Saudi Journal of Gastroenterology
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CASE REPORT Table of Contents   
Year : 2004  |  Volume : 10  |  Issue : 2  |  Page : 92-95
Fibrolamellar hepatocellular carcinoma with alpha-one antitrypsin liver disease

1 Department of Medicine, King Faisal Specialist Hospital, Riyadh, Saudi Arabia
2 Department of Pathology, King Faisal Specialist Hospital, Riyadh, Saudi Arabia

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Date of Submission03-Nov-2002
Date of Acceptance29-Jul-2003

How to cite this article:
Al Bugami MM, Farahat KL, Al-Ashgar HI, Hainau B. Fibrolamellar hepatocellular carcinoma with alpha-one antitrypsin liver disease. Saudi J Gastroenterol 2004;10:92-5

How to cite this URL:
Al Bugami MM, Farahat KL, Al-Ashgar HI, Hainau B. Fibrolamellar hepatocellular carcinoma with alpha-one antitrypsin liver disease. Saudi J Gastroenterol [serial online] 2004 [cited 2022 Oct 7];10:92-5. Available from:

Alpha-one antitrypsin (AAT) deficiency is an autosomal hereditoy disorder affecting the lung and liver. AAT is a glycoprotein synthesized in and secreted by the hepatocytes. It is a serine protease inhibitor inhibiting neutrophil elastase from destroying the lung. More than 75 alleles of the AAT gene have been identified and categorized into an arrangement designated as the protease inhibitor (Pi) system [1] . These alleles can be categorized into four groups on the basis of the AAT levels that occur in the serum: (I) " normal," associated with normal serum levels of AAT with normal function; (II) "deficient," associated with serum AAT levels < 35 percent of average normal level; (III) "null," where there is no detectable AAT protein in serum; (IV) "dysfunctional," in which the AAT protein is present but does not function normally. The normal and deficient AAT alleles are assigned a letter code (A to Z) on the basis of the electrophoretic mobility of the molecule. The most common deficiency allele associated with emphysema is the Z allele; the liver disease associated with AAT deficiency is much less common than emphysema [2],[3] . Its most common manifestations are hepatitis with jaundice in the neonate. This is usually self-limiting, but in 1 to 3 percent of AAT-deficient individuals, it progresses to liver cirrhosis and eventually to hepatic failure [2] . The pathophysiology of liver injury is not fully understood, and might be secondary to the accumulation and possibly altered degradation of abnormal AAT in the hepatocytes [4] .

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare histological variant of hepatocellular carcinoma (HCC), and accounts for fewer than 10% of all cases of HCC. It tends to _occur in young adult without underlying cirrhosis and with normal serum alphafetoprotein [5] . It is non­encapsulated but well circumscribed and contains fibrous lamellae. FL-HCC does not have favorable prognosis and does not respond differently to HCC current therapeutic regimens [6] . It grows slowly but metastasis has been-reported and medium survival was 14 months in patients with metastases [7] . We report an association between this rare histological variant of HCC and AAT deficiency in an adolescent. This association has been described in only two studies [8],[9] .

   Case Report Top

A 15-year-old Saudi male, nonsmoker presented with painless right hypochondrium swelling for two years, which was increasing in size in the last four months. He has no fever, or weight loss and no significant family history. Physical examination showed large firm mass with irregular surface extending from the right hypochordrium to the right iliac fossa without bruit. No lymphadenopathy on systemic examination. The complete blood count and renal profile were normal. Liver enzymes showed the following: Alkaline phosphatase 187 (40-50) U/L, alanine aminotransferase 52 (10-40) U/L, aspartate aminotransferase 66 (10-40) U/L, total Bilirubin 5 (0-2 1) U/L. Hepatitis B and C virus were negative. Alphafetoprotein was normal and AAT level was 2.87 (0.83­1.99).

Liver ultrasonography showed a large heterogeneous lobulated mass with right pre-aortic lymph nodes. Abdominal computed tomography (CT) confirmed the presence of a large nonenhancing mass occupying the caudate lobe and right posterior segment of the liver extending inferiorly down to the level of the iliac crest. There was evidence of perfusion defect in the right lobe posterior segment. This was most likely due to invasion of the tumor into the posterior segmental branch of the right portal vein. No other satellite lesions in the liver could be seen. On the other hand, chest CT showed multiple bilateral parachymal lung nodules representing metastatic lesions. No evidence of mediastinal lymphadenopathy.

Liver biopsy was done and showed neoplastic hepatocytes arranged in trabeculae, which were separated by fibrous strands [Figure - 1]. The neoplastic and non­neoplastic liver parenchyma as well contained PAS-positive diastase-resistant globules. The immunohistochemical stain for AAT was positive both in the neoplastic and non-neoplastic tissue. The reaction was strongest in the tumor cells [Figure - 2]. Furthermore, the electron microscopy demonstrated accumulation of flocculent material of medium electron density in the cytoplasm of some but not all hepatocytes. This cellular ultrastructure is typical of alpha-one antitrypsin deficiency. Unfortunately, the patient was inoperable and died two weeks after diagnosis.

