Hypoglycemia associated with lipid accumulation in primary hepatocellular carcinoma

Abstract

A 54‐year‐old Chinese patient with a slowly growing hepatocellular carcinoma developed persistent hypoglycemia and received continuous dextrose infusion for some 5 months before death. In contrast to all save 1 previously reported patients, the blood glucose response to intravenous glucagon was normal. At necropsy the liver appeared to consist almost entirely of tumor. Histologically, the well‐differentiated malignant cells were loaded with fat, and on chemical analysis the lipid content was 475 mg per gm of tumor tissue. The glycogen content was not increased and was reduced by 23% after storage at 37°C for 4 hours. Enzyme studies of the tumor showed reduced activities of glucose‐6‐phosphatase, fructose‐1, 6‐diphosphatase, pyruvate carbox‐ylase, and phosphoenolpyruvate carboxykinase. There was increased activity of glucose‐6‐phosphate dehydrogenase. Phosphorylase activity was recorded only upon addition of adenylic acid. These findings were similar to those of tumors of patients who did not have hypoglycemia. The small amount of normal residual liver available for examination showed similar enzyme changes. In the residual liver of nonhypoglycemic patients the rate‐limiting enzymes for gluconeogenesis were normal. It is postulated that the main factors responsible for the development of early hypoglycemia and lipid accumulation in the tumor were the diversion of the substrates of the Krebs cycle from gluconeogenesis towards lipogenesis and the failure of lipolysis in the tumor. It is considered probable that the slow rate of growth of the tumor and the prolonged dextrose infusion contributed towards lipogenesis. The same abnormalities were probably present, but to a lesser extent, in the residual liver.

Paraneoplastic syndromes in patients with hepatocellular carcinoma in Taiwan

“…Hepatocellular carcinoma (HCC) is the most common malignancy in Taiwan. During its clinical course, patients may manifest a variety of paraneoplastic syndromes, including hypercholesterolemia, hypoglycemia, hypercalcemia, and erythrocytosis 1–8. According to our previous reports, the incidences of these syndromes were 11.4% if hypercholesterolemia, 2.8% if hypoglycemia, 1.8% if hypercalcemia, and 2.5% if erythrocytosis 9–12…”

The New Perspectives Journal of Medicine

“…因 (4) 。然而，一种的特定形式的HCC -透明细胞肝细胞 癌(CCHCC)，有更好的预后。CCHCC很早就被发现 具有肝糖原蓄积的表现，在HE染色中，透明细胞出现 "空泡"、"泡沫"甚至"膨胀"，积累糖原 (5,6) 和(或)脂肪 (6,7) 。除CCHCC外，在局灶性结节性增生 (8,9) 和许多透明 细胞肝细胞腺瘤中也发现了含有丰富糖原的透明细胞。 糖原蓄积也出现在上述良性疾病中，其与CCHCA是否存 在相关性，尚不清楚。美国学者Salani F等在2020年也报 道了类似的发现，在73例的HCC病理切片中，发现有18 例(13%)含有透明细胞癌 (10) 。这似乎说明含有CCHCC 成分的病理表现可能并不罕见。全世界范围内，单纯的 CCHCC占HCC比例的差异很大，从不到1%到37% (11)(12)(13) 的均有报道，这可能不仅反映了地理分布和患者群体的 差异，而且还取决于不明确的诊断标准。一些学者认为 <30%的透明细胞癌成分就足够了 (14,16) ，只有在肝癌中超 过30% (17,18) 甚至要求大于50%的透明细胞癌成分时才能诊 断CCHCC (11,12) (19) 。还提 出了一种脂肪变性亚型(steatotic subtype, S-HCC)，包 括有或没有脂肪性肝炎的肿瘤内含脂质肝细胞癌，尽管 该亚型目前尚未在WHO分类中得到承认 (20) 。 总之，目前的形态学定义是，将含有80%以上的"透 明细胞"的肝细胞癌进一步分类为C-HCC、SH-HCC、 S-HCC或WHO定义的CCHCC。然而，这些亚型并没有明 确的诊断标准。C-HCC具有明确的形态学特征，一组高 复发风险的亚型。尽管SH-HCC与肝脏背景的关系以及该 肿瘤的分子基础机制尚不清楚。在真正开始研究这些亚 型的生物学相关性之前，还需要进行更多的研究来建立 广泛的共识定义，并可以重复应用。 CCHCC需要与肾细胞癌和其他类型的肝外透明细胞 癌的转移瘤区分开来 (21)(22)(23) 。最近，一种由嗜酸细胞和透明 细胞组成的纤维层细胞HCC (24) ，透明细胞胆管瘤 (25,26) 和透 明细胞胆管瘤 (73-77) 被描述为非常罕见的实体，这也需要鉴 别诊断。在纤维层状HCC的透明细胞变异中，透明的细 胞质是由于空泡，可能是由线粒体的改变引起的，而不 是糖原或脂肪 (24) 。透明细胞胆管瘤和胆管癌的细胞质变 化的性质存在争议。一些研究者从组织化学或电子显微 镜方法得出结论，透明细胞积累了粘液物质，但没有脂 质或糖原 (25,27) ；其他学者观察到粘液与淀粉酶敏感周期酸 席夫(PAS)阳性物质，可能是糖原，或无法证明任何粘 液物质 (28,29) ，但脂质液泡或糖原。偶尔，肝血管平滑肌脂 肪瘤可能主要由具有清晰细胞特征的上皮样细胞(糖细 胞)组成，也应与CCHCC区分开来。黑素细胞标记物的 表达，如黑素a-a和HMB-45，以及细胞角蛋白的缺失，有 利于血管平滑肌脂肪瘤的诊断 (30) 。除此以外，一些肿瘤 标记物也被发现也有助于鉴别诊断，大量的标记物如肝 细胞标记物HepPar-1(图1G)、精氨酸酶-1抗体和细胞角 蛋白如CK8/18 (31,32) 均可用于CCHCC的鉴别诊断。Oliveira 等人提出，白蛋白mRNA是区分CCHCC与其他类型透明 细胞癌的可靠标记物 (33,34) 。已报道了2例同时发生CCHCC 和RCC的病例，但通过应用上述一些细胞标记物，排除 了将其误解为转移性疾病的可能性。通过应用抑制素-α和 类固醇生成因子-1的染色，可以区分 (35)<...…”