Do diabetes and obesity promote hepatic fibrosis in familial heterozygous hypobetalipoproteinemia?
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- Ballestri, S., Lonardo, A., Losi, L. et al. Intern Emerg Med (2009) 4: 71. doi:10.1007/s11739-008-0178-3
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The course of NAFLD secondary to familial heterozygous hypobetalipoproteinemia (FHBL), a definite etiology of secondary nonalcoholic fatty liver disease (NAFLD) [1–3] featuring low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB) plasma levels less than fifth percentile , is unknown. We report on a case with FHBL due to compound heterozygosity and apoB non-detectable in serum in which a long-term follow-up and paired liver biopsies were available.
A 58 year-old obese woman with FHBL was observed in June 2007 for abdominal pain and poorly controlled type 2 diabetes (T2D). The T2D began at the age of 40. It was complicated by peripheral neuropathy of the legs, and a chronic vascular encephalopathy that was documented by computed tomography. The patient was initially treated with a combination therapy (i.e., metformin plus glibenclamide plus insulin). Additional medications used were gabapentin for the peripheral neuropathy, thiamazole for multinodular hyperthyroidism, and escitalopram for mild psychodepressive disorder.
In June 2007, the patient’s BMI was 41 Kg/m2. Glycemic control was poor (fasting glucose 464 mg/dl at admission, hemoglobin A1c 11%). The liver chemistry tests were substantially normal (AST 28 U/l, ALT 25 U/l, GGT 32 U/l, ALP 53 U/l, bilirubin 0.6 mg/dl, albumin 3.2 g/dl, INR 0.83). Thyroid function tests were normal too (TSH 0.36 μIU/ml, FT4 9.9 pg/ml, FT3 2.3 pg/ml).
Glycemic control was attained through insulin administration.
In short, NAFLD secondary to this specific FHBL in a patient with T2D and obesity progressed from early stage NAFLD to advanced fibrosing-NASH in pre-cirrhotic stage. Moreover, we also observed that fatty changes did not disappear in this unique patient with FHBL-NASH precirrhosis.
The prevalence of fatty liver in FHBL is reported to be as high as 59 versus 29% in controls . Though displaying massive steatosis comparable to that seen in HCV-3 infection, FHBL livers do not have the same HCV-induced necro-inflammatory and fibrosing liver changes . In NAFLD, the presence and number of components of the metabolic syndrome increases the risk for progression of liver disease , but it has been speculated that in FHBL fat accumulation in the hepatocytes is thought to be per se a relatively benign phenomenon, thus necessitating some additional injury for hepatic inflammatory-fibrotic changes to develop. The metabolic syndrome or its individual components (especially T2D and obesity) could be among the most important stimuli.
In theory, the contributing role of potentially hepatoxic drugs such as thiamazole and escitalopram cannot be ruled. However, these drugs, to the best of our knowledge, have never been convincingly associated with the risk of drug-related liver cirrhosis .
At variance with NASH-cirrhosis, fibrosing FHBL maintains fatty changes when cirrhosis develops [9, 10] (Fig. 2). The reason for this is that steatogenesis in FHBL is linked to fat trapping in hepatocytes due to impaired secretion of apolipoproteins into the bloodstream [1, 4]. Given that such pathogenesis is genetic and thus irreversible, fatty changes do not disappear in FHBL-pre-cirrhosis.
In conclusion, clinical surveillance of FHBL patients is warranted in the presence of the metabolic syndrome or its components.
The Authors are indebted to Professors S. Calandra, M.D. and P. Tarugi, Ph.D. for molecular characterization of apoB gene mutations in this case.