Hyperlipoproteinemia type 5
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Synonyms and keywords: : Hyperchylomicronemia, Late-Onset, Hyperchylomicronemia With Hyperprebetalipoproteinemia, Familial mixed hyperlipidemia, Type V hyperlipemia, Hyperlipidemia type V, Type 5 hyperlipoproteinemia, Type 5 hyperlipemia, Type 5 HLP, Type V HLP, Combined fat and carbohydrate Induced hyperlipidemia, Mixed hypertriglyceridemia, Endogenous hypertriglyceridemia.

# Overview
Type 5 Hyperlipoproteinemia (HLP V) is a rare disorder of lipo-protein metabolism characterized by fasting chylomicronemia and elevated levels of cholesterol in the very low density (VLDL) lipoprotein fraction. The triglyceride(TG) levels are invariably greater than 1000mg/dl thereby increasing the risk of pancreatitis.It has been postulated that HLP V is the result of a defective clearance of TG-rich lipoproteins(VLDLs and Chylomicrons),although lipoprotein lipase is not completely absent. Another suggested mechanism is of VLDL TG's overproduction. Some patients seem to have "Primary" HLP V which usually appears first in adulthood,this phenotype is often associated with secondary factors,almost always Diabetes Mellitus.May be associated with Eruptive Xanthomas and Hyperuricemia. The primary goal of therapy is to reduce the TG level to <500mg/dl for the intent of reducing the risk of pancreatitis.

# Historical Perspective
- In 1967, Dr. Fredrickson applying electrophoresis methods to the separation of lipoproteins developed a classification of lipoprotein disorders.

# Classification

# Pathophysiology  
The two main sources of plasma triglycerides (also known as triacylglycerol) are exogenous (i.e., from dietary fat) and carried in chylomicrons, and endogenous (from the liver) and carried in very-low-density lipoprotein (VLDL) particles. In capillaries within fat and muscle tissue, these lipoproteins and chylomicrons are hydrolyzed by lipoprotein lipase into free fatty acids. After a meal, over 90% of the circulating triglycerides originate in the intestine and are secreted in chylomicrons, whereas during periods of fasting, endogenous triglycerides secreted by the liver as VLDL predominate. The increase in plasma of triglyceride-rich lipoproteins results from increased production from the liver and intestine (by means of upregulated synthetic and secretory pathways) or through decreased peripheral catabolism (mainly from reduced lipoprotein lipase activity).

## Pathogenesis  
The pathogenesis of type V is not fully understood.It was proposed to be as a result of "TWO HITS".FIRST HIT = Genetic Predisposition, SECOND HIT = Exacerbation by secondary factors that worsens lipid levels,often resulting in profound Hyperlipidemia.Although initially described in patients hospitalized because of Alcoholism,uncontrolled diabetes, nephrosis,hypothyroid,dysglobulinemia. The plasma lipoprotein pattern returns to normal if underlying disorder is successfully treated.In some cases however,no underlying cause is found and the subject is considered to have a "PRIMARY" abnormality of LP metabolism.However; VLDL appears to be the most affected lipoprotein fraction in type V and there is three-fold increase in synthesis rate as well as decreased fractional catabolism of VLDL..Molecular basis for Type V HLP is not clearly understood. In patients with type V HLP, the presence of underlying diseases or contributing factors such as Diabetes and alcohol abuse occurs in ~67% of patients and the remaining patients usually show type IV HLP and have hypertriglyceridemia in the family.Transiently impaired LPL activity with no defect in LPL enzyme induced severe hypertriglyceridemia in infants. The transient occurrence of inhibitor(s) for LPL was proposed..Although elevation of both Cholesterol and TG has been associated with premature atherosclerosis,no systematic evaluation of a large group of type V subjects for CAD has been presented,also there is no evidence in families of excessive coronary artery disease.Mutations in GPIHBP1, APOA5 were rare but the associated clinical phenotype was severe.The triglycerides in chylomicrons are hydrolyzed by lipoprotein lipase (LpL) along the luminal surface of the capillaries. However, the endothelial cell molecule that facilitates chylomicron processing by LpL has not yet been defined. It has been shown that glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) plays a critical role in the lipolytic processing of chylomicrons.GPIHBP1-deficient mice exhibit a striking accumulation of chylomicrons in the plasma, even on a low-fat diet, resulting in milky plasma and plasma triglyceride levels as high as 5000 mg/dl. Normally, Gpihbp1 is expressed highly in heart and adipose tissue, the same tissues that express high levels of LpL. In these tissues, GPIHBP1 is located on the luminal face of the capillary endothelium. Expression of GPIHBP1 in cultured cells confers the ability to bind both LpL and chylomicrons. These studies strongly suggest that GPIHBP1 is an important platform for the LpL-mediated processing of chylomicrons in capillaries.

