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{| class="wikitable"
! colspan="3" |Laboratory Findings
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Sandbox
{| class="wikitable"
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! Prince || Tarek || Aysha
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| Hello || Hi || Goodbye
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<span lang="en" dir="ltr">prognosis.22982649
The probability of MPE was higher in patients with larger tumors, mediastinal fadsafadsf lymph node involvement, and adenocarcinoma, NSCLC not otherwise specified, or large-cell histology. In patients with stage M1b, median overall survival (3 months versus 5 months), estimated 1-year survival (12.6% versus 24.8%), and 2-year survival (5.4% versus 11.3%) were significantly lower in patients with MPE compared with those without MPE</span>
# jdfajdslf;ads
# ajfl;sdjfas
# sdfjad;sflkads
# 
One hundred ninety cases of PPE were diagnosed. The annual incidence of PPE in the population under 18 years of age increased from 19.9 cases per 100,000 in 2004 to 35.2 per 100,000 in 2006. S. pneumoniae was the main causal agent identified: 82.9% of the 21.6% patients with positive culture. Non-vaccine serotypes (NVS) predominated (81.5%), and serotype 1 was responsible for 38.5% of cases. The use of polymerase chain reaction (PCR) test to detect S. pneumoniae increased etiological diagnosis from 21.6% to 42.1%. Antigen assays used to detect pneumococcus in pleural fluid demonstrated 87.9% sensitivity and 100% specificity when PCR was used as the gold standard. There has been an increase in the incidence of PPE that parallels the increase in CAP. S. pneumoniae remains the principal causal agent, and NVS clearly predominate. The use of PCR to detect S. pneumoniae substantially increases etiologic diagnosis. The use of antigen assays to detect pneumococcus in pleural fluid is a quick and sensitive diagnostic method, and thus a valid alternative to PCR. 19911359
The during 7 years 258 patients with malignant effusion (ME) of different ethiology were treated in clinic, that composed 13.8% among all patients with pleural effusion. It was discovered the increase of this complication frequence in 1.6 time. The main reasons of ME were lung cancer--in 42.6% of observations, pleural mezothelioma--in 19.3%, mammary glands cancer--in 6.9%, real reason of ME was not found in 13.9%. Aged patients (oldest 60 years) are risk group for discovering of ME, for pleural mezothelioma the next ages are risk 30-40 and oldest 60 years.15560580
Studies with data on incidence and serotypes were included; reviews, case reports, and conference abstracts were excluded. Of 152 papers, 84 fitted the inclusion criteria. A few pneumococcal serotypes were predominant causes of CPP, particularly serotypes 1, 19A, 3, 14, and 7F. CPP was a more common manifestation of pneumococcal disease among older (>2 years old) than younger children. The data support increases in both reported incidence rates and proportions of CPP in children and adults during the period 1990-2012; specific increases varied by geographic region. The proportions of serotype 3 and, particularly in Asia, serotype 19A CPP have increased, whereas most studies show declines in serotype 14. Serotype 1 has been a predominant cause of CPP since 1990, while antibiotic resistance was infrequent among serotype 1 isolates. The reported incidence and proportions of CPP among pneumonia cases steadily increased from 1990 to 2012. Several factors might account for these increases, including enhanced disease detection due to a higher index of suspicion, more sophisticated diagnostic assays, and changes in the prevalence of serotypes with capacity to invade the pleural space that were not targeted by the 7-valent pneumococcal conjugate vaccine (PCV7).  24563274
txt
whereas 37 +/- 27% considered that exploratory thoracentesis was likely to determine the cause of the effusion, and 17.36 +/- 16% considered that its results were likely to result in a change in their therapeutic attitude.11689765
The common clinical features include chest pain, pleural effusion, and radiologic findings of irregular pleural thickening or pleural densities. Therapeutic modalities used in the past have included surgery, radiation therapy, and, more recently, chemotherapy. A combined modality approach to treatment appears more promising.
PMID: 921093
Only complicated parapneumonic effusions need to be drained. Therapeutic evacuation modalities include repeated therapeutic thoracentesis, chest tube drainage or thoracic surgery. The choice of the first-line evacuation treatment is still controversial and there are few prospective controlled studies. The effectiveness of fibrinolytic agents is not established except when they are combined with DNase. Antibiotics are mandatory; they should be initiated as quickly as possible and should be active against anaerobic bacteria except for in the context of pneumococcal infections. There are few data on the use of chest physiotherapy, which remains widely used. Mortality is still high and is influenced by underlying comorbidities.25595878
dx
COMPLES was based on the combination of pleural fluid adenosine deaminase (ADA), the percentage of mononuclear cells (MNC %), pH, and age. The cutoff values and assigned scores were: ADA (<46 IU/L [0 points], 46-100 IU/L [4 points], ≥100 IU/L [6 points]), MNC % (<10 % [0 points], 10-50 [3 points], >50 [8 points]), pH (<7.07 [0 points], 7.07-7.20 [3 points], >7.20 [5 points]), and age (≥30 [0 points], <30 years [3 points]). A sum of 12 or more points had 97 % sensitivity, 92 % specificity, likelihood ratio positive 12.3, likelihood ratio negative 0.03, and area under the curve of 0.947 for identifying CTPE versus CPPE in the validation set.27401009
The diagnosis of PE in children is based on chest radiographs, thoracentesis and pleural fluid analysis 12457598
more often on the right side, and the tuberculin test is negative in one third of cases.24721286
The combination of adenosine deaminase 27135844 and lymphocyte percentage may be useful in this respect. Treatment is the same as for any TB. The addition of corticosteroids is not advisable, and chest drainage could help to improve symptoms more rapidly in large effusions.24721286
1<ref name="history">{{cite book |last=Howe |first=BE Jr. |date=1988 |title=Emergency War Surgery, Second United States Revision of the Emergency War Surgery NATO |publisher=U. S. Government Printing Office |isbn= 9780160014932}}</ref>




