|Hepatocellular carcinoma in an individual who was hepatitis C positive. Autopsy specimen.|
It occurs in the setting of chronic liver inflammation, and is most closely linked to chronic viral hepatitis infection (hepatitis B or C) or exposure to toxins such as alcohol or aflatoxin. Certain diseases, such as hemochromatosis and alpha 1-antitrypsin deficiