familial hypobetalipoproteinemia ( fhbl ) is a rare autosomal co - dominant genetic disorder of lipid metabolism .
it is characterized by serum low - density lipoprotein ( ldl ) cholesterol or apolipoprotein b ( apob ) levels 5th percentile .
apob is the largest of the apolipoproteins and is important in the formation and secretion of very - low - density lipoprotein ( vldl ) and chylomicrons .
these two isoforms are derived from differential splicing of rna from a single apob gene .
apob-48 is synthesized by enterocytes and is a key component of chylomicrons , while apob-100 is synthesized by the liver and is the key protein component of vldl and ldl particles ; b-100 also contains the binding site for hepatocyte uptake .
the apob gene is found on chromosome 2p24 and is unlinked to other apolipoprotein gene clusters . since the discovery of the first kindred with fhbl , many subsequent kindreds have been described , leading to the identification of numerous single nucleotide substitutions , gene deletions , splicing variations and linkage abnormalities in the apob gene that can lead to defects in vldl and chylomicron production and secretion .
persons with fhbl can be heterozygotes or homozygotes , with severity of the clinical phenotype related to the number of defective apob alleles .
heterozygotes often have no clinical manifestations other than very low serum apob - containing lipoprotein levels ; these low levels of atherogenic lipoprotein particles may actually confer cardiovascular protection . in contrast , fhbl homozygotes can have a range of clinical symptoms , including fat malabsorption , neurologic symptoms , red cell acanthocytosis , retinitis pigmentosa and/or nonalcoholic fatty liver disease .
in fact , the clinical presentation of homozygous fhbl can be indistinguishable from that of abetalipoproteinemia ( abl ) due to mutation in mttp , which is the gene that encodes microsomal triglyceride transfer protein .
we describe here a case of nonalcoholic steatohepatitis ( nash ) that led to the diagnosis of fhbl .
a 44-year - old man was referred to the vancouver general hospital division of gastroenterology for advice regarding management of nash .
he was a shop owner , a life - long nonsmoker and drinking about half a bottle of wine a week .
, he was told that ast ( normal 535 u / l ) , alt ( normal 756 u / l ) and ggt ( normal
878 u / l ) were all about 2-fold above the upper limits of normal .
a liver biopsy was recommended , however the patient declined the procedure and elected to initiate a weight loss program with dietary modification and increased exercise for presumed nash .
about 3 years before presentation , he was found to have elevated transaminases on blood work done for an insurance application , with alt 130 u / l and ast 111 u / l .
after about 6 months of strict diet and exercise , as well as a 10-pound intentional weight loss , his liver enzymes normalized with alt 44 u / l and ast 41 u / l .
he reintroduced mild alcohol intake and reduced the amount of exercise , and 6 months later his liver enzymes were again elevated with alt 94 u / l and ast 80 u / l .
other causes for elevated liver enzymes , including anti - nuclear antibody , ceruloplasmin and alpha-1 antitrypsin , were normal or negative . however , he was found to have an elevated ferritin at 737 g / l ( normal 18250 g / l ) .
subsequent testing revealed him to be heterozygous for the c282y mutation in the hfe gene for hemochromatosis .
, he was a stocky male with a body mass index of 32 kg / m .
review of his blood tests from 3 years before revealed ldl cholesterol 0.24 mmol / l ( normal 1.83.5 mmol / l ) , high - density lipoprotein cholesterol 1.29 mmol / l ( normal 0.91.5
a liver biopsy had been done in 2009 by the referring physician and had shown normal liver architecture .
there was very mild portal and pericellular centrilobular fibrosis , mild focal mononuclear cell infiltration and moderate macrovesicular steatosis .
she was obese , had type 2 diabetes and had recently been diagnosed with esophageal varices .
his mother ( i-2 ) and several maternal relatives were known to have a very low cholesterol level .
apob immunoblotting on fasting plasma showed only a band at the expected apob-100 position , arguing against truncation mutations .
dna was extracted from plasma samples from the patient and subsequently from all first - degree relatives and sent to the cardiovascular genetics lab in london , ontario .