Line 142: Line 52:
==References==
==References==
{{reflist|2}}
{{reflist|2}}
__NOTOC__
{{SI}}
{{CMG}}; {{AE}} {{PTD}}
{{SK}} FHC; FH; type IIA hyperlipoproteinemia; hyper-low-density-lipoproteinemia; familial hypercholesterolemic xanthomatosis; LDL receptor disorder
==Overview==
'''Familial hypercholesterolemia''' (also spelled '''familial hypercholesterolaemia''') is a rare [[genetic disorder]] characterized by very high [[LDL]] cholesterol and early [[cardiovascular disease]] running in families.
==Classification==
Familial hypercholesterolemia may be classified according to the severity of the mutation involving the [[LDL-cholesterol]] (LDL-C) receptor or depending on the [[inheritance|mode of inheritance]] as follows:
*'''Heterozygous''' vs '''homozygous'''<ref name="pmid7584986">{{cite journal| author=Grossman M, Rader DJ, Muller DW, Kolansky DM, Kozarsky K, Clark BJ et al.| title=A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia. | journal=Nat Med | year= 1995 | volume= 1 | issue= 11 | pages= 1148-54 | pmid=7584986 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7584986  }} </ref><ref name="pmid15321837">{{cite journal| author=Austin MA, Hutter CM, Zimmern RL, Humphries SE| title=Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. | journal=Am J Epidemiol | year= 2004 | volume= 160 | issue= 5 | pages= 407-20 | pmid=15321837 | doi=10.1093/aje/kwh236 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15321837  }} </ref>
**This is particularly important because, phenotypically, familial hypercholesterolemia (FH) is characterized by increased [[plasma]] levels of [[total cholesterol]] and [[low-density lipoprotein cholesterol]], tendinous [[xanthomata]], and premature symptoms of [[coronary heart disease]]. These are more pronounced in homozygous than heterozygous individuals.
*'''Polygenic''' vs '''monogenic'''
**Polygenic hypercholesterolemia is a major source of atherosclerotic [[cardiovascular disease]]. [[Xanthelasma]], premature [[CHD]], tendon [[xanthomata]], and [[obesity|childhood obesity]] are common in monogenic hypercholesterolemia. Tendon [[xanthomata]] and [[obesity|childhood obesity]] are not observed in polygenic hypercholesterolemia.
==Pathophysiology==
Both forms of FH are caused by the same problem: a mutation in either the [[LDL]] receptor or the [[ApoB]] protein. There is one known ApoB defect (R3500Q) and a multitude of [[LDL receptor]] defects, the frequency of which is different for each population. The [[LDL receptor]] [[gene]] is located on the short arm of [[chromosome]] 19 (19p13.1-13.3). It comprises 18 [[exons]] and spans 45kb, and the gene product contains 839 [[amino acids]] in mature form.
Familial disorders of cholesterol metabolism may result from one of the following:
*Overproduction of lipoproteins
*Impaired removal of lipoproteins (this may result from primary defect with the lipoprotein or its receptor).
[[Low density lipoprotein|LDL]] cholesterol normally circulates in the body for 2.5 days, after which it is cleared by the [[liver]]. In FH, the half-life of an LDL particle is almost doubled to ''4.5 days''. This leads to markedly elevated LDL levels, with the other forms of cholesterol remaining normal, most notably [[High density lipoprotein|HDL]].  Goldstein and Brown (1974) showed that the classic form of familial hypercholesterolemia results from defects in the cell surface receptor that normally removes LDL particles from the blood plasma.
The excess circulating LDL is taken up by cells all over the body but most notably by [[macrophages]] and especially the ones in a primary streak (the earliest stage of [[atherosclerosis]]). [[Oxidation]] of LDL increases its uptake by [[foam cells]].
Although atherosclerosis can occur in all people, many FH patients develop accelerated atherosclerosis due to the excess LDL. Some studies of FH cohorts suggest that additional risk factors are generally at play when an FH patient develops atherosclerosis.<ref>Scientific Steering Committee on behalf of the Simon Broome Register Group (Ratcliffe Infirmary, Oxford, England), "Risk of fatal coronary heart disease in familial hypercholesterolaemia", ''British Medical Journal'' 303 (1991), pp. 893-896.</ref><ref>E.J.G. Sijbrands, et al., "Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study", ''British Medical Journal'' 322 (2001), pp. 1019-1023.</ref>
