Hypobetalipoprotenemia diagnosis and treatment

1. AMOL S DAHALE
MODERATOR- Dr. A.S.PURI

2.  Physiology of lipid digestion and absorption
 Hypobetalipoproteinemia

4.  Triacylglycerol -90-95%
 Phospholipids-
 Sterols
 Others ( Fat soluble vitamins)
Iqbal J et al Am J Physio Endocrino Metab2009

5. Triacyglcerol –
 Oleic acid and Palmitate dominant fat
ingested
 Maximum energy derived from it
Phospholipids-
 10-20 gm/day from bile
 1-2 gm/day from diet
Sterol-
 Cholesterol- animal origin
 Sitosterol- plant origin non absorbsle

6.  Oral cavity- Lingual Lipases-TG
 Stomach- Lingual and Gastric enzymes and
Emulsification
 Duodenum- Mixing with Bile and Pancreatic
Juice, Hydrolysis and Micellization
 Jejunum-Absoption along mucosa in upper
2/3 part.

7.  Lipid must pass through three physical
Phases for absorption:
 Water in the lumen,
 Lipid in the epithelial membrane,
 Water in the lymphatics and bloodstream.
More than 95% of ingested fat is absorbed by
adults.
Sleisenger & Fordratans Text book of Gastroenerology 9thEd

10.  Milk derived lipase
 Lingual lipsae
 Gastric lipase
 Pancraetic lipase

12.  3 Class of lipids:
 CLASS- 1
 CLASS -2
 CLASS-3
Yong Hi et al Immun, Endo & Metab Agents In Med Chem,2009

14. Non-polar Lipids Octadecane, carotene, squalene,
cholesteryl oleate, cholesteryl
linoleate, and paraffin oil.
Polar Lipids: I Triacylglycerols,
diacylglycerols, long-chain
protonated fatty acids, and fat-
soluble vitamins
Polar Lipids:II Phospholipids, monoacylglycerols,
monoethers, and alphahydroxy
fatty acids.
Polar Lipids:IIIA Sodium salts of long-chain fatty
acids, many anionic, cationic and
nonionic detergents, and
lysophosphatidylcholine
Polar Lipids:IIIB Bile salts, sulfated bile alcohols,
and saponins .

15.  Hydrophobic (Class-I)coated with hydrophilic
components( Class-II & IIIB)
 Phospholipids,bile salts acts as emulsifier as
well as mechanical activity in stomach

18.  Micelle
 Vesicle

19. Unstirred Water Layer
 An unstirred water layer is present on the
surface of the intestinal epithelium, which in
humans is approximately 40 μm deep.
 This layer may be rate limiting for uptake
of long-chain fatty acids but not for short-
or medium chain fatty acids.

24.  Cholesterol esters, in the presence of bile
salts andcalcium, are hydrolyzed by carboxyl
ester lipase (CEL) (pancreatic cholesterol
esterase) to release the free sterol, in which
form it is absorbed.
Abumrad NA et al Physiol Rev 2012

27.  Apolipoproteins are proteins which combines
lipid componant to form lipoproteins.
 They makes lipid carriable in Aqueous media

32.  EXCESS
 DECREASE

34.  Premucosal-Bile, Pancreas, Stomach
 Mucosal-
 Decrease mucosa
 Disorganised
 Diseased mucosa
Normal mucosa with internal defects
 Postmucosal-Lymphatic Blockage
Mayo clinic Board Review for Gatroenterology 4th Ed

35. Quantitative test Van de Komer test ( Gold Standard)
Semiquantitive test Acid steatocrit testing
Qualitative test Sudan III staining
Breath test C14 olein breath test
Serum test B carotene levels

37.  TERMINOLOGY
 INTRODUCTION
 CLASSIFICATION
 PRIMARY CAUSES
 SECONDARY CAUSES
 PATHOPHYSILOGY
 EPIDEMILOGY
 CLINICAL FEATURES
 LABORATORY FEATURES
 DIAGNOSIS
 POSSIBLE TRATMENTS

38.  Neuroacanthocytosis syndromes
 Hypolipidemia
 Hypocholesterolemia
 Hypobetalipoproteinemia
 Hypotrigycedemia
Jung et al. Orphanet Journal of Rare Diseases
2011, 6:68
Minicocci et al J Lip Res 2013

39.  Hypobetalipoproteinemia is group of heterogenous
disorder comprising disorders characterised by
reduced plasma levels of Total Cholesterol , LDL- C,
and Apo B.
 Hypolipidemia is defined as a total cholesterol (TC) <
120 mg/dL (< 3.1 mmol/L) or low-density
lipoprotein (LDL) cholesterol < 50 mg/dL (< 0.13
mmol/L).
The Merck Manual of Diagnosis & Therapy,
19th Edition
 The Lipid Research Clinics population prevalence
study's fifth percentile for LDLC (<75 mg/dL) and TC
(< 130 mg/dL) also taken as cutoff in one study
Glueck CJ et al Metabolism 1997

40.  LDL
 VLDL
 Chylomicrons

41.  Primary –
Dominant- FamilialHypobetalipoproteinemia
Recessive- Abetalipoproteinemia
Chylomicron Retension Disease
Primary orphan HBL
 Secondary-
Diet, Drugs, Disease related
Tarugi P et al Advan Clin Chem 2011

42.  Liver and Intestine are main site of Apo B
production
 Apo B play primary role in transport of
cholesterol and triglyceride
 Two forms in plasma-Apo-B48 and Apo-
B100
Kane JP et al The Metab & Mol
basis Vol-II 2001