## Genetics
Precise genetic patterns have not been determined for type V HLP and it has been suggested that type V may be due to number of genetic defects. Among them, the apo E and its isoforms may have an important clinical significance in type V HLP and may affect the catabolism of triglyceride rich lipoproteins. The presence of apo E4 allele may be the genetic factor that predisposes to the development of type V due to delayed lipoprotein clearance.APOE is a normal constituent of VLDL and HDL.The primary function is to serve as a ligand for the recognition of LP's to endothelial lipases.APOE is a polymorphic protein coded by 3 common alleles on chromosome 19.3 common alleles of APOE code for 3 isoforms .

## Associated Conditions 
- diabetes mellitus
- Hypothyroidism
- alcohol abuse
- glycogen storage disease type I
- Hyperuricemia
- Pancreatitis
- Eruptive xanthomas.

# Causes
Type V hyperlipoproteinemia is more complicated and more closely related to acquired environmental factors. It rarely shows familial occurrence, but its inheritance is variable. Therefore, type V HLP is usually considered to be triggered by acquired environmental factors in individuals with some congenital susceptibility to altered triglyceride metabolism (genetic factors). While the involved environmental factors vary, involvement of heavy drinking, type 2 Diabetes, hormonal therapy and medications are frequently observed.

## Causes by Pathophysiology

# Differentiating HLP type 5 from other conditions associated with raised triglycerides
HLP type 5 must be differentiated from other diseases that cause abnormal increase in triglycerides in the blood.
- Familial hyperchylomicronemia
- Familial hypercholesterolemia/ Familial combined hyperlipidemia
- Dysbetalipoprotenemia
- Primary hypertriglyceridemia/ Primary hypertriglyceridemia
- Drugs Causing high triglyceride levels:
Atypical antipsychotic drugs(Fluperlapine, Clozapine, Olanzapine), Beta-blockers (especially non-beta 1-selective), Bile acid sequestrants, Cyclophosphamide, Glucocorticoids, Immunosuppressive drugs (Cyclosporine, Sirolimus), Interferon, L-asparaginase, Oral estrogens, Protease inhibitors, Raloxifene, Retinoids, Rosiglitazone, Tamoxifen, Thiazide diuretics.
- Atypical antipsychotic drugs(Fluperlapine, Clozapine, Olanzapine), Beta-blockers (especially non-beta 1-selective), Bile acid sequestrants, Cyclophosphamide, Glucocorticoids, Immunosuppressive drugs (Cyclosporine, Sirolimus), Interferon, L-asparaginase, Oral estrogens, Protease inhibitors, Raloxifene, Retinoids, Rosiglitazone, Tamoxifen, Thiazide diuretics.

# Epidemiology and Demographics

## Prevalence/Incidence
It is difficult to accurately estimate the prevalence of HLP V in the general population,although the estimated incidence being <1/1,000,000. but a survey of about 40,000 people by the Lipid Research Clinic reported the frequency of individuals with a plasma TG level of 2,000 mg/dl or higher to be about 0.018%.

## Age
Average triglyceride levels in type V hyperlipoproteinemia were lower for women than for men before age 50.

## Gender
- TG levels increase with increasing age
- Male relatives had substantially higher average TG levels than women,except for the age group 50-59.
- Average triglyceride levels in type V hyperlipoproteinemia were lower for women than for men before age 50.
- For all ages combined 38/88 M and 19/93 F were considered Hypertriglyceridemic.