The degree of atherosclerosis roughly depends of the ''amount'' of LDL receptors still expressed by the cells in the body and the ''functionality'' of these receptors. In the hetrozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In more serious forms, the homozygouse form, the "broken" receptor is not expressed at all.
In ''heterozygous'' FH, only one of the two [[DNA]] copies ([[allele]]s) is damaged, and there will be at least 50% of the normal LDL receptor activity (the "healthy" copy and whatever the "broken" copy can still contribute).
In ''homozygous'' FH, however, both alleles are damaged in some degree, which can lead to extremely high levels of LDL, and to children with extremely premature heart disease. A further complication is the lack of effect of [[statin]]s (see below).
==Epidemiology==
===Prevalence===
*The prevalence of FH is 1 in 300 to 500 in many populations, making FH among the most common of serious genetic disorders
===Ethnicity===
*In a few populations (such as French Canadians and Dutch Afrikaners), the prevalence of FH may be as high as 1 in 100
===United States===
*There are approximately 620,000 FH patients currently living in the United States
==Screening==
Universal screening for elevated serum cholesterol is recommended.<ref name=FH-Screening>Journal of Clinical Lipidology. Clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial Hypercholesterolemia: Screening, diagnosis and management of pediatric and adult patients. (2011) https://www.lipid.org/sites/default/files/articles/familial_hypercholesterolemia_1.pdf Accessed on October 27 2016</ref>
===General population screening===
Familial hypercholesterolemia (FH) should be suspected when untreated fasting LDL cholesterol or non HDL cholesterol levels are at or above the following:
*Adults (≥ 20 years):
**LDL cholesterol ≥ 190 mg/dL or non-HDL cholesterol ≥ 220 mg/dL
*Children, adolescents and young adults (< 20 years):
**LDL cholesterol ≥160 mg/dL or non- HDL cholesterol ≥ 190 mg/dL
Cholesterol screening should be considered beginning at age 2 for children with a family history of premature cardiovascular disease or elevated cholesterol. All individuals should be screened by age 20.
Although not present in many individuals with familial hypercholesterolemia (FH), the following physical findings should prompt the clinician to strongly suspect FH and obtain necessary lipid measurements if not already available:
*Tendon xanthomas at any age (most common in Achilles tendon and finger extensor tendons, but can also occur in patellar and triceps tendons). B Arcus corneae in a patient under age 45)
*Tuberous xanthomas or xanthelasma in a patient under age 20 to 25
At the LDL cholesterol levels listed below the probability of FH is approximately 80% in the setting of general population screening.
*These LDL cholesterol levels should prompt the clinician to strongly consider a diagnosis of FH and obtain further family information:
**LDL cholesterol ≥ 250 mg/dL in a patient aged 30 or more
**LDL cholesterol ≥ 220 mg/dL for patients aged 20 to 29
**LDL cholesterol ≥ 190 mg/dL in patients under age 20
===Screening in children===
Lipid screening recommnedations for familial hypercholesterolemia in children are varies by age and their risk factors.<ref name="pmid22084329">{{cite journal| author=Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. National Heart, Lung, and Blood Institute| title=Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. | journal=Pediatrics | year= 2011 | volume= 128 Suppl 5 | issue=  | pages= S213-56 | pmid=22084329 | doi=10.1542/peds.2009-2107C | pmc=4536582 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22084329  }} </ref><ref name="pmid25845026">{{cite journal| author=Gooding HC, Rodday AM, Wong JB, Gillman MW, Lloyd-Jones DM, Leslie LK et al.| title=Application of Pediatric and Adult Guidelines for Treatment of Lipid Levels Among US Adolescents Transitioning to Young Adulthood. | journal=JAMA Pediatr | year= 2015 | volume= 169 | issue= 6 | pages= 569-74 | pmid=25845026 | doi=10.1001/jamapediatrics.2015.0168 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25845026  }} </ref>
====Child-parent familial hypercholesterolemia screening in primary care====
*Recent study shows the feasibility and efficacy of child-parent familial hypercholesterolemia screening in primary care setting.
