The telomere hypothesis of cancer initiation indicates that telomere shortening initiates cancer by induction of chromosomal instability. To test whether this hypothesis applies to human hepatocellular carcinoma (HCC), we analyzed the telomere length of hepatocytes in cytological smears of fine-needle biopsies of liver tumors from patients with cirrhosis (n ‫؍‬ 39). The tumors consisted of 24 HCC and 15 regenerative nodules as diagnosed by combined histological and cytological diagnostics. In addition, we analyzed the telomere length of hepatocytes in HCC and surrounding noncancerous liver tissue within individual patients in another cohort of 10 patients with cirrhosis. Telomere length analysis of hepatocytes was correlated with tumor pathology and ploidy grade of the tumors, which was analyzed by cytophotometry. Telomeres were significantly shortened in hepatocytes of HCC compared to hepatocytes in regenerative nodules or surrounding noncancerous liver tissue. Hepatocyte telomere shortening in HCC was independent of the patient's age. There was no overlap in mean telomere lengths of individual samples when comparing HCC with regenerative nodules or noncancerous surrounding liver. Within the HCC group, telomeres were significantly shorter in hepatocytes of aneuploid tumors compared to diploid tumors. In conclusion, our data suggest that the telomere hypothesis of cancer initiation applies to human HCC and that cell type-specific telomere length analysis might indicate the risk of HCC development. (HEPATOLOGY 2004;40:80 -86.) L iver cirrhosis is the major risk factor for the development of hepatocellular carcinoma (HCC), and the incidence of HCC in cirrhotic patients is 3% to 6% annually. 1-3 One of the common features of human epithelial cancer is the prevalence of chromosomal instability (CIS). 4 As in other epithelial cancers, HCCs show a high incidence of CIS. 5 A current hypothesis is that telomere shortening and loss of telomere function play a role in the induction of CIS. 6,7 The main function of telomeres is the capping of chromosomal ends. 8 Due to the "end-replication problem" of DNA polymerase, telomeres shorten during each round of cell division. 9 Telomere shortening limits the proliferative capacity of primary human cells to a finite number of cell divisions 10 and appears to restrain the regenerative capacity of tissues and organs in aging and chronic diseases. 7 In the liver, hepatocyte telomere shortening has been linked to cirrhosis formation. 11 When telomeres reach a critically short length, they lose capping function, resulting in chromosomal fusions. 12 When cells with fused chromosomes enter the cell cycle, these fusions will be disrupted during mitosis, resulting in the breakage of chromosomes and chromosomal gains and losses. 13 This phenomenon has been termed the fusion-bridge-breakage cycle and might contribute to the induction of CIS and cancer in the aged. 13 In line with this hypothesis, the initiation of cancer is increased by telomere shortening in telomerase-deficient mice. 1...

Hepatic involvement in hereditary hemorrhagic telangiectasia (HHT) is highly variable andH ereditary hemorrhagic telangiectasia (HHT, Rendu-Osler-Weber syndrome) is an autosomal-dominant genetic disorder characterized by the development of angiodysplasias with dilated vessels as well as arteriovenous aneurysms and shunts. Mutations of at least 2 genes (i.e., endoglin, acitivin receptor-like kinase-1) have been identified, which lead to the typical clinical picture of HHT comprising epistaxis, telangiectasias of the skin and mucous membranes, and a characteristic family history.Visceral and hepatic lesions have been described frequently in patients with hepatic involvement. The proportion of patients with hepatic involvement ranges from 8% to 31%. 1 Severe complications such as cardiac failure and portal hypertension may develop and often require invasive therapeutic measures. [2][3][4] Hepatic involvement in HHT is highly variable. It may be confused with differential diagnoses such as cirrhosis, focal nodular hyperplasia, and hepatic congestion. The situation is complicated further by the fact that patients with long-standing HHT may be infected with the hepatitis C virus due to recurrent blood transfusions. The molecular basis of hepatic HHT involvement has not yet been characterized.The gold standard to diagnose hepatic involvement in HHT is the selective angiography of the hepatic artery. However, this is an invasive, labor-intensive, and expensive procedure. Therefore, ultrasound was proposed as a Abbreviations: HHT, hereditary hemorrhagic telangiectasia; RI, resistance index; PI, pulsatility index. From the

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(Gut 1998;42:123-126)