direct automated sequencing revealed two different mutations in the apob gene , namely r463w and v703i .
these were found to be on opposite chromosomes , so the proband is a compound heterozygote .
family relationships , cholesterol levels and apob mutation analysis are shown in figure 1 and table 1 .
our patient was advised to return to regular exercise and to maintain a healthy low - fat diet .
his weight decreased by about 5 kg over 6 months and his alt normalized to 25 u / l .
rare monogenic disorders have been very informative for identifying key components of the metabolism of apob - containing lipoproteins and triglycerides .
these disorders include abl due to mutation of the mttp gene , hypobetalipoproteinemia due to mutation of the apob gene , familial combined hypolipidemia due to mutation of the angptl3 gene and pcsk9 deficiency due to mutations in the pcsk9 gene [ 10 , 11 ] .
in addition to being important in metabolism , some of the gene products causing these disorders are now targets for new drugs designed to lower ldl cholesterol .
for instance , mipomersen is an anti - sense rna biologic that reduces ldl cholesterol by targeting the apob gene , while lomitapide reduces ldl cholesterol by inhibiting microsomal triglyceride transfer protein [ 12 , 13 ] .
there are also numerous new biologic drugs in development that lower ldl cholesterol by targeting pcsk9 .
while these new drugs seem to be very effective at lowering ldl cholesterol , there is concern about potential long - term side effects , such as hepatosteatosis .
clinical evaluation of  experiments of nature such as fhbl patients who carry a germ - line mutation in apob can provide clues of the potential long - term benefits and adverse reaction of pharmacologic therapies that target these key metabolic pathways .
about 45 different truncated forms of apob have been discovered to date , ranging from apob-2 to apob-90 [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ] .
the numbers represent estimated apob mass based on polyacrylamide gel electrophoresis , with apob-100 being normal .
truncated apob can form varying sizes and densities of lipoprotein particles depending on the length of truncation .
truncated apob particles have a lower production rate and higher clearance rate , resulting in low plasma levels of apob [ 19 , 40 , 41 , 42 ] .
apob smaller than apob-27.6 is undetectable in plasma due to rapid clearance . in fhbl heterozygotes with apob truncation ,
the average plasma concentration of apob is around 2530% of normal [ 43 , 44 ] .
fhbl due to angptl3 gene linked to chromosome 3p21 is associated with about a 50% reduction in apob levels compared to normal individuals , as well as an elevated rate of catabolism of vldl apob [ 10 , 45 , 46 , 47 ] .
at least some individuals with this subtype of fhbl have gain - of - function mutations of pcsk9 .
this is a serine protease that destroys ldl receptors in the liver and thereby controls the level of ldl in plasma .
mutations that increase pcsk9 activity cause hypercholesterolemia , whereas mutations that inactivate pcsk9 have the opposite effect . in fhbl ,
there have been several reports of nonalcoholic fatty liver disease in fhbl subjects as detected by ultrasound or liver biopsy [ 28 , 49 , 50 , 51 , 52 ] .
analyzed liver fat by magnetic resonance spectroscopy , body mass index , waist circumference and glucose tolerance of 21 individuals with fhbl due to apob truncations compared with 14 controls . despite similar mean values for obesity and insulin indexes , there was a 5-fold increase in liver fat in fhbl subjects .
similar studies with fhbl subjects due to chromosome 3p21 linkage or pcsk9 mutations revealed normal hepatic fat content , an important phenotypic difference between these mutations and apob truncation [ 7 , 46 ] . the proband in this report is a 44-year - old man with nash secondary to fhbl . genetic analysis revealed compound heterozygosity for two mutations , each of which results in amino acid substitution . as shown in figure 1 , he inherited the r463w mutation from his mother ( subject i-2 )
. heterozygosity for this mutation is associated with hypobetalipoproteinemia , while homozygosity has a more severe phenotype .
interestingly , the r463w mutation was first reported in an extended christian lebanese family , which is also the ethnic background of our proband 's mother .
this is a novel mutation , and analysis using the polyphen program predicts the effect of this amino acid substitution as  possibly damaging to apob function .