*The conclusion remains that child–parent familial hypercholesterolemia screening is a simple, practical, and effective way of screening the population to identify and prevent a common inherited cause of premature cardiovascular disease.<ref name="pmid27783906">{{cite journal| author=Wald DS, Bestwick JP, Morris JK, Whyte K, Jenkins L, Wald NJ| title=Child-Parent Familial Hypercholesterolemia Screening in Primary Care. | journal=N Engl J Med | year= 2016 | volume= 375 | issue= 17 | pages= 1628-1637 | pmid=27783906 | doi=10.1056/NEJMoa1602777 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27783906  }} </ref>
==Prognosis==
*Approximately 1 in one million persons is [[homozygous]] (or compound heterozygous) for LDLR mutations and has extreme hypercholesterolemia with rapidly accelerated atherosclerosis when left untreated.
==Diagnosis==
== Signs and symptoms ==
*Elevated serum [[cholesterol]], most notably the [[LDL]] fraction ([[VLDL]] and [[triglyceride]]s are typically normal)
** on lipoprotein [[electrophoresis]] (rarely done), a [[hyperlipoproteinemia type II]] pattern is recognised
*Premature [[cardiovascular disease]], such as:
**[[Angina pectoris]], leading to [[PTCA]] or [[CABG]]
**[[Myocardial infarction]]
**[[Transient ischemic attack]]s (TIA's)
**[[Cerebrovascular accident]]s/[[Stroke]]s
**[[Peripheral artery disease]] (PAOD)
*A ''[[family history]]'' of premature [[atherosclerosis]]
===Physical Examination===
The following signs are not always present:
====Eyes====
*[[Xanthelasma|Xanthelasma palpabrum]] (yellowish patches above the eyelids)
*[[Arcus senilis]] corneae, whitish discoloration of the iris
====Extremities====
*Tendon [[xanthoma]]s (thickening of [[tendon]]s due to accumulation of [[macrophage]]s filled with [[cholesterol]]).
===Laboratory Studies===
LDL-receptor gene defects can be identified with genetic testing. Testing is generally undertaken when:
* A family member has been shown to have a mutation;
* High cholesterol is found in a young patient with [[atherosclerosis|atherosclerotic]] disease;
* [[Tendon xanthomas]] are found in a patient with high cholesterol.
==Treatment==
=== Heterozygous FH ===
Heterozygous FH can be treated effectively with [[statins]]. These are drugs that inhibit the body's ability to produce [[cholesterol]] by blocking the enzyme [[HMG-CoA reductase|hydroxymethylglutaryl CoA reductase]] (HMG-CoA-reductase). Maximum doses are often necessary. Statins work by forcing the liver to produce more LDL receptor to maintain the amount of cholesterol in the cell. This requires at least one functioning copy of the gene (see below).
In case statins are not effective, either a drug from the [[fibrate]] or [[bile acid sequestrant]] class can be added, as well as [[niacin]]/[[acipimox]]. As the combination of fibrates and statins is associated with a markedly increased risk of [[myopathy]] and [[rhabdomyolysis]] (breakdown of muscle tissue, leading to [[acute renal failure]]), these patients are monitored closely.
=== Homozygous FH ===
Homozygous FH is a different story. As previously mentioned, the LDL levels are much higher and the most effective treatments (statins) require at least one copy of the functional LDL receptor gene. In this case, high amounts of bile acid sequestrants are often given; occasionally high-dosed statins can help express a dysfunctional (but some times working) LDL receptor. Other treatments used are [[LDL apheresis]] (clearing LDL by blood filtration, similar to [[dialysis]]) and - as a last resort - a [[liver transplant]]. The last option will introduce liver cells with working LDL receptors, effectively curing the condition.
==History==
The Norwegian physician Dr C Müller first associated the physical signs, high cholesterol levels and autosomal dominant inheritance in 1938. In the early 1970s and 1980s, the genetic cause for FH was described by Dr [[Joseph L. Goldstein]] and Dr Michael S. Brown of Dallas, Texas [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=4355366].
==References==
{{Reflist|2}}
==External links==
*[http://www.medped.org MEDPED] (Make Early Diagnosis to Prevent Early Deaths)
*[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=144010 NCBI] (Familial Hypercholesterolemia Page at National Center for Biotechnology Information)
*[http://www.heartuk.org.uk/index.html H·E·A·R·T UK] (H·E·A·R·T UK, Familial Hypercholesterolemia charity based in the United Kingdom)
{{Endocrine, nutritional and metabolic pathology}}
[[Category:Cardiology]]
[[Category:Inborn errors of metabolism]]
[[Category:Lipid disorders]]
[[Category:Lipopedia]]
{{Lipopedia}}
{{WikiDoc Help Menu}}
{{WikiDoc Sources}}