   Discussion Top

Our patient has evidence of fibrolamellar carcinoma by liver biopsy. The presence of AAT deficiency was found on liver biopsy both in neoplastic and non-neoplastic liver parenchyma, but serum level of AAT was normal. The phenotype pattern of AAT was not identified by electrophoresis of patient's serum. We couldn't screen family for AAT deficiency because his father refused. Zhou and Fischer studied 164 consecutive cases of primary liver carcinoma for evaluation of the tumour type (i.e, HCC, cholangiocarcinoma [CC], and combined hepatocholangiocarcinoma [CHCC]) and for signs of AAT deficiency in the surrounding liver tissue. Hepatocellular globular AAT deposits, as detected by a monoclonal antibody to the mutant PiZ AAT, were seen in 13 cases (7.9%). Four cases only of 111 HCC types (3.5%) were positive for this antitrypsin variant [10] . As in our patient, the diagnosis of AAT deficiency was primarily made by immunohistochemical identification of AAT deposits in liver epithelia. Furthermore, EM showed the typical accumulation of flocculent material in the cytoplasm of hepatocytes seen in AAT deficiency. The pathogenic relationship between AAT deficiency with hepatic cirrhosis and HCC has previously been reported [11],[12],[13],[14]. Liver cirrhosis is reported to be the main predisposing risk factor for liver carcinoma in AAT deficiency. However, in the above mentioned study, the AAT-associated carcinoma arose in all, but one, noncirrhotic liver tissue, suggesting that liver cirrhosis is not a pre-condition for the development of these tumours in AAT deficiency patients. Our patient developed FL-HCC, a histological variant that occurs almost always in noncirrhotic liver, suggesting that accumulation of AAT in the liver might have a carcinogenic effect.

The association between AAT deficiency and FL-HCC has been described in two studies. The first one reported a patient with PiMZ phenotype who developed FL­HCC, and in the second, three patients were PiMZ and had FL-HCC [8],[9] . These studies, together with our case report, highlight not only the rare association between AAT deficiency and FL-HCC, but also support the evidence of the deleterious effect of the intracellular aggregation of AAT that occurs in the hepatocyte. Finally, the diagnosis of AAT deficiency should be considered, not only in case of liver cirrhosis, but also in all cases of liver carcinoma, and in particular the CHCC type. The FL-HCC variant is rare. It must also be stressed that diagnosis should be made by phenotype analysis and not the serum AAT level. However, the immunohistochemical study of liver biopsy offers a valuable tool for the diagnosis of AAT deficiency.

   References Top

1.Brandtly M, Nukiwa T, Crystal RG. Molecular basis of alpha- l-antitrypsin deficiency. Am J Med 1988; 84: 13-31.  Back to cited text no. 1    
2.Eriksson S, Carlson J, Velez R. Risk of cirrhosis and primary liver cancer in alpha-l-antitrypsin deficiency. N Engl J Med 1986; 314: 736-9.  Back to cited text no. 2  [PUBMED]  
3.Sveger T. Liver disease in alpha- l-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976; 294: 1316.  Back to cited text no. 3  [PUBMED]  
4.Sleisenger and Fordtran's Gastrointestinal and liver disease; W B Saunders 1988; 6: 1084-85.  Back to cited text no. 4    
5.Okuda K. Natural history of hepatocellular carcinoma including fibrolamellar and hepato­cholangiocarcinoma variants. J Gastroenterol Hepatol. 2002; 17: 401-5.  Back to cited text no. 5    
6.Katzenstein HM, Krailo MD, Malogolowkin MH, et al. Fibrolamellar hepatocellular carcinoma in children and adolescents. Cancer 2003; 97: 2006-12.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Epstein BE, Pajak TF, Haulk TL, Herpst JM, Order SE, Abrams RA. Metastatic nonresectable fibrolamellar hepatoma: prognostic features and natural history. Am J Clin Oncol 1999; 2: 22-8.  Back to cited text no. 7    
8.Rabinovitz M, Gavaler JS, Kelly RH, Prieto M, Van Thiel DH. Lack of increase in heterozygous alpha- l-antitrypsin deficiency phenotypes among patients with hepatocellular and bile duct carcinoma. Hepatology 1992; 15: 407-10.  Back to cited text no. 8  [PUBMED]  
9.Govindarajan S, Ashcavai M, Peters RL .Alpha­1-antitrypsin phenotypes in hepatocellular carcinoma. Hepatology 1981; 1: 628-31.  Back to cited text no. 9  [PUBMED]  
10.Zhou H, Fischer HP. Liver carcinoma in PiZ alpha 1 antitrypsin deficiency. Am J Surg Pathol 1998; 22: 742-8.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Eriksson S, Moestrup T, Hagerstrand I. Liver, lung and malignant disease in heterozygous (PiMZ) alpha 1-antitrypsin deficiency. Acta Med Scand 1975; 198: 243-7.  Back to cited text no. 11    
12.Rawlings W Jr, Moss J, Cooper HS, Hamilton SR. Hepatocellular Carcinoma and Partial deficiency of alpha-l-antitrypsin (MZ). Ann Intern Med. 1974; 81: 771-3.  Back to cited text no. 12    
13.Rubel LR, Ishak KG, Benjamin SB, Knuff TE. Alpha-l-antitrypsin deficiency and hepatocellular carcinoma. Association with cirrhosis, copper storage and Mallory bodies. Arch Pathol Lab Med. 1982; 106: 678-81.  Back to cited text no. 13    
14.Askari FK. Molecular mechanism of hepatocellular injury in alpha 1-antitrypsin deficiency. Hepatology 1995; 21: 1745-7.  Back to cited text no. 14  [PUBMED]  

Correspondence Address:
Hamad Ibrahim Al-Ashgar
King Faisal Specialist Hospital, P 0 Box 3354, Riyadh 11211
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

PMID: 19861832

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