Internal and Emergency Medicine

, Volume 4, Issue 1, pp 71–73

Do diabetes and obesity promote hepatic fibrosis in familial heterozygous hypobetalipoproteinemia?

Authors

  • Stefano Ballestri
    • Department of Internal Medicine, Endocrinology, Metabolism and GeriatricsUniversity of Modena and Reggio Emilia, Nuovo Ospedale Civile Sant’Agostino Estense di Baggiovara
  • Amedeo Lonardo
    • Department of Internal Medicine, Endocrinology, Metabolism and GeriatricsUniversity of Modena and Reggio Emilia, Nuovo Ospedale Civile Sant’Agostino Estense di Baggiovara
  • Luisa Losi
    • Department of PathologyAzienda Ospedaliero-Universitaria Policlinico di Modena, University of Modena and Reggio Emilia
  • Elisa Pellegrini
    • Department of Internal Medicine, Endocrinology, Metabolism and GeriatricsUniversity of Modena and Reggio Emilia, Nuovo Ospedale Civile Sant’Agostino Estense di Baggiovara
  • Marco Bertolotti
    • Department of Internal Medicine, Endocrinology, Metabolism and GeriatricsUniversity of Modena and Reggio Emilia, Nuovo Ospedale Civile Sant’Agostino Estense di Baggiovara
    • Department of Internal Medicine, Endocrinology, Metabolism and GeriatricsUniversity of Modena and Reggio Emilia, Nuovo Ospedale Civile Sant’Agostino Estense di Baggiovara
CE - Letter to the Editor

DOI: 10.1007/s11739-008-0178-3

Cite this article as:
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) [13] featuring low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB) plasma levels less than fifth percentile [4], 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.

The patient’s alcohol consumption was nil. Laparoscopic cholecystectomy had been performed in 1998 for acute biliary pancreatitis. At that time, intraoperative wedge liver biopsy disclosed NAFLD type 1–2 according to Matteoni et al. with thin fibrous septa [5] (Fig. 1). BMI was 30 Kg/m2. An abdominal ultrasound imaging (US scan) suggested steatosis. Plasma lipid values compatible with FHBL had been noted since 1998 (total Cholesterol 61 mg/dl, LDL-C 21 mg/dl, HDL-C 28 mg/dl, Triglycerides 50 mg/dl, ApoA1 83 mg/dl, ApoB < 40 mg/dl). The apoB gene molecular analysis confirmed a severe form of FHBL in 2005. The patient is a double heterozygote for two mutations both with pathologic effect. The first one is a non-sense mutation (G→A), in hexon 19, resulting in a truncated apoB (apoB-20.6), not secreted in plasma. The second one is a nucleotidic substitution (T→A) in intron 14 (IVS 14 -4T/A) whose translation product would be a small-size truncated apoB, and so not secreted.
https://static-content.springer.com/image/art%3A10.1007%2Fs11739-008-0178-3/MediaObjects/11739_2008_178_Fig1_HTML.jpg
Fig. 1

Liver biopsy findings in 1998 (a, b). a (Ematoxylin Eosin ×4), b (Ematoxylin Eosin ×10)—Wedge liver biopsy sample (1998) disclosed liver thin fibrous septa. Mild chronic inflammatory changes with rare granulocytes were found in portal spaces and septa without extension beyond the portal tract. Lobular hepatocytes showed mild anisonucleosis, many glycogenated nuclei and medium-macrovesicular steatosis affecting 70–80% of the hepatocytes. No iron storage was detected either in Kuppfer or in hepatocytes. These changes were deemed compatible with a toxic-dysmetabolic etiology

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).

A repeat liver biopsy showed advanced fibrosing-NASH in the pre-cirrhotic stage with marked steatosis (Fig. 2). The antinuclear antibody test, extractable nuclear antigens, antimitochondrial antibodies, anti-HCV antibodies, and HbsAg and Lupus Anticoagulant studies were all negative. The HBsAb (>22 mIU/ml) and anti-smooth muscle antibody (1:80) were positive. The US scan confirmed hepatomegaly, with hyperechoic structure and mild hypertrophy of the spleen.
https://static-content.springer.com/image/art%3A10.1007%2Fs11739-008-0178-3/MediaObjects/11739_2008_178_Fig2_HTML.jpg
Fig. 2

Liver biopsy findings 2007 (a, b). a (Ematoxylin Eosin 4 × 2), b (Ematoxylin Eosin 10 × 2)—The repeat liver biopsy (2007) showed fibrosis with porto-portal and porto-central septa and partial nodularity. In portal spaces we observed a moderate chronic inflammatory infiltrate with several plasma cells and a moderate focal piecemeal necrosis. In the lobule, scattered necrotic foci, micro-macrosteatosis in 80% of hepatocytes were observed. Glycogenated nuclei were found. Iron and copper depots were absent. In conclusion, this is a pre-cirrhotic stage of chronic liver disease with marked steatosis compatible with a metabolic etiology

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 [4]. 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 [6]. In NAFLD, the presence and number of components of the metabolic syndrome increases the risk for progression of liver disease [7], 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 [8].

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.

Acknowledgments

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.

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© SIMI 2008