Revision as of 16:20, 4 November 2016


Historical Perspective


Classification

Pathophysiology

Causes

Differentiating Familial hypercholesterolemia from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

Chest X Ray

CT

MRI

Echocardiography or Ultrasound

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Prevention

References



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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2]

Synonyms and keywords: FHC; FH; type IIA hyperlipoproteinemia; hyper-low-density-lipoproteinemia; familial hypercholesterolemic xanthomatosis; LDL receptor disorder

Overview

Familial hypercholesterolemia (also spelled familial hypercholesterolaemia) is a rare genetic disorder characterized by very high LDL cholesterol and early cardiovascular disease running in families.

Classification

Familial hypercholesterolemia may be classified according to the severity of the mutation involving the LDL-cholesterol (LDL-C) receptor or depending on the mode of inheritance as follows:

Pathophysiology

Both forms of FH are caused by the same problem: a mutation in either the LDL receptor or the ApoB protein. There is one known ApoB defect (R3500Q) and a multitude of LDL receptor defects, the frequency of which is different for each population. The LDL receptor gene is located on the short arm of chromosome 19 (19p13.1-13.3). It comprises 18 exons and spans 45kb, and the gene product contains 839 amino acids in mature form.

Familial disorders of cholesterol metabolism may result from one of the following:

  • Overproduction of lipoproteins
  • Impaired removal of lipoproteins (this may result from primary defect with the lipoprotein or its receptor).

