criteria (DLCNC) ( Table 2 ) and the Make Early Diagnosis, Prevent Early Deaths (MEDPED) Criteria (USA) ( Table 3 ).
| Simon Broome Criteria (UK) | ||
|---|---|---|
| Definite FH | ||
| Cholesterol concentrations as defined in table below and tendon xanthomas, or evidence of these signs in first- or second-degree relative or DNA-based evidence of an LDL-receptor mutation, familial defective apo B-100, or a PCSK9 mutation. | ||
| Total cholesterol | LDL-C | |
| Child/young person | >260 mg/dL | >155 mg/dL |
| >6.7 mmol/L | >4 mmol/L | |
| Adult | >290 mg/dL | >190 mg/dL |
| >7.5 mmol/L | >4.9 mmol/L | |
| Probable FH Tendon xanthomas in the patient or in a 1st or 2nd degree relative. | ||
| Possible FH (if patient has cholesterol concentrations as defined in table and at least one of the following). | ||
| -Family history of myocardial infarction: aged younger than 50 years in second-degree relative or aged younger than 60 years in first-degree relative. | ||
| -Family history of raised total cholesterol: greater than 290 mg/dL (7.5 mmol/l) in adult first- or second-degree relative or greater than 260 mg/dL (6.7 mmol/L) in child, brother or sister aged younger than 16 years. | ||
| Dutch criteria | |
|---|---|
| 1 point | 1st degree relative with premature cardiovascular disease or LDL-C >95th percentile, or personal history of premature peripheral or cerebrovascular disease, or L DL-C between 155 and 189 mg/dL |
| 2 points | 1st degree relative with tendinous xanthoma or corneal arcus, or1st degree relative child (<18 yrs) with LDL-C > 95th percentile, or personal history of coronary artery disease |
| 3 points | LDL-C between 190 and 249 mg/dL |
| 4 points | Presence of corneal arcus in patient less than 45 yrs old |
| 5 points | LDL-C between 250 and 329 mg/dL |
| 6 points | Presence of a tendon xanthoma |
| 8 points | LDL-C above 330 mg/dL, or functional mutation in the LDLR gene |
| MEDPED Criteria (USA) | ||||
|---|---|---|---|---|
| Age | Total Cholesterol (LDL-C) levels in mg/dL | |||
| 1st degree | 2nd degree | 3rd degree | General population | |
| <18 | 220 (155) | 230 (165) | 240 (170) | 270 (200) |
| 20–29 | 240 (170) | 250 (180) | 260 (185) | 290 (220) |
| 30–39 | 270 (190) | 280 (200) | 290 (210) | 340 (240) |
| > 40 | 290 (205) | 300 (215) | 310 (225) | 360 (260) |
Diagnosis of FH is based on LDL-C levels (cut points usually vary with age), presence of tendon xanthomata (not specific but suggestive in a young patient) and autosomal-dominant inheritance of premature CHD or hypercholesterolemia . Achilles thickness above 5.8 mm, measured by ultrasonography, was considered as the most useful threshold for diagnosis of FH, procuring sensitivity of 75% and specificity of 85% . Moreover, it has been shown that Achilles thickness was directly associated with carotid intima-media thickness independently of other risk factors. Thus, ultrasonography can help identify FH patients at higher CHD risk .
Genetic screening is not necessary for diagnosis and management of FH, particularly if the level of LDL-C is above the 95th percentile and if there is a family history of early CVD or xanthomas. Cascade screening (testing lipid levels in all first-degree relatives of diagnosed FH patients), as opposed to population screening, is currently considered the most cost-effective method for the detection of new FH cases . FH screening in children is controversial; however, it is important, in all children consulting a physician, to look for high cardiovascular risk (genetic, classic cardiovascular risk factors) . Women with FH should receive pre-pregnancy counselling and instructions to stop medications before contraception, during pregnancy and lactation.
Management
Adults
There are currently national and international guidelines for the treatment of FH patients, summarised by Robinson and Goldberg , deriving from the United States , the European Union the United Kingdom (NICE) and Canada .
Taking into account the very high risk of premature CHD and the lifetime risk of CHD, treatment must be early and lifelong. Treatment should be initiated for both children and adults if, after lifestyle changes, LDL cholesterol > 190 mg dl −1 (or non-HDL-C > 220 mg dl −1 ). International guidelines have proposed LDL-C and, in some cases, non-HDL-C or ApoB as targets for therapy .