## Race
In Western population, LPL gene abnormalities were observed in 10% of patients with type V HLP.

# Risk Factors
- Family history of dyslipidemia
- Diabetes
- Alcohol abuse
- Obesity

# Screening
- Because of clustering of susceptibility alleles and secondary factors in families, biochemical screening and counselling for family members is essential, but routine genetic testing is not warranted
- Severe and very severe hypertriglyceridemia increase the risk for pancreatitis, whereas mild or moderate hypertriglyceridemia may be a risk factor for cardiovascular disease. Therefore,according to the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III guideline committee's recommendations, screening adults for hypertriglyceridemia as part of a lipid panel at least every 5 yr.

# Natural History, Complications and Prognosis

## Natural History 
Mixed hyperlipidemiaa common disorder that becomes more prevalent with increasing age.A history of acute pancreatitis was observed in about 17% of the patients, demonstrating that hyperlipidemia is frequently complicated by pancreatitis also in Japanese, in whom the fat intake is lower than in Western people, and stressing the importance of its prevention and management.
- Restriction of dietary fat eliminates chylomicrons and the lipoprotein panel changes to type 4 hyperlipoproteinemia.
- Often,the treatment of secondary factors contributing to HLP V (diet,obesity,glucose intolerance,alcohol,estrogen) converts type 5 to type 4 thereby modifying the glyceridemia ,the major manifestation of this disorder and reducing the risk of pancreatitis.

## Complications
- Triglyceride induced Pancreatitis
In patients with very high triglyceride levels and acute triglyceride-induced pancreatitis with hyperchylomicronemia, initial management may include hospitalization and fasting. Especially if glucose levels are elevated, then insulin therapy may also help reduce triglyceride levels (such as intravenous insulin in patients with poorly controlled diabetes mellitus). However, especially among patients with type 2 diabetes mellitus, the acute effect on chylomicron production may be absent, with the main potential benefit being a reduction in free fatty acid flux, and reduced very low density lipoprotein hepatic secretion.
When and where available, therapeutic plasma exchange and double-filtration may provide clinical benefit.
Parenteral nutrition is reserved for severe cases where fasting is prolonged, and enteral nutrition is not feasible or inadequate because of persistent gastrointestinal dysfunction. 
Once active symptoms of pancreatitis have subsided (ie, no nausea and vomiting, resolution of abdominal pain, no requirements for pain medication, and evidence of bowel motility such as bowel movements or active bowel sounds), then a clear liquid diet may be initiated, advancing to a whole food, low fat diet (6-15% of energy consumption).
Another nutritional approach is a diet rich in omega-3 fatty acids and medium chain triglycerides. 
When patients with very high triglycerides are managed as an outpatient, then after managing potential secondary causes of hypertriglyceridemia (and other potential causes of pancreatitis), and after implementation of very low fat, limited refined carbohydrate diet, and (when possible), an increase in physical activity, then fasting triglycerides can be monitored every 3-4 days, with an expectation that chylomicron triglycerides may decrease by 20-25% daily. 
Once pancreatitis is resolved and triglycerides are reduced to less than 1000 mg/dL, then non-saturated fats and non trans fats can be gradually increased to 25%, and then 35% of caloric intake. 
Beyond treatment of triglyceride-induced acute pancreatitis, appropriate nutritional intervention is also an important strategy for treating dyslipidemia and reducing ASCVD risk.
- Atherosclerosis
- Lipemia retinalis

## Prognosis
The prognosis is uncertain.Patients with HLP V are at an extremely high risk of developing Pancreatitis ( 17%). If the disease is inadequately managed, the prognosis is poor, especially if other risk factors are present. If the patient complies with lipid-lowering therapy, dietary modification, and lifestyle modification and if therapy is successful, outcome is improved significantly. Increased fat intake may cause recurrent bouts of illness possibly leading to pseudocyst formation,hemorrhage and death

# Diagnosis
Diagnosis of lipid genetic abnormalities is usually by :
- Clinical presentation
- History (including age of onset of symptoms in the patient and family members)
- Physical findings (Eruptive Xanthomas)
- Lab evaluation (Lipid levels and Apolipoprotein assays).
Diagnosis of more rare dysfunctions can sometimes be assisted by genetic or functional testing (Gene sequencing,LPL activity)