LDL cholesterol normally circulates in the body for 2.5 days, after which it is cleared by the liver. In FH, the half-life of an LDL particle is almost doubled to 4.5 days. This leads to markedly elevated LDL levels, with the other forms of cholesterol remaining normal, most notably HDL. Goldstein and Brown (1974) showed that the classic form of familial hypercholesterolemia results from defects in the cell surface receptor that normally removes LDL particles from the blood plasma.

The excess circulating LDL is taken up by cells all over the body but most notably by macrophages and especially the ones in a primary streak (the earliest stage of atherosclerosis). Oxidation of LDL increases its uptake by foam cells.

Although atherosclerosis can occur in all people, many FH patients develop accelerated atherosclerosis due to the excess LDL. Some studies of FH cohorts suggest that additional risk factors are generally at play when an FH patient develops atherosclerosis.[3][4]

The degree of atherosclerosis roughly depends of the amount of LDL receptors still expressed by the cells in the body and the functionality of these receptors. In the hetrozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In more serious forms, the homozygouse form, the "broken" receptor is not expressed at all.

In heterozygous FH, only one of the two DNA copies (alleles) is damaged, and there will be at least 50% of the normal LDL receptor activity (the "healthy" copy and whatever the "broken" copy can still contribute).

In homozygous FH, however, both alleles are damaged in some degree, which can lead to extremely high levels of LDL, and to children with extremely premature heart disease. A further complication is the lack of effect of statins (see below).

Epidemiology

Prevalence

  • The prevalence of FH is 1 in 300 to 500 in many populations, making FH among the most common of serious genetic disorders

Ethnicity

  • In a few populations (such as French Canadians and Dutch Afrikaners), the prevalence of FH may be as high as 1 in 100

United States

  • There are approximately 620,000 FH patients currently living in the United States

Screening

Universal screening for elevated serum cholesterol is recommended.[5]

General population screening

Familial hypercholesterolemia (FH) should be suspected when untreated fasting LDL cholesterol or non HDL cholesterol levels are at or above the following:

  • Adults (≥ 20 years):
    • LDL cholesterol ≥ 190 mg/dL or non-HDL cholesterol ≥ 220 mg/dL
  • Children, adolescents and young adults (< 20 years):
    • LDL cholesterol ≥160 mg/dL or non- HDL cholesterol ≥ 190 mg/dL

Cholesterol screening should be considered beginning at age 2 for children with a family history of premature cardiovascular disease or elevated cholesterol. All individuals should be screened by age 20.

Although not present in many individuals with familial hypercholesterolemia (FH), the following physical findings should prompt the clinician to strongly suspect FH and obtain necessary lipid measurements if not already available:

  • Tendon xanthomas at any age (most common in Achilles tendon and finger extensor tendons, but can also occur in patellar and triceps tendons). B Arcus corneae in a patient under age 45)
  • Tuberous xanthomas or xanthelasma in a patient under age 20 to 25

At the LDL cholesterol levels listed below the probability of FH is approximately 80% in the setting of general population screening.

  • These LDL cholesterol levels should prompt the clinician to strongly consider a diagnosis of FH and obtain further family information:
    • LDL cholesterol ≥ 250 mg/dL in a patient aged 30 or more
    • LDL cholesterol ≥ 220 mg/dL for patients aged 20 to 29
    • LDL cholesterol ≥ 190 mg/dL in patients under age 20

Screening in children

Lipid screening recommnedations for familial hypercholesterolemia in children are varies by age and their risk factors.[6][7]

Child-parent familial hypercholesterolemia screening in primary care

  • Recent study shows the feasibility and efficacy of child-parent familial hypercholesterolemia screening in primary care setting.
  • The conclusion remains that child–parent familial hypercholesterolemia screening is a simple, practical, and effective way of screening the population to identify and prevent a common inherited cause of premature cardiovascular disease.[8]

Prognosis

  • Approximately 1 in one million persons is homozygous (or compound heterozygous) for LDLR mutations and has extreme hypercholesterolemia with rapidly accelerated atherosclerosis when left untreated.

