the diagnosis is based on high blood tyrosine level and abnormal urinary excretion of succinylacetone ( sa ) ( 1 ) . according to onset of symptoms ht1
is classified in acute ( < 2 months ) , subacute ( 2 to 6 months ) and chronic ( > 6 months ) forms ( 2 ) .
most common causes of death are liver failure and bleeding , hepatocellular carcinoma ( hcc ) and pseudo porphyric crisis with respiratory failure ( 3 ) .
since 1992 , the 2- ( 2-nitro-4trifluoro - methyl benzoyl)-1 , 3-cyclohexanedione ( ntbc ) has offered as a new promising tool for the treatment ( 4 , 5 ) .
, there are few reports of the long - term prognosis ( 5 , 7 ) .
this study reports beside its clinical and biochemical presentation , the outcome of ntbc [ 2- ( 2-nitro-4-trifloro - methylbenzoyl)-1 , 3-cyclohexanedion ] treatment of the disease and evaluates its biochemical markers in 16 pediatric libyan patients .
a retrospective clinical study was undertaken on 16 libyan patients with hereditary tyrosinemia type i ( hti ) who were diagnosed or referred to a single center at elkhadra hospital , one of the main referral hospitals in western libya , which provides medical services to pediatric age groups up to 16 years old .
our orientation was based on the presence of rickets with hepatomegaly or liver disease with high alpha fetoprotein ( afp ) .
two patients were detected by screening at the age of one week and 1.5 months because of older affected siblings .
the diagnosis of hti was confirmed by high tyrosine level in blood and sa urinary excretion by liquid chromatography tandem mass spectrometry ( lc - ms / ms ) .
the investigation ( blood for amino acids , urine for organic acids and sa or dried blood spots for the same tests ) were sent to laboratories and were done either in tunisia , germany , france or lebanon .
x - ray of bones , echocardiography , abdominal ultrasonography and when indicated , abdominal ct scan were monitored .
follow up visits were done iat least monthly in the first 6 months , then every 3 months thereafter .
one patient was treated with diet protein restriction due to unavailability of ntbc on diagnosis ; and 15 patients were treated with ntbc ( initially 1 mg / kg / day in 2 divided doses , the dose thereafter was adjusted according to clinical response ranging 0.5 - 2 mg / kg / day ) ( 8 , 9 ) .
prescribed diet consisted of avoiding high protein , continuing breast feeding and employing a special milk formula .
the goal of the diet was to maintain the blood levels of tyrosine below 500 mol / l ( by restricted tyrosine and phenylalanine each one dose not exceed 200 mg / day ) .
supplementation by fat soluble vitamins d and k in liver dysfunction and phosphate in hypophosphatemia were provided . with spss program version 16
the paired samples t - test was used , p value < 0.05 was considered statistically significant .
with spss program version 16 the paired samples t - test was used , p value < 0.05 was considered statistically significant .
sixteen patients were diagnosed with hti , rate of diagnosis was 1 - 2 children / year , 81.2% ( n = 13 ) were born to consanguineously married couples , and 2 families had 2 affected children each .
the median age at onset of first symptoms was 4.5 months ( range 1 week - 8 months ) .
median age of first visit presentation to our unit was 7 months ( range : 1 week to 38 months ) .
the median age at diagnosis was 8 months ( range 1 week - 40 months ) .
the median age at starting treatment was 9 months ( range 1 week - 43 months ) , the median interval between diagnosis and treatment was 0.5 months ( range 0 - 11 months ) .
the main clinical presentation at first visit was hepatomegaly , jaundice , rickets with prolonged pt and hypophosphatemia which were seen in 14 ( 87.5% ) patients .
bleeding tendency , ascites and edema with abnormal nodular liver imaging were seen in 3 ( 18.7% ) patients with liver failure .
anemia and thrombocytopenia ( 5 patients ) were transient and normalized after initiation of treatment .
other associated less common presentations were night irritability ( 3 patients ) , severe failure to thrive ( 3 patients ) , multiple fractures ( 1 patient ) ( figure 1 ) .
no child had symptoms related to cardiovascular or central nervous system ( tables 1 and 2 ) . at presentation , extremely high afp ( figure 2 ) and high alp were seen in all patients , the ggt was high in 87.5% ( n = 14 ) but was normal for age in 2 patients who were diagnosed by screening , alt was high in 68.7% ( n = 11 ) and ast in 56.2% ( n = 9 ) ( table 2 ) . overall 9-year survival rate has been 81.2% whereas it was 86.6% in ntbc treated patients .  
abbreviations : alp , alkaline phosphatase ; alt , alanine aminotransferase ; ast , aspartate aminotransferase ; ggt , gamma glutamyl transferase .
we compared the onset of treatment and the drop of afp levels in two groups .
the first group was five patients with poor response who began treatment at median of 13 months post onset of first symptoms ( range : sex to 35 months ) .
the second group was 11 patients with good response who began treatment at median of three months post onset of first symptoms ( range : one to 14 months ) .
we observed that by the third month post treatment that level of afp in the second group had faller by more than 50% of pre - treatment values in 90% ( n.10 ) of patients .
we observed this drop in only 20% ( n.1 ) of the first group ( p = 0.003 ) .
the outcome of ntbc treatment after one year in 13 survived patients was as follows : pt was the first liver function marker that showed normalization ( median 14 days , range 0 - 240 days ) , while other biochemical liver markers such as transaminases ( gpt , got ) , ggt , alp , bilirubin , serum albumin , afp and renal function took longer to improve .