although the two v703i heterozygotes in this kindred , subjects i-1 and ii-1 , had normal ldl cholesterol levels when the second allele encoded normal apob-100 , it is possible that this mutation , in the context of a defective form of apob-100 , such as the r463w mutation , contributes to increased intracellular degradation of apob .
this might act to compound the impairment of vldl secretion in subject ii-2 who had one copy of r463w , as evidenced by his lower ldl cholesterol level compared to the two r463w simple heterozygotes ( subjects i-2 and ii-3 ) .
although nash is common in fhbl patients , the long - term effects of fhbl are still unclear [ 28 , 49 , 51 , 54 ] .
interestingly , harada et al .   reported a patient with recurrent nash and cirrhosis due to fhbl post liver transplantation .
this suggests that at least in some forms of fhbl , the intestinal defect may be sufficient to cause the phenotype .
however , his sister ( subject ii-3 ) has developed esophageal varices , possibly due to liver cirrhosis from fhbl compounded by diabetes mellitus .
diet and exercise continue to be the mainstay of treatment for patient with nash induced by fhbl . as in our patient ,
fat malabsorption can be managed through diet modification by limiting intake of fats containing long - chain fatty acids as well as supplementing fat - soluble vitamins .
reports have suggested that the cellular membranes of patients with fhbl are relatively deficient in vitamin e ; indeed severe vitamin e deficiency in both homozygous fhbl and abl is responsible for the development of neurologic signs and symptoms [ 55 , 56 ] .
while the most common neurologic symptom is decreased or absent deep tendon reflexes , ataxia , proprioceptive deficits and pain have been described in both homozygous fhbl and abl [ 57 , 58 , 59 ] .
there are reports of success with vitamin e treatments for neurologic symptoms in fhbl and abl [ 57 , 60 ] .
there is some evidence that combination therapy of vitamin a and e can slow the progression of retinal degeneration and may lead to restoration of vision if started early [ 61 , 62 , 63 ] .
our patient was started on vitamin e and multivitamin supplementation for primary prevention , as he does not currently have any neurological , hematological or ocular abnormalities .
fhbl is an uncommon autosomal co - dominant disorder of lipid metabolism that is often overlooked because low levels of ldl cholesterol may not attract the attention of health care providers . in the present case liver enzyme abnormalities
patients with fhbl and nash can progress to end - stage liver failure , therefore monitoring and risk reduction is important
. finally , patients with such rare disorders can provide insight into the possible long - term consequences of new ldl - lowering biologic therapies .
 familial hypobetalipoproteinemia ( fhbl ) is a rare genetic disorder of lipid metabolism that is associated with abnormally low serum levels of low - density lipoprotein ( ldl ) cholesterol and apolipoprotein b. it is an autosomal co - dominant disorder , and depending on zygosity , the clinical manifestations may vary from none to neurological , endocrine , hematological or liver dysfunction . nonalcoholic fatty liver disease is common in persons with fhbl , however progression to nonalcoholic steatohepatitis is unusual . we describe here a patient with a novel apob mutation , v703i , which appears to contribute to the severity of the fhbl phenotype . 
 he had liver enzyme abnormalities , increased echogenicity of the liver consistent with steatosis , very low ldl cholesterol at 0.24 mmol / l ( normal 1.83.5 mmol / l ) and an extremely low apolipoprotein b level of 0.16 
 g / l ( normal 0.61.2 
 g / l ) . 
 apob gene sequencing revealed him to be a compound heterozygote with two mutations ( r463w and v703i ) . 
 apob r463w has previously been reported to cause fhbl . 
 genetic sequencing of his first - degree relatives identified the apob v703i mutation in his normolipidemic brother and father and the apob r463w mutation in his mother and sister , both of whom have very low ldl cholesterol levels . 
 these results suggest that the apob v703i mutation alone does not cause the fhbl phenotype 
 . however , it is possible that it has a contributory role to a more aggressive phenotype in the presence of apob r463w . 
Introduction
Case Report
Discussion
Conclusion