Fat accumulation in enterocytes: a key to the diagnosis of abetalipoproteinemia or homozygous hypobetalipoproteinemia

A 20-year-old woman was referred by her ophthalmologist to investigate the reason for her hypovitaminosis A and secondary night blindness. She had no other symptoms of deficiencies in fat-soluble vitamins, no abdominal complaints, and no weight loss.

Laboratory examination revealed a deficiency in vitamin A (< 12 µg/dL, normal range 30 – 80) and vitamin E (< 0.30 mg/dL, normal range 0.5 – 1.8), a very low prothrombin time (30 %), and very low levels of cholesterol (30 mg/dL), triglycerides (4 mg/dL), and LDL-cholesterol (below the level of detection). Her level of 25-hydroxy vitamin D appeared to be normal, but at the time of her first admission, vitamin D substitution had already been started. A slightly raised alanine aminotransferase was also detected (33 U/L).

Further work-up excluded cystic fibrosis, exocrine pancreas insufficiency, and celiac disease. Gastroscopy revealed a very pale duodenal mucosa; the villi, however, could be easily recognized ([Fig. 1]). Videocapsule endoscopy revealed a pale small bowel mucosa with extremely pronounced villi ( [Fig. 2], [Video 1]). Biopsies of the duodenal mucosa revealed areas of extended supranuclear vacuolization of the cytoplasm in the villi. These areas were interspersed with normal areas ([Fig. 3] and [Fig. 4]).

Fig. 1 A 20-year-old woman was referred by her ophthalmologist to investigate the reason for her hypovitaminosis A and secondary night blindness. A macroscopic image taken during gastroscopy shows a pale duodenal mucosa.

Fig. 2 Videocapsule image illustrating the pale yet pronounced aspect of the villi.

Videocapsule endoscopy in a 20-year-old woman suffering from hypovitaminosis A and secondary night blindness revealed a pale small-bowel mucosa with extremely pronounced villi.

Fig. 3 Microscopic image showing vacuolization, especially on the top of the villi. Vacuolization causes a paler aspect because of fat dissolving during the process of embedding the tissue in paraffin wax (“empty” vacuoles instead of fat accumulation).

Fig. 4 Negative periodic acid-Schiff staining shows no microorganisms nor accumulation of glycogen, supporting the assumption that the vacuolization is due to lipid accumulation.

These findings suggested a diagnosis of either abetalipoproteinemia or homozygous hypolipobetaproteinemia, disorders that are caused by mutations in both alleles of the microsomal triglycerides transfer protein (MTP) or in the APO-B gene, respectively [1] [2] This results in the failure of APO B-100 synthesis in the liver and APO B-48 synthesis in enterocytes, leading to fat accumulation in the small intestine. This diagnosis can be confirmed by sequencing the MTP and APO-B genes [1].

This disorder can be treated by a low-fat diet, supplementation of essential fatty acids, and high oral doses of fat-soluble vitamins [1]. Follow-up is necessary to monitor potential ophthalmologic, neurologic, hematologic, and hepatologic complications [1] [2].

This patient illustrates that the disorder is sometimes diagnosed in adulthood when the phenotype is mild [1] [2] [3]. The prognosis is variable but adherence to the treatment regime can restore neurological function and prevent subsequent disease progression [1] [2].

Endoscopy_UCTN_Code_CCL_1AB_2AZ_3AZ

Competing interests: None

Acknowledgment

Histologic images were kindly provided by Stephanie Verschuere, MD, Pathology Department UZ Ghent.

• References

• 1 Lee J, Hegele R. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J Inherit Metab Dis 2014; 37: 333-339
• 2 Cefalù A, Pirruccello J, Noto D et al. A Novel APOB mutation identified by exome sequencing cosegregates with steatosis, liver cancer, and hypocholesterolemia. Arterioscler Thromb Vasc Biol 2013; 33: 2021-2025
• 3 Welty F. Hypobetalipoproteinemia and abetalipoproteinemia. Curr Opin Lipidol 2014; 25: 161-168