Diagnosis

Signs and symptoms

Physical Examination

The following signs are not always present:

Eyes

Extremities

Laboratory Studies

LDL-receptor gene defects can be identified with genetic testing. Testing is generally undertaken when:

  • A family member has been shown to have a mutation;
  • High cholesterol is found in a young patient with atherosclerotic disease;
  • Tendon xanthomas are found in a patient with high cholesterol.

Treatment

Heterozygous FH

Heterozygous FH can be treated effectively with statins. These are drugs that inhibit the body's ability to produce cholesterol by blocking the enzyme hydroxymethylglutaryl CoA reductase (HMG-CoA-reductase). Maximum doses are often necessary. Statins work by forcing the liver to produce more LDL receptor to maintain the amount of cholesterol in the cell. This requires at least one functioning copy of the gene (see below).

In case statins are not effective, either a drug from the fibrate or bile acid sequestrant class can be added, as well as niacin/acipimox. As the combination of fibrates and statins is associated with a markedly increased risk of myopathy and rhabdomyolysis (breakdown of muscle tissue, leading to acute renal failure), these patients are monitored closely.

Homozygous FH

Homozygous FH is a different story. As previously mentioned, the LDL levels are much higher and the most effective treatments (statins) require at least one copy of the functional LDL receptor gene. In this case, high amounts of bile acid sequestrants are often given; occasionally high-dosed statins can help express a dysfunctional (but some times working) LDL receptor. Other treatments used are LDL apheresis (clearing LDL by blood filtration, similar to dialysis) and - as a last resort - a liver transplant. The last option will introduce liver cells with working LDL receptors, effectively curing the condition.

History

The Norwegian physician Dr C Müller first associated the physical signs, high cholesterol levels and autosomal dominant inheritance in 1938. In the early 1970s and 1980s, the genetic cause for FH was described by Dr Joseph L. Goldstein and Dr Michael S. Brown of Dallas, Texas [3].

References

  1. ↑ Grossman M, Rader DJ, Muller DW, Kolansky DM, Kozarsky K, Clark BJ; et al. (1995). "A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia". Nat Med. 1 (11): 1148–54. PMID 7584986.
  2. ↑ Austin MA, Hutter CM, Zimmern RL, Humphries SE (2004). "Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review". Am J Epidemiol. 160 (5): 407–20. doi:10.1093/aje/kwh236. PMID 15321837.
  3. ↑ Scientific Steering Committee on behalf of the Simon Broome Register Group (Ratcliffe Infirmary, Oxford, England), "Risk of fatal coronary heart disease in familial hypercholesterolaemia", British Medical Journal 303 (1991), pp. 893-896.
  4. ↑ E.J.G. Sijbrands, et al., "Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study", British Medical Journal 322 (2001), pp. 1019-1023.
  5. ↑ Journal of Clinical Lipidology. Clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial Hypercholesterolemia: Screening, diagnosis and management of pediatric and adult patients. (2011) https://www.lipid.org/sites/default/files/articles/familial_hypercholesterolemia_1.pdf Accessed on October 27 2016
  6. ↑ Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. National Heart, Lung, and Blood Institute (2011). "Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report". Pediatrics. 128 Suppl 5: S213–56. doi:10.1542/peds.2009-2107C. PMC 4536582. PMID 22084329.
  7. ↑ Gooding HC, Rodday AM, Wong JB, Gillman MW, Lloyd-Jones DM, Leslie LK; et al. (2015). "Application of Pediatric and Adult Guidelines for Treatment of Lipid Levels Among US Adolescents Transitioning to Young Adulthood". JAMA Pediatr. 169 (6): 569–74. doi:10.1001/jamapediatrics.2015.0168. PMID 25845026.
  8. ↑ Wald DS, Bestwick JP, Morris JK, Whyte K, Jenkins L, Wald NJ (2016). "Child-Parent Familial Hypercholesterolemia Screening in Primary Care". N Engl J Med. 375 (17): 1628–1637. doi:10.1056/NEJMoa1602777. PMID 27783906.

External links

  • MEDPED (Make Early Diagnosis to Prevent Early Deaths)
  • NCBI (Familial Hypercholesterolemia Page at National Center for Biotechnology Information)
  • H·E·A·R·T UK (H·E·A·R·T UK, Familial Hypercholesterolemia charity based in the United Kingdom)

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