At present there is no established therapy for treating patients with hereditary hemorrhagic telangiectasia (HHT) and symptomatic hepatic involvement. We present the results of a prospective study with 15 consecutive patients who were treated with staged hepatic artery embolization (HAE). Branches of the hepatic artery were selectively catheterized and embolized in stages using polyvinyl alcohol particles (PVA) and platinum microcoils or steel macrocoils. Prophylactic antibiotics, analgesics and anti-emetics were administered after every embolization. Clinical symptomatology and cardiac output were assessed before and after therapy as well as at the end of follow-up (median 28 months; range 10-136 months). Five patients had abdominal pain and four patients had symptoms of portal hypertension. The cardiac output was raised in all patients, with cardiac failure being present in 11 patients. After treatment, pain resolved in all five patients, and portal hypertension improved in two of the four patients. The mean cardiac output decreased significantly ( P<0.001) from 12.57+/-3.27 l/min pre-treatment to 8.36+/-2.60 l/min at the end of follow-up. Symptoms arising from cardiac failure resolved or improved markedly in all but one patient. Cholangitis and/or cholecystitis occurred in three patients of whom two required a cholecystectomy. One patient with pre-existent hepatic cirrhosis died as a complication of the procedure. Staged HAE yields long-term relief of clinical symptoms in patients with HHT and hepatic involvement. Patients with pre-existing hepatic cirrhosis may be poor candidates for HAE.

We conclude that thrombocytopenia in patients with liver disease is unlikely to be explained only based on a deficient hepatic production of thrombopoietin. Patients with chronic viral hepatitis have significantly elevated thrombopoietin levels; the involved pathomechanisms require further study.

Hereditary hemorrhagic telangiectasia (HHT), or Osler-Rendu-Weber syndrome, is a heterogeneous inherited disorder characterized by multi-systemic vascular dysplasia and wide variation in its phenotypic expression. Hepatic manifestation is seen in about 8 to 30 % of the patients. The molecular basis for liver involvement is unknown. We screened the two known HHT disease loci, the ALK1 (ACVRL1) and ENG genes, for mutations in a clinically well-characterized group of HHT patients with or without liver involvement. Mutations in the ALK1 gene were detected in eight out of 10 HHT patients with hepatic manifestation. Among nine HHT patients without liver involvement, four had mutations in the ALK1, and three in the ENG genes, respectively. In one patient with hepatic manifestation a mutation was detected in both the ALK1 and ENG genes. No mutation could be detected in two patients with liver involvement and, likewise, in two patients without hepatic manifestation. In this study, we have identified five novel ALK1 and one ENG disease-causing mutations. We conclude that hepatic manifestation in HHT patients is associated with mutations in the ALK1 gene, but rarely with ENG mutations. © 2005 Wiley-Liss, Inc.KEY WORDS: HHT; Osler-Rendu-Weber syndrome; ALK1; ACVRL1; ENG INTRODUCTIONOsler-Rendu-Weber syndrome or hereditary hemorrhagic telangiectasia (HHT, MIM# 187300 and 600376) is an autosomal dominat disease with age-dependent penetrance and variable expression of the clinical manifestation. The estimated prevalence is in the order of 1 out of 10,000 (Guttmacher et al., 1995). According to the Curaçao DOI: 10.1002/humu.9311 2 Kuehl et al.criteria , the clinical diagnosis of HHT requires that at least three out of four conditions, i.e. epistaxis, telangiectasia, visceral lesions, and a family history with HHT, should be present in order to ensure the diagnosis. While the cutaneous and mucocutaneous manifestations have mostly a relative good prognosis, the involvement of the visceral organs, if untreated, can trigger mortality (Kjeldsen et al., 1999;Shovlin and Letarte, 1999).Hepatic manifestation of HHT is estimated to affect about 8 to 30% of the patients (Reilly and Nostrant, 1984;Bauer et al., 1995;Kjeldsen et al., 1999). The hepatic vascular malformation can be diagnosed by ultrasound (Caselitz et al., 2003) and is mostly associated with fibrosis and/or atypical cirrhosis (Reilly and Nostrant, 1984). In severe cases, the reduced liver function associated with HHT may lead to progressive hepatic failure (Weik and Greiner 1999).Little is known about the genetic basis of the observed clinical heterogeneity of HHT. Even within the same family there could be great variations with respect to manifestation and severity of the disease. (Shovlin, 1997). Disease-causing mutations had been identified in both the endoglin (ENG, MIM# 131195) gene (McAllister et al., 1994) on chromosome 9 (HHT type 1) and in the activin receptor-like kinase (ALK1, also designated ACVRL1, MIM# 601284) gene (Johnson et al., 1996) on chromosome 12 (HHT ...

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