in subacute form , normalization of afp was 50% in the first year and 100% in the second year , pt was normalized 100% and other liver markers 75% ; one patient had abnormal liver imaging ( hepatomegaly without nodules which sustained for longer ) . in chronic form ,
normalization of afp was 16.6% and 83.3% in the 3rd year and later , the pt was 83.3% and other liver function markers were normalized in 66.6% ; persistence of abnormal liver imaging ( hepatomegaly ) was seen in one patient . in none of forms increase of afp was seen ( figure 2 ) .
the constant features were decreased rates of weight gain and poor dentition , caries or delayed eruption of deciduous teeth occurred in all patients , the first permanent teeth erupted at due time and were healthy .
neuropsychosocial development , motor function and speech were normal for age in all survived patients , but are not assessed by any standardized test system .
three patients who presented severe liver cirrhosis ( splenomagly , esophageal varices with pt 21% to 24% ) and persisting high afp died .
they were at onset of symptoms 1 , 5 and 8 months , and at diagnosis 6 , 6 , 40 months old .
the treatment was started at 7 months ( diet only ) , 8 months and 43 months ( ntbc and diet ) .
the interest for genetic disorders is relatively recent in libya , where many sick babies or unexplained infant deaths may be attributable to inborn errors of metabolism .
the preliminary investigations fail to give a diagnostic clue , the patients actually pass away without metabolic workup because lack of awareness and limited diagnostic facilities .
hti is a genetic autosomal recessive disorder ; the risk is greater in mating relationships where the parents are close relatives .
libya displays some of the highest consanguinity rates in the world . according to 2008 estimate it was as high as 48.4% in a total population of 6.18 million ( 11 ) .
considering that 16 patients all of whom , were referred to a single hospital , with 81.2% consanguinity rate , it seems that hti is one of the most commonly recognized rare disorders in libya . from other countries in north africa , namely tunisia , more
than 70 cases were reported since 1987 with 25 ntbc treated patients since 2000 ( dr .
h azzouz , tunisia experience in management of hti , memg 2012 ) , from algeria 30 treated patients and morocco 3 patients ( swedish orphan communication ) .
the first option is dietary treatment that results in a poor outcome and caries a high risk of hcc , the second option is the liver transplantation which became the efficient treatment with good survey , and the third option is the ntbc which has been available since 1992 , has transformed the prognosis and has obviously improved the survival rate of hti in all forms particularly in acute liver failure .
ntbc has been used since 2001 as treatment for hti in libya . of patients exposed to ntbc , 60% of patients
( n = 9 ) with more than 3 years , 40% ( n = 6 ) with more than 6 years and 2 patients with more than 8 years of ntbc exposure . in none of the patients liver transplant
three patients died , the cause of death was either late diagnosis or delayed starting of treatment but hcc was not ruled out ( 12 , 13 ) .
we found that elevated ggt was a better marker ( figure 3 ) with respect to following : 1 ) at presentation it was high and increased earlier than other enzymes in 87.5% of patients .
2 ) remained longer high in the first 6 months after starting treatment except in 2 asymptomatic screened babies .
4 ) it was the first enzyme that raised alarm when treatment in patients who previously had responded well was inadequate .
all patients showed remarkable improvement of the signs of rickets after one year of treatment .
the renal tubulopathy associated with hti treated with ntbc is usually reversible ( 14 ) .
no patient presented with neurological manifestation but we faced porphyric like crisis in one very well responding , early treated asymptomatic screened patient after 6 years of ntbc treatment there occurred a sudden acute shortage in ntbc , his -aminolevulinic acid was high , more than 20 times above the upper limit of normal , the recovery was achieved with reintroducing ntbc and supportive treatment .
the side effects of ntbc , were seen in most of our patients leucopenia and thrombocytopenia , were transient but we never observed toxic signs of the eyes such as keratitis , photophobia and corneal opacities ( 15 ) , nor did we observe skin exfoliative dermatitis a sign of high blood tyrosine associated with uncontrolled diet restriction .
7 . introducing of neonatal metabolic screening , possibility of liver transplantation , promotion of local metabolic laboratories and a molecular testing is needed .
 background : hereditary tyrosinemia type i ( hti ) is a metabolic disease caused by deficiency of fumarylacetoacetate hydrolase enzyme.objectives:this study reports beside its clinical and biochemical presentation , the outcome of ntbc [ 2- ( 2-nitro-4-trifloro - methylbenzoyl)-1 , 3-cyclohexanedion ] treatment of the disease and evaluates its biochemical markers in 16 pediatric libyan patients.patients and methods : the diagnosis was based on presence of high tyrosine levels in blood and succinylacetone in urine.results:the consanguinity rate was 81.2% , the median age at onset , at diagnosis and at starting treatment were 4.5 , 8 , and 9.5 months respectively . at presentation hepatomegaly , jaundice , rickets and high gamma glutamyl transferase ( ggt ) were observed in 87.5% of patients . 
 all patients had extremely high alpha fetoprotein ( afp ) and high alkaline phosphatase ( alp ) levels . 
 fifteen patients were treated with ntbc , normalization of pt ( prothrombine time ) was achieved in average in 14 days . 
 the other biochemical parameters of liver function ( transaminases , ggt , alp , bilirubin and albumin ) took longer to improve and several months to be normalized . 
 survival rate with ntbc was 86.6% . 
 patients who started treatment in a median of 3 months post onset observed a fast drop of afp in 90.6% of patients ( p = 0.003 ) . 
 abnormal liver function and rickets were the common presentations , ggt was an early cholestatic sensitive test . 
 alp was constantly high even in asymptomatic patients.conclusions:in ht1 a faster dropping of afp is a marker of good prognosis . 
1. Background
2. Objectives
3. Patients and Methods
3.1. Statistical Analysis
4. Results
5. Discussion