Homozygous familial hypobetalipoproteinemia caused by APOB gene variations: a case report and review of literature / 中华儿科杂志

Objective: To summarize the genotypes and clinical characteristics of homozygous family hypobetalipoproteinemia (Ho-FHBL) caused by apolipoprotein B (APOB) gene variations. Methods: The clinical, laboratory, genetic, and liver histology data of a boy with Ho-FHBL managed in the hepatology ward of the Children's Hospital of Fudan University in May 2021 were retrospectively analyzed. The literature was searched from China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, China VIP database, China Biology Medicine disc and PubMed database (up to May 2022) with "familial hypobetalipoproteinemia" or "hypobetalipoproteinemias" or "hypo beta lipoproteinemia" or "hypolipoproteinemias" as the search terms. All relevant literatures were reviewed to summarize the clinical and genetic features of Ho-FHBL caused by APOB gene variations. Results: The male patient was admitted to the hospital due to abnormal liver function tests for 8 months at the age of 4 years and 6 months. Blood biochemistry showed transaminitis and abnormally low serum levels of lipids. Liver biopsy revealed fatty liver with inflammation and early cirrhosis (Brunt score was F3G2S4). Whole exome sequencing revealed two novel variants of APOB gene (c.3745C>T, p.Q1249 * from the father and c.4589_4592delinsAGGTAGGAGGTTTAACTCCTCCTACCT, p.T1530Kfs * 12 from the mother). He was diagnosed as Ho-FHBL caused by APOB gene compound heterozygous variations. Literature search retrieved 36 English literatures and 0 Chinese literature. A total of 55 (23 males and 32 females) Ho-FHBL cases, including this one, were caused by 54 APOB gene pathogenic variants (23 frameshift, 15 nonsense, 7 missense, 8 splice and 1 gross deletions). The age of the last follow-up was between 1 month and 75 years. Among them, 28 cases had lipid malabsorption, 19 cases had early dysplasia, 12 cases had no symptoms. Twenty-one patients had symptoms related to fat soluble vitamin deficiency, including 14 cases of acanthocytosis, 10 cases of neurological symptoms, and 6 cases of ocular lesions. Thirty-four patients had liver involvement, including 25 cases of elevated transaminase, 21 cases of fatty liver, 15 cases of hepatomegaly, 9 cases of liver fibrosis, 3 cases of liver cirrhosis, 1 case of hepatic hemangioma and 1 case of liver neoplastic nodule. Conclusions: The variants of APOB gene in Ho-FHBL are mainly frameshift and nonsense variations. Patients may have lipid malabsorption and (or) early dysplasia, or symptom-free. Liver involvement is common.

Liver structural injury in leptin-deficient (ob/ob) mice: lipogenesis, fibrogenesis, inflammation, and apoptosis / Lesión estructural del hígado en ratones con deficiencia de leptina (ob/ob): lipogénesis, fibrogénesis, inflamación y apoptosis

SUMMARY: Nonalcoholic fatty liver disease (NAFLD) might progress the steatosis to nonalcoholic steatohepatitis (NASH), reaching a cirrhosis state and possibly hepatocellular carcinoma. The liver of three-month-old C57BL/6J mice (wild-type, WT group, n=10) and leptin- deficient obese mice (ob/ob group, n=10) were studied, focusing on the mechanisms associated with the activation of the hepatic stellate cells (HSCs) and pro-fibrogenesis. The obese ob/ob animals' liver showed steatosis, increased lipogenesis gene expressions, inflammation, increased pro-inflammatory gene expressions, inflammatory infiltrate, and potential apoptosis linked to a high Caspase 3 expression. In ob/ob mice, liver sections were labeled in the fibrotic zones by anti-alpha-smooth muscle actin (alpha-SMA) and anti-Reelin, but not in the WT mice. Moreover, the alpha-SMA gene expression was higher in the ob/ob group's liver than the WT group. The pro-fibrogenic gene expressions were parallel to anti- alpha-SMA and anti-Reelin immunofluorescence, suggesting HSCs activation. In the ob/ob animals, there were increased gene expressions involved with lipogenesis (Peroxisome proliferator-activated receptor-gamma, Cell death-inducing DFFA-like effector-c, Sterol regulatory element-binding protein-1c, and Fatty acid synthase), pro-fibrogenesis (Transforming growth factor beta1, Smad proteins- 3, Yes-associated protein-1, Protein platelet-derived growth factor receptor beta), pro-inflammation (Tumor necrosis factor-alpha, and Interleukin-6), and apoptosis (Caspase 3). In conclusion, the results in obese ob/ob animals provide a clue to the events in humans. In a translational view, controlling these targets can help mitigate the hepatic effects of human obesity and NAFLD progression to NASH.