## Diagnostic Criteria
- I. Demonstration of an increase in VLDL in addition to hyperchylomicronemia.
- II. The absence of LPL deficiency, Apolipoprotein C-II deficiency, Apo E deficiency.
Definitely diagnosed if both I and II are fulfilled.
Diagnostic criteria to confirm HLP V include:
- TG > 250 mg/dl
- CM were present in plasma after an overnight stand at 4C
- Floating beta (type 3) abnormality was absent
- PHLA(post heparin lipolytic activity) was present by electrophoretic strip.
Type 4 satisfies 1,3,4 except for CM(2)
- Fasting chylomicronemia can be diagnosed by confirming the presence of chylomicrons and excess VLDL on agarose gel electrophoresis or ultracentrifugal analysis. A simple technique is to refrigerate plasma overnight and examine the specimen for a creamy supernatant from chylomicrons and a turbid VLDL-rich infranatant.This latter finding of a turbid infranatant is not seen in patients with type I hyperlipoproteinemia, in which only chylomicrons accumulate and the infranatant is clear.
- Also,the identification of other primary relatives with dyslipidemias is useful in making the diagnosis.

## History and Symptoms
HTGemia is usually asymptomatic until TG levels are greater than 1000-2000 mg/dl. Signs and symptoms may include the following.
- GI : Pain in the mid-epigastric, chest, or back regions; nausea, vomiting.
- Respiratory: Dyspnea
- Dermatologic: Xanthomas xanthomas
- Ophthalmologic: Lipemia Retinalis
- Neurological:Recent memory loss,coma.
Always enquire about history of :
- Family history of Diabetes,Cardio vascular disease and Dyslipidemia's.
- Alcohol consumption,Intake of medications.
- Pregnancies,menstruation
- Episodes of Gout,Pancreatitis,CVD.

## Physical Examination
Physical examination of patients with HLP V is usually normal.
- General examination should include documentation of:
Body weight,height,blood pressure.
- Body weight,height,blood pressure.
- Body weight,height,blood pressure.
The additional findings may be subjective and include:
- ABDOMEN: Hepatosplenomegaly.
- SKIN:Eruptive Xanthomas: Eruptive xanthomas (see the images below) are sometimes found when sustained elevated triglycerides are well above 1000 mg/dL. These are 1- to 3-mm yellow papules on an erythematous base that are most prominent on the back, buttocks, chest, and proximal extremities. The lesions are caused by accumulations of chylomicrons within macrophages and disappear gradually when triglycerides are kept below 1000 mg/dL.
- Eruptive Xanthomas on an elbow
- EYE : Lipemia Retinals : Triglyceride levels of 4000 mg/dL or higher may cause lipemia retinalis, in which funduscopic examination reveals retinal blood vessels (and occasionally the retina) that have a pale pink, milky appearance.The ocular changes are usually not seen until the triglyceride level reaches at least 2000 mg/dL in the early stages; they are best observed in the peripheral fundus. The vessels initially appear salmon-pink, but when the triglyceride level rises further, they become whitish. These changes, which begin in the periphery, progress toward the posterior pole as the triglyceride level rises. In severe cases, the vessels are creamy white, and differentiating the arteries from the veins is difficult. The findings can fluctuate widely from day to day, depending on the triglyceride level.
- NEUROLOGICAL: Memory loss, dementia, and depression have been reported in patients with the chylomicronemia syndrome.

## Laboratory Findings
- Laboratory findings consistent with Type 5 hyperlipoproteinemia include the following:-
- LIPID ANALYSIS
-Measurement of plasma lipid and lipoprotein levels after an overnight fast.
- Elevated triglycerides are determined by direct laboratory analysis of serum or plasma,however determining which lipoprotein abnormality is the cause of hypertriglyceridemia is less straightforward.
- Lipoprotein Electrophoresis
- Lipoprotein quantification
Tests to rule out secondary causes of hypertriglyceridemia include:
- Fasting or random glucose levels
- Thyroid-stimulating hormone ]] levels
- Urinalysis, creatinine, and microalbumin
- S.Uric acid
- LFT's(Liver Function Tests)
- Serum Protein Electrophoresis
- EKG
- BMI
-If the diagnosis of eruptive xanthomas is in doubt, obtaining a biopsy of the suspicious lesions will reveal accumulations of fat (not cholesterol).
-The only procedure that reliably distinguishes between a mixed hyperlipoproteinemia (increased LDL cholesterol and triglycerides) and type III hyperlipoproteinemia (increased IDL) is beta quantification (lipoprotein electrophoresis)
Chylomicron Determination
- If the triglyceride levels are greater than 1000 mg/dL and the presence of chylomicrons must be confirmed, the simplest and most cost-effective test involves overnight refrigeration of an upright tube of plasma or serum. If a creamy supernatant is seen the next day, chylomicrons are present. If the infranatant is cloudy, high levels of very low-density lipoprotein (VLDL) are present (type V hyperlipidemia)