43.  Apo B100 – 4538 AA ( Chr-2)
 Full length transrcibed form
 Forms component of VLDL,IDL,LDL.
 Apo B48- 2152 AA.
 Synthesized in intestine
 Essential for Chylomicron formation.
 It is result of post translational modification
of Apo 100 mRNA inserting stop codon.
Kane JP et al The Metab & Mol
basis Vol-II 2001

44.  Once formed Apo B undergo Lipidation
 It is two step process
 In first step partially trancsribed Apo B undergo partial lipidation that
prevent degrading.
 During full transcrption ApoB go in to ER where full lipidation occurs
with help of MTP (CHR-4).
 After this it go to Golgi complex for excretion
 A specialised transport system transports ER derived vesicles to Golgi.
 It is mediated by Coat protein II.
 One of the subunit of this Cop II is essential
 In human this is Sari Gtpase( CHR-5).
 Mutation in it cause CMRD
Gibbons GF et al Bio Soc
Trans 2004
Hussain MM et al Curr Opi
Lipidol 2005

46.  Availability of Lipid at ER
 Characteristics of Apo B- Length, Signal
peptide polymorphism,Apo B folding
 Microsomal trigyceride transfer protein
 Cellular stress
 LDL-R- increasing internal digestion
 LDL-R -degrading LDL by incr uptake-PCSK-
9
Ginseberg HN et al J Lip
Res 2009
Sundaram M et al Nutr
Metab 2010

47.  FHBL
-Defected Apo B Secretion-
Truncated Apo B
Mutant with high affinity to MTP
-Increased Liver uptake-
PCSK9 inactivation

51.  Inconclusive gene analysis

52.  FHBL- 9:10,000 Anderson et al Acta Pedia Scanda 1979
1:3000 Welty FK et al Arterio Thrombo
Vasc Bio 1998
1:500-1:1000 Linton MF et al J Lipidio Res
1993
 ABL- < 1 In One million
 CMRD- Very Rare

53.  Clinical phenotype varies
 Depends upon residual function of- Apo B
lipoproteins
 In general recessive forms more severe than
dominant

54.  Heterozygoates asymptomatic
 But most of them develop fatty liver and mild
int. malabsortion
 In Homozygoate and Compo hetrozygoates
phenotype depends upon severity

55.  Fatty liver-
-54% Prevalence
-Fivefold increase in TG content
-Mechanism-
 VLDL particles smaller than normal not
excreted
 Less than normal Apo-B 100 from normal
allele.
Sankatsingh et al Arterioscler. Thromb. Vasc. Biol.2005

56.  Cardiac
 No prospective study
 Noninvasive markers encouraging
 In PCSK9 Patient study shows reduction
 Cancer risk
 Reverse causality

57. NATURAL HISTORY
 At birth – infant normal and neonatal period
uncomplicated
 After neonatal period patients develop steatorrhoea
and abdo distension
Diagnosis of Celiac Ds made and kept on GFD diet
 As child grows fat restricted diet become apparent
and fat soluble vitamin deficiencies starts to appear
 At end of first decade clumsiness, ataxia,
Misdiagnosed as Fredrich’s
 At puberty retinal degeneration appears
 At adult life varied clinical syndromes ,patient may
develop cardiovascular abnormalities

58.  Classical triad
 Retinitis
 Ataxia
 Loss of deep tendon reflexes
 In infancy steatorhhoea- treated as celiac
 No response to GFD
 Failure to thrive
 Acanthocytoisis

59.  Later in life neurological manifestations-
Post column neuropathy,
Myopathy,
Spinocereballar ataxia
Coagulopathy
Retinitis pigmentosa
 Anemia
 Associations
Ileal adenocarcinoma
Metastatic spinal cord glioblastoma
Fatty liver

60.  Symptomatology resemble of those of ABL
 Neurological manifestations are mild

62.  Vegetarians
 CLD
 Chr Pancreattis
 ESRD on Hemodialysis
 Hyperthyroidism
 B thallasemia
 Sickle cell disease
 Cancer
 Nonspecific chronic illness
 Undernutrition or malnutrition
 Severe infection
 HIV infection
 Malabsorption
 Repetitive plasmapheresis

70.  Fat loading done after 6 hr fast in small
children and 12 hr fast in large childern
 2gm/kg margarine given
 Blood withdrawn at 0,2,4 hr
 The rise of plasma TG levels >55mg/100 ml
(>0.6 mmol/1) at 2 hr can discriminate
between patients with gastrointestinal
disease and normal controls or patients with
functional disturbances.
Jonas A et al Archives of Disease in Childhood, 1979

71.  GENE CARD TEST FOR ABL-
100% sensitive
100% specific
Burnett JR et al Euro J Human
Gen 2012

72.  Dietary restriction of Fat in Infancy esp. with
that of LCFA level. Havel RJ et al Meta Basis of Inher
Disease 6th Ed 1989
 MCT can be used – but poor carrier for fat
soluble vitamins and risk of hepatic fibrosis
Illingworth DR et al
Metabolism 1979
 5gm Veg oil cont Ess fat Acids. Kayden Persn
Communications
 As age increase dietary fat absortption
increase and can be taken as much as
tolerated- 60-70 gm can tolerated

73.  Vita E-100-300mg/day
Kayden HJ et al . Adv. Exb. Med. Biol. 201:
67-81. 1985
 Oral soluble Vitamin A-200-400 IU/kg day
Illingworth DR Arch. Neuml. 1980
 Vit K if required