RESUMEN: La enfermedad del hígado graso no alcohólico (HGNA) puede progresar de la esteatosis a esteatohepatitis no alcohólica (ENA), alcanzando un estado de cirrosis y posiblemente carcinoma hepatocelular. Se estudió el hígado de ratones C57BL / 6J de tres meses de edad (tipo salvaje, grupo WT, n = 10) y ratones obesos con deficiencia de leptina (grupo ob/ob, n = 10), centrándose en los mecanismos asociados con la activación de las células estrelladas hepáticas (HSC) y profibrogénesis. El hígado de los animales obesos ob/ob mostró esteatosis, aumento de la expresión génica de la lipogénesis, inflamación, aumento de la expresión génica proinflamatoria, infiltrado inflamatorio y posible apoptosis ligada a una alta expresión de Caspasa 3. En ratones ob/ob, las sec- ciones de hígado se marcaron en las zonas fibróticas con anti-alfa- actina de músculo liso (alfa-SMA) y anti-Reelin, pero no en los ratones WT. Además, la expresión del gen alfa-SMA fue mayor en el hígado del grupo ob/ob que en el grupo WT. Las expresiones génicas profibrogénicas fueron paralelas a la inmunofluorescencia anti-alfa-SMA y anti-Reelin, lo que sugiere la activación de las HSC. En los animales ob/ob, hubo un aumento de las expresiones génicas involucradas con la lipogénesis (receptor activado por proliferador de peroxisoma gamma, efector c similar a DFFA inductor de muerte celular, proteína de unión al elemento regulador de esterol-1c y sintasa de ácidos grasos), pro-fibrogénesis (factor de crecimiento transformante beta 1, proteínas Smad-3, proteína-1 asociada a Yes, receptor beta del factor de crecimiento derivado de plaquetas de proteínas), proinflamación (factor de necrosis tumoral alfa e interleucina-6) y apoptosis (caspasa 3). ). En conclusión, los resultados en animales obesos ob/ob proporcionan una pista de los eventos en humanos. Desde un punto de vista traslacional, el control de estos objetivos puede ayudar a mitigar los efectos hepáticos de la obesidad humana y la progresión de HGNA a ENA.

MTP -493G/T gene polymorphism is associated with steatosis in hepatitis C-infected patients

The reduction of hepatic microsomal transfer protein (MTP) activity results in fatty liver, worsening hepatic steatosis and fibrosis in chronic hepatitis C (CHC). The G allele of the MTP gene promoter, -493G/T, has been associated with lower transcriptional activity than the T allele. We investigated this association with metabolic and histological variables in patients with CHC. A total of 174 untreated patients with CHC were genotyped for MTP -493G/T by direct sequencing using PCR. All patients were negative for markers of Wilson’s disease, hemochromatosis and autoimmune diseases and had current and past daily alcohol intake lower than 100 g/week. The sample distribution was in Hardy-Weinberg equilibrium. Among subjects with genotype 1, 56.8 percent of the patients with fibrosis grade 3+4 presented at least one G allele versus 34.3 percent of the patients with fibrosis grade 1+2 (OR = 1.8; 95 percentCI = 1.3-2.3). Logistic regression analysis with steatosis as the dependent variable identified genotypes GG+GT as independent protective factors against steatosis (OR = 0.4, 95 percentCI = 0.2-0.8; P = 0.01). The results suggest that the presence of the G allele of MTP -493G/T associated with lower hepatic MTP expression protects against steatosis in our CHC patients.

Pathologically different features and fibrosis scores in chronic hepatitis C genotypes 3 and 1.

BACKGROUND: Chronic hepatitis C genotypes 3 and 1 are the two most common genotypes in Thailand. OBJECTIVE: Identify the pathologically different features between genotypes 3 and land to compare the fibrosis score of Knodell HAI and Ishak modified HAI. MATERIAL AND METHOD: The pathological features of 114 liver biopsies were evaluated. RESULTS: Steatosis was more commonly found in genotype 3 than in genotype 1 (97.1% vs. 77.8%, p = 0.001). Portal lymphoid follicles were commonly found, but bile duct damage was uncommon. The majority of portal tracts showed partial involvement. The majority of patients had Knodell fibrosis 1 and Ishak fibrosis 3. CONCLUSION: Steatosis is significantly more common in genotype 3, while other features do not show any differences. The portal tracts show partial involvement because inflammatory cells tend to aggregate and form lymphoid follicles. The most comparable fibrosis scores are Knodell fibrosis 1 and Ishak fibrosis 3.