High-potency statins (atorva-, rosuva-, pitava-, simva-statin) should be the first-line treatment for all adults (>20 years of age) with FH, to achieve an LDL-C reduction greater than 50%, supported by extensive clinical trial evidence . An individual-level meta-analysis of 26 randomised placebo-controlled trials of statin therapy (170 000 participants) , found that high-dose statins reduce cardiovascular risk more than moderate-dose statins regardless of LDL cholesterol levels. In FH, only observational studies have shown that statins modify the clinical course of the disease . However, no data on the long-term efficacy and safety of high-dose statins used in combination with other drugs are available. Statins may reduce slowly the size of tendon xanthomas and may decrease the frequency and severity of attacks of arthritis and tendinitis .
Ezetimibe (CT absorption inhibitor which lowers LDL-C and non-LDL-C by 15–20%, CVD events by 17–22%) when associated with simvastatin , niacin and bile acid sequestrants (colesevalam/colestipol, cholestyramine) are treatment options for intensified drug treatment in higher-risk patients to achieve LDL-C < 100 mg dl −1 (established CHD or atherosclerotic CVD, diabetes, family history of premature CHD (men < 45 years of age, women <55 years of age), currently smoking, two or more CHD risk factors, or high Lp(a) > 50 mg dl −1 ) .
Risk factors for CVD (the same in FH as in the general population) should be treated (advising physical activity, healthy diet, weight control, avoiding tobacco, limiting alcohol consumption and enforcing treatment of hypertension) . Lifestyle modifications should always be implemented, giving a HDL-C decrease of 10–15% .
Plasma exchange has been replaced by LDL apheresis which substantially lowers Lp (a) and is indicated in high-risk adult patients refractory or intolerant to drug therapy .
Children, adolescents and young adults (>20)
To identify children with FH, universal screening is recommended from age 9 to 11 years, earlier (>2 years of age) if there are major CHD risks factors (obesity, hypertension, diabetes) or a family history of HC or premature CHD. To rule out secondary forms of dyslipidemia (diabetes, hypothyroidism, nephrotic syndrome and liver disease), an evaluation of history, physical examination and selected laboratory tests must be carried out . FH must be suspected if untreated LDL-C > 160 mg dl −1 (4 mmol l −1 ) or non-HDL-C > 190 mg dl −1 . The cut-off level is 135 mg dl −1 in the Netherlands . The confirmation of FH in one parent is needed . CHD risk assessment includes measurement of Lp(a) levels and counseling for the prevention of cardiovascular risk development.
The therapeutic decision is based on the results from at least two fasting lipid profiles. A restricted fat and CT diet is mandatory, under the supervision of a dietician or nutritionist . Statins should be prescribed after lifestyle changes (prevention of CVD in long term) at the age of 8 years or older (earlier if homozygous FH) to obtain more than 50% reduction in LDL-C or LDL-C < 130 mg dl −1 . Safety and efficacy of statins for lowering LDL-C by 23–40% were demonstrated by several clinical trials in children and adolescents with FH and by a systematic review and meta-analyses of clinical trials and observational studies .
Intensified drug treatment has to be considered if the treatment goal is not reached or if there is the presence of additional CHD risk factors; bile acid sequestrants are able to bind bile salts in the intestinal lumen but are poorly tolerated; only colesevelam has a paediatric indication. Ezetimibe is not Food and Drug Administration (FDA) approved (reduces HDL-C by an additional 20% when added to statin) and there is no evidence regarding the benefit on cardiovascular outcomes. There is a limited experience with niacin or fibrates in children .
Homozygous FH is characterised by TC over 16 mmol and very high LDL-C (650–1000 mg dl −1 ), with normal TGY; xanthomas are the most common revealed features. Management is vital because FH homozygous patients develop premature CHD and early-onset CVD, needing cardiovascular investigation and follow-up, management by a lipid specialist. There are no accepted guidelines for follow-up (echocardiograms, stress echocardiography, assessment of coronary arteries) .
Treatment comprises high-dose statins, but often needs LDL apheresis to remove selectively Apo-B-containing particles from the circulation. However, no clinical trials have yet demonstrated the regression or the absence of progression of clinical parameters according to the levels of LDL-C. Liver transplantation has the advantage of providing functional LDLRs ; gene therapy is a potential new treatment.