## Imaging Findings
Generally there are no specific radiological findings associated with HLP V.
However in some cases Abdominal X-ray shows Pancreatic Calcification.

## Other Diagnostic Studies
Genetic analysis based on HTG as a trait is not adequate.
There are no other diagnostic studies associated with the diagnosis of HLP V.

## Recommendations for Hypertriglyceridemia  
- Individuals found to have any elevation of fasting triglycerides should be evaluated for secondary causes of hyperlipidemia including endocrine conditions and medications. Treatment should be focused on such secondary causes.
- Patients with primary hypertriglyceridemia should be assessed for other cardiovascular risk factors, such as central obesity, hypertension, abnormalities of glucose metabolism, and liver dysfunction.
- Evaluation of patients with primary hypertriglyceridemia for family history of dyslipidemia and cardiovascular disease to assess genetic causes and future cardiovascular risk.

# Treatment
The evaluation and treatment decisions for HLP V should be based on patient-centered and individual circumstances. Lifestyle therapies, such as appropriate nutrition and physical activity, are important elements of ASCVD risk reduction, with or without lipid-altering drug therapy. For patients in whom lipid-altering drug therapy is indicated, statin treatment is the primary pharmacologic modality for reducing ASCVD risk.

### Clinical algorithm for screening and management of elevated TG

## Medical Therapy 
When the triglyceride concentration is very high (500 mg/dL, and especially if 1000 mg/dL), the primary goal of therapy is to reduce the triglyceride level to <500 mg/dL for the intent of reducing the risk of pancreatitis.
When triglycerides are between 200 and 499mg/dL, the primary targets of lipid therapy are nonHDL-C and LDL-C for the purpose of reducing ASCVD risk.
NonHDL-C comprises the cholesterol carried by all atherogenic particles, including LDL, intermediatedensity lipoproteins, very low-density lipoproteins (VLDL) and VLDL remnants, chylomicron remnants, and lipoprotein.

## Surgery
The effect of bariatric surgery on lipid levels is variable and dependent upon the type of bariatric surgical procedure (e.g., gastric bypass, gastric sleeve, adjustable gastric banding).Gastric bypass procedures generally produce greater improvements in lipid and other metabolic parameters because of greater reductions in body fat, alterations in gut and other hormones, and improvements in inflammatory factors.Bariatric surgery significantly improved multiple metabolic parameters, and reduced overall mortality.Regarding lipids, compared with conventional therapy, bariatric surgery significantly reduced the incidence of hypertriglyceridemia (defined as  150 mg/dL) and the incidence of low HDL-C (defined as <39 mg/dL) but no significant reduction in  hypercholesterolemia (defined as 200 mg/dL).

## Primary Prevention
As type 5 HLP is a genetic disease there is no primary prevention before the presentation. Although, there is a possibility to reduce its incidence by controlling the environmental factors, especially in those with a family history of dyslipidemia.

## Secondary Prevention
- Lifestyle interventions are a key to reduce triglycerides that includes
weight loss if overweight or obese
physical activity ( 150 minutes per week of moderate or higher intensity activity)
- weight loss if overweight or obese
- physical activity ( 150 minutes per week of moderate or higher intensity activity)
- Restriction of alcohol
- Restriction of sugar/refined carbohydrate intakes
- For patients with very high TG level (500 mg/dL),chylomicronemia will generally be present. For such patients, a low-fat diet (,15% of energy) may be helpful to reduce entry of new chylomicron particles into the circulation.
- For patients with triglycerides <500 mg/dL, partial replacement of dietary carbohydrate (especially sugars and other refined carbohydrates) with a combination of unsaturated fats and proteins may help to reduce the triglyceride and non-HDL-C concentrations.