Hepatocellular carcinoma in a 12-year-old child with PiZZ α1-antitrypsin deficiency

Abstract

We read with great interest the review by Rudnik and Perlmutter 1 on the mechanisms of carcinogenesis in PiZZ ␣1-antitrypsin deficiency (A1ATD). We would like to endorse their hypothesis and previous animal models 2 by describing the development of hepatocellular carcinoma (HCC) in a 12-year-old girl with end-stage liver disease related to PiZZ A1ATD.The diagnosis of PiZZ A1ATD was made at the age of 3.5 years following investigations into the child's hepatosplenomegaly. She was noted to have a history of unexplained prolonged neonatal jaundice and mild developmental delay. Her clinical course was complicated by an episode of hematemesis at age 4 that required variceal sclerotherapy. At age 11, she suffered a blunt abdominal trauma. A computed tomography scan suggested a splenic infarction and significant splenic varices, but no intrahepatic lesions. The child recovered clinically under conservative management. Eight months later, a follow-up ultrasound scan detected a subcapsular nodule (diameter 2.6 cm) in segment V of the right lobe. A biphasic computed tomography scan indicated arterialization of the nodule and the presence of small para-aortic and mesenteric nodes. Her serum ␣-fetoprotein level was 4 (normal value Ͻ7 IU/L), her carcino-embryonic antigen level was less than 2 (nv Ͻ5 g/L), and her Ca-199 level was 11 (nv Ͻ37 kU/L). The child was scheduled for liver transplantation, and a hepatectomy 5 months later confirmed a single subcapsular nodule measuring 0.8 ϫ 2.5 ϫ 1.5 cm located in the right lobe of the liver, which exhibited cirrhosis. Six months after the operation, the child is well with normal graft function and no signs of recurrence.The tumor was composed of two-cell-thick liver cell plates surrounded by diffusely capillarized CD34-positive sinusoids. Lesional hepatocytes showed minimal cytological atypias and no mitotic activity. The proportion of proliferating hepatocytes was less than 1% using Ki67 (MIB-1) immunostaining (Fig. 1A). Only about a third of the lesional hepatocytes contained diastase-resistant periodic acid Schiff (dPAS)-positive fine intra-cytoplasmic granules, confirmed to be ␣1-antitrypsin via immunohistochemistry (Fig. 1B). Hepatocytes with ␣1-antitrypsin deposits were more present at the periphery of the tumor and in particular at the interface with fibrous tissue (Fig. 1C). The background liver showed periseptal hepatocytes containing abundant intracytoplasmic dPAS-positive deposits of variable size, ranging from fine granular material to globules up to 20 m in diameter (Fig. 1D).The extent of deposition of dPAS-positive material is an age-related phenomenon in PiZ A1ATD 3 that is also observed in older individuals who carry only one PiZZ allele. 4,5 The diminished presence of dPASpositive deposits in the HCC cells of our patient is compatible with the hypothesis that globule-containing periportal hepatocytes could generate a proliferative stimulus, leading to a higher turnover of globuledevoid perivenular hepatocytes and, ultimately, neoplastic change. Whether the abdomi...

Mysteries of α1-antitrypsin deficiency: emerging therapeutic strategies for a challenging disease

“…Liver cells that have accumulated more polymerized ATZ (so-called globule-containing hepatocytes) are relatively impaired in proliferation but induce chronic hyperproliferation in the globule-devoid hepatocytes by a trans-effect. Interestingly, most hepatocellular carcinomas described in individuals with ATD are negative for AT staining but in many cases are surrounded by AT-positive, globule-containing hepatocytes, consistent with the concept that globule-containing hepatocytes drive the chronic hyper-proliferative process that leads to carcinoma (Hadzic et al, 2006; Zhou and Fischer, 1998; Zhou et al, 2000). …”

Liver Repopulation and Carcinogenesis: Two Sides of the Same Coin?

“…63 In fact, the latter population occupies an increasing proportion of the liver as the animal ages, ultimately becoming the site of origin for liver cancer. 62 It is noteworthy that these findings have recently been matched with a clinical counterpart: Hadzic et al 64 reported that hepatocellular carcinoma arising in a patient with ␣-1AT deficiency was also devoid of globules, whereas surrounding hepatocytes were loaded with protein deposits. Interestingly, Rudnick et al 63 have further suggested that ␣-1AT deficiency could possibly benefit from therapeutic strategies based on normal hepatocyte transplantation, given that endogenous parenchymal cells are relatively refractory to growth stimuli.…”

Hepatic Progenitor Cell Proliferation and Liver Injury in α‐1‐Antitrypsin Deficiency

“…A “low grade” hepatocellular regenerative response, presumably compensatory, has also been identified, although the mechanisms linking injury, regeneration, and the development of HCC are poorly understood[6]. It is well known that this, and other, metabolic diseases can be a risk factor for HCC, but possible links to pre-existing dysplasia, adenoma formation, the proliferative response, and other mechanisms are unknown [14, 15]. As a result of our previous observations in the transgenic mouse system, we proposed that at least part of the mechanism of the regeneration in this disease characterized by chronic liver injury could involve hepatic progenitor cells, and that knowledge of the characteristics of this response and the cells involved could further advance the understanding of the liver injury, dysplasia, and HCC formation in this disease.…”