ARH (OMIM#603813)
It is an inherited lipid metabolism disorder characterised in homozygous subjects by high levels of plasma LDL-C between 400 and 600 mg dl −1 , large tendon xanthomas present from early childhood and premature atherosclerosis (40%), due to mutations in a specific adaptor protein for the LDLR required in hepatocytes for the endocytosis of LDL particles via the LDLR . The clinical phenotype is similar to that observed in receptor defective homozygous FH . ARH is rare with the exception of the island of Sardinia (Italy) where 24 ARH families have been identified. ARH carrier status in heterozygous subjects does not influence LDL-C levels and the risk of CHD . Xanthomas can be tuberous, tendinous or planar, associated with corneal arcus and xanthelasmas; in some cases, joint pain can occur . CHD is reported in nearly half of the ARH patients, lesions of the aortic valve being rare or delayed in contrast to frequent carotid arteries lesions. ARH patients respond to statins, bile acid sequestrants or the combination of the two, with a significant reduction of serum CT .
Familial ligand-defective apoB-100 (FDB or ADH2) (OMIM#107730)
FH and familial-defective apoB 100 (FDB) are characterised by increased plasma total and LDL-C levels, and risk of CHD. FDB is clinically indistinguishable from FH. The clinical phenotype is similar (but rather milder) to that observed in FH and is seen in subjects with a mutation in the gene for apoB, the ligand for the LDLR . Thus, FDB homozygotes have lower TC and LDL-C levels (elevated clearance of LDL precursors and reduced LDL production) than values observed in FH, and later onset and less severe CHD than FH homozygous .
Sitosterolemia (OMIM#210250)
Sitosterolemia is a very rare autosomal recessive inherited disorder characterised by markedly elevated plasma sterol concentrations, leading to xanthomatosis in children and premature CAD in young adults.
Metabolic pathway
Sitosterolemia is characterised by increased absorption and decreased biliary excretion of plant sterols (such as sitosterol, sitostanol, campesterol and stigmasterol) and LDL-C in the most paediatric patients .
Genetics
The genetic defect was mapped to chromosome 2p21 , involving mutations in two genes, the adenosine triphosphate-binding cassette (ABC) transporters ABCG5 and ABCG8 expressed at the apical membranes of intestinal mucosal cells and the bile canalicular membrane of hepatocytes, and regulating the outbound excretion of sterols . About 410 different ABCG5/8 mutations have been described in 65 sitosterolemia families .
Clinical features
Sitosterolemia is characterised by xanthomas, arthritis and premature vascular disease.
Xanthomas present in childhood or early adult life with tendon and subcutaneous xanthomas due to accumulation of plant sterols within the tissues. Tendinous xanthomas, over the patellar, plantar, Achilles and extensor tendons of the hand, are present in all cases and appear in childhood ; less commonly, tuberous xanthomas at the elbows and knees, and xanthelasma may be present.
Recurrent arthralgias or arthritis of the knee and ankle joints can occur, ascribed to sitosterol deposits .
Sitosterolemia can be associated with haemolysis due to increased osmotic fragility of erythrocytes , enlarged spleen and macrothrombocythemia (large platelets) and liver disease .
Premature CHD has been reported in some patients , as early as 5 years and mild elevations of plant sterols may increase the risk of CVD as the hyperabsorption of CT in young patients . Thus, early treatment is essential to prevent CVD.
Diagnosis
Elevated plant sterols, particularly sitosterol, are the biochemical hallmark of sitosterolemia, but routine colorimetric and enzymatic methods cannot distinguish plant sterols from CT and need to use high-performance liquid or gas chromatography . Elevated CT levels are frequently associated with children.
Management
Classic treatments for sitosterolemia encompass a low plant sterol diet (avoiding vegetable oils, margarine, nuts, avocados, chocolate and shellfish), cholestyramine (12 g day −1 ) and partial ileal bypass surgery which decreases plasma plant sterol concentrations by about 50%. Thus, these treatments have shown only partial efficacy and compliance to diet and cholestyramine therapy is poor . Ezetimibe, an inhibitor of intestinal CT and plant sterol absorption through its binding to Niemann-Pick C1-like 1 transporter (NPC1L1) , localised to the brush border of enterocytes and the apical membranes of hepatocytes, has been shown to effectively reduce plasma plant sterols in patients with and without sitosterolemia . A recent clinical trial , set up in adolescents and adults, has demonstrated that treatment with ezetimibe 10 mg ( n = 30) versus placebo ( n = 7), for up to 2 years, led to further improvements in lipid- and sterol-related parameters (compared to baseline: –43.9% for plasma sitosterol, –50.8% for campesterol) in patients with homozygous sitosterolemia, with an overall favourable safety profile. It has also been shown that ezetimibe 40 mg day −1 for 26 weeks was no more effective than 10 mg day −1 in reducing plasma plant sterol levels in 27 adult patients with sitosterolemia . In children, the efficacy of ezetimibe is more satisfactory on CT levels than on plant sterol levels . Ezetimibe has become the first-line treatment for patients with sitosterolemia.
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