Prevalence of the hemochromatosis gene mutation in patients with nonalcoholic steatohepatitis and correlation with degree of liver fibrosis / Prevalência de mutação para o gene da hemocromatose em pacientes com esteatohepatite não-alcoólica e correlação com o grau de fibrose hepática

BACKGROUND: Nonalcoholic steatohepatitis is a chronic liver disease with a high prevalence in the general population and a potential to evolve into cirrhosis. It is speculated that iron overload could be associated with liver injury and unfavorable progress in affected patients. AIMS: To evaluate the prevalence of mutation of the hemochromatosis gene (HFE) in patients with nonalcoholic steatohepatitis and to correlate it with histological findings in liver specimens. PATIENTS AND METHODS: Twenty-nine patients with nonalcoholic steatohepatitis were evaluated. The presence of mutation in the hemochromatosis gene (C282Y and H63D) was tested in all patients and its result was evaluated in relation to hepatic inflammatory activity, presence of fibrosis, and iron overload in the liver. The control group was composed of 20 patients with normal liver function tests and 20 patients infected with the hepatitis C virus, with elevated serum levels of aminotransferases and with chronic hepatitis as shown by biopsy. RESULTS: Mutation of the hemochromatosis gene (C282Y and/or H63D) was diagnosed in 16 (55.2 percent) patients with nonalcoholic steatohepatitis, in 12 (60 percent) patients with hepatitis C and in 8 (40 percent) patients with no liver disease. No association was found between the presence of mutation and inflammatory activity, nor with the presence of fibrosis in patients with nonalcoholic steatohepatitis. An association was found between the presence of mutation and the occurrence of iron overload in liver, but there was no association between liver iron and the occurrence of fibrosis. CONCLUSIONS: The findings suggest that iron does not play a major role in the pathogenesis and progression of nonalcoholic steatohepatitis, and routine tests of the hemochromatosis gene mutation in these patients should not be recommended.

RACIONAL: A esteatohepatite não-alcoólica é uma doença crônica, com elevada prevalência na população e com potencial evolutivo. Especula-se que a sobrecarga de ferro possa estar associada com a injúria hepática e com uma evolução desfavorável destes pacientes. OBJETIVOS: Avaliar a prevalência da mutação do gene da hemocromatose (HFE) em pacientes com esteatohepatite não-alcoólica e correlacioná-la com os achados histológicos hepáticos. PACIENTES E MÉTODOS: Foram avaliados 29 pacientes com esteatohepatite não-alcoólica. A presença da mutação do HFE (C282Y e H63D) foi testada em todos os pacientes e seu resultado foi avaliado em relação a atividade inflamatória hepática, presença de fibrose e depósitos hepático de ferro. Como grupo controle estudou-se 20 pacientes com provas de função hepática normal e 20 pacientes portadores do vírus da hepatite C, com elevação dos níveis de aminotransferases e biópsia revelando hepatite crônica. RESULTADOS: A mutação do HFE (C282Y e/ou H63D) foi diagnosticada em 16 (55,2 por cento) pacientes com esteatohepatite não-alcoólica, em 12 (60 por cento) pacientes com hepatite C e em 8 (40 por cento) pacientes sem doença hepática. Não se observou associação entre a presença da mutação e a atividade inflamatória e a presença de fibrose nos pacientes com esteatohepatite não-alcoólica. Foi observada associação entre a presença de mutação e a ocorrência de depósitos de ferro hepático, porém, não ocorreu associação entre o ferro hepático e a ocorrência de fibrose. CONCLUSÕES: Os achados sugerem que o ferro não exerce papel importante na patogenia e na evolução da esteatohepatite não-alcoólica e a pesquisa rotineira da mutação do HFE nestes pacientes não deve ser recomendada.

Relation of Apolipoprotein E Polymorphism to Clinically Diagnosed Fatty Liver Disease / 대한간학회지

BACKGROUND/AIMS: Apolipoprotein E (Apo E) is important in plasma lipid metabolism and is a component of several plasma lipoprotein-lipid particles. Three major Apo E isoforms are encoded by three common allelic forms, epsilon2, epsilon3, and epsilon4 at the APO E locus. The goal of this study was to examine the association between polymorphisms in the apolipoprotein E gene (APOE) and fatty liver disease. METHODS: We examined the distribution of APOE alleles from 116 fatty liver patients and 50 controls in Korea. RESULTS: The frequencies of APOE alleles in fatty liver patients were 6.5% in epsilon2, 85.7% in epsilon3 and 7.8% in epsilon4. The corresponding frequencies in control subjects were 4.0% in epsilon2, 91.0% in epsilon3 and 5.0% in epsilon4. There were no significant differences in the distribution of APOE genotypes between fatty liver patients and controls. APOE epsilon2 and epsilon4 allele frequencies in fatty liver patients were more than those in controls. However, there was no significant differences in APOE epsilon2 and epsilon4 allele frequencies. CONCLUSIONS: These results suggest that APOE alleles seem not to be directly associated with the pathogenesis of fatty liver disease.