Disease Severity
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Patients with LAL-D are deficient in the vital LAL enzyme, which can result in significant morbidities1
Nearly 50% progressed to fibrosis, cirrhosis, or liver transplant within 3 years of first clinical manifestation.2
In a separate clinical study, 50% (5/10) of patients exhibited worsening of hepatic steatosis after 20 weeks3,b
a Based on modeling, using a subset of 31 patients (≥5 years of age) in an observational study who received a liver biopsy, and 1 additional patient with no biopsy who received a liver transplant. Patients with LAL-D selected by their clinician for liver biopsy are expected to have more evidence of disease progression than those not selected for biopsy.2
b This is based on liver histopathological analyses of hematoxylin- and eosin-stained fat in paired morphometric assessments of hepatic steatosis in a subgroup of 10 patients with LAL-D in the placebo arm of 30 who underwent biopsy.2,3
Patients with LAL-D are at continuous risk of liver damage, including steatosis, fibrosis, cirrhosis, and liver failure4
The progressive nature of LAL-D leaves patients at chronic risk of devastating hepatic complications4
Patients with LAL-D may be more likely to develop progressive liver disease than patients with NAFLDa,b,c
Liver disease can progress rapidly in LAL-D, unlike progression in patients with NAFLD/NASH.5
In a meta-analysis, in patients with NAFLD or NASH, the average progression of fibrosis from stage 0 to stage 1 took 14.3 years [95% CI, 9.1-50.0 years] and 7.1 years [95% CI, 4.8-14.3 years], respectively.5,e
NOTE: These studies represent individual publications using different populations of patients. Data are not directly comparable.
a Clinical study of patients with LAL-D (N=66; age range, 4-58 years; mean age, 16 years). Graph shows data from biopsied patients (n=32 of 66), and includes patients with a baseline Ishak score ≥3.2,4,6
b Clinical study (N=67; age range, 5.5-11.3 years) and retrospective longitudinal cohort study (N=66; age range, 3.2-19.6 years) in pediatric patients with NAFLD. Graph shows data from biopsied patients (n=96 of 133), and includes patients with stage 2-3 fibrosis or cirrhosis.6-8
c Case review (N=135; age range, 1-82 years at last report) and observational study (N=48; age range, 6-48 years at time of consent) of pediatric and adult patients with LAL-D.1,2,9
d No instances of liver transplant were reported for 1 of the studies.9
e Systemic review and meta-analysis of the rate of fibrosis progression in adult patients with biopsy-proven NAFLD (N=81) or NASH (N=21) and stage 0 fibrosis at baseline who underwent paired biopsies ≥1 year apart.8
Dyslipidemia, often appearing at a young age in patients with LAL-D, may create higher risk of CHD10,11
ABNORMAL LIPOPROTEIN LEVELS IN PATIENTS WITH LAL-D MAY PUT THEM AT RISK OF CHD4,10
a Adjusted RR for incidence of CHD by lipid category in the pooled Framingham Heart Study dataset (n=3101 women, mean age 49 years; n=2693 men, mean age 48 years).5
b CHD is defined in the Framingham Heart Study as fatal and nonfatal myocardial infarction, acute coronary insufficiency, and sudden cardiovascular death.5
c Mean data from patients aged 31 to 58 years (n=6) in a clinical study of patients with LAL-D (N=66).6
d RR compared with LDL-c <3.4 mmol/L and HDL-c ≥1.6 mmol/L, which correspond to an RR of 1.00.6
e RR (95% CI) for each parameter were as follows: for LDL-c ≥4.1 mmol/L: women, RR 2.45 (1.37-4.39); men, RR 2.04 (1.44-2.90); for HDL-c <1.0 mmol/L: women, RR 4.93 (2.53-9.59); men, RR 3.25 (1.69-6.26).6
While CHD risk estimate is assessed in patients under the age of 30 years, dyslipidemia often starts from a young age in patients with LAL-D5,9
Progression of atherosclerosis in patients with LAL-D can begin to manifest at a young age, as also reported for other disorders with high cardiovascular risk, such as HeFH3,12
• Mean LDL-c was 5.4 mmol/L in patients with LAL-D (mean age, 16.1 years), compared with 6.1 mmol/L in patients with HeFH (mean age, 12.9 years)2,13,iii,iv
• Mean ApoB, the main protein constituent of LDL-c and non-HDL-c, was 1.7 g/L in patients with LAL-D, compared with 1.4 g/L in patients with HeFH2,13,14,iii,iv
~2 TO 5 TIMES:
The amount of increased risk LAL-D patients with abnormal LDL-c and/or HDL-c have for developing CHD11,i,ii
Pediatric symptom onset, severE morbidities, and mortality in patients with LAL-D
LAL-D puts patients at early risk of severe complications and premature death. Test early for LAL-D1
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Footnotes:
i Adjusted RR for incidence of CHD by lipid category in the pooled Framingham Heart Study dataset (n=3101 women, mean age 49 years; n=2693 men, mean age 48 years).2
ii CHD is defined in the Framingham Heart Study as fatal and nonfatal myocardial infarction, acute coronary insufficiency, and sudden cardiovascular death.10
iii Mean data from a clinical study of patients with LAL-D [n=66 for mean LDL-c; n=30 for mean ApoB).3
iv Mean data from a clinical study of pediatric patients with HeFH (n=194).13
v Clinical study of patients with LAL-D (N=66).6
vi Clinical review of patients with LAL-D (N=124).1
vii Observational study of patients with LAL-D (N=48).9
viii Age distribution is based on age at symptom onset as reported for 131 patients in the review.1
References: 1. Bernstein DL, et al. J Hepatol. 2013;58:1230-43. doi:10.1016/j.jhep.2013.02.014. 2. Data on file, Alexion Pharmaceuticals. 3. Abel F, et al. Poster presented at: the International Liver Congress 2016. April 13-17, 2016; Barcelona, Spain. 4. Burton BK, et al. N Engl J Med. 2015;373:1010-20. doi:10.1056/NEJMoa1501365. 5. Singh S, et al. Clin Gastroenterol Hepatol. 2015;13:643-54.e9. doi:10.1016/j.cgh.2014.04.014. 6. Shiha G, et al. INTECH. 2011. http://www.intechopen.com/books/liver-biopsy/ishak-versusmetavirterminol.... 7. Feldstein AE, et al. Gut. 2009;58:1538-44. doi:10.1136/gut .2008.171280. 8. Alkhouri N, et al. Liver Int. 2013;33:79-85. doi:10.1111/liv.12024. 9. Burton BK, et al. N Engl J Med. 2015;373:1010-20. doi:10.1056/NEJMoa1501365. 10. Reiner Ž, et al. Atherosclerosis. 2014;235:21-30. doi:10.1016/j.atherosclerosis.2014.04.003. 11. Liu J, et al. Am J Cardiol. 2006;98:1363-8. doi:10.1016/j.amjcard.2006.06.032. 12. Wiegman A, et al. JAMA. 2004;292:331-7. doi:10.1001/jama.292.3.331. 13. Kusters DM, et al. JAMA. 2014;312:1055-7. 14. Verbeek R, et al. Curr Opin. 2015;26:502-10. doi:10.1097/MOL.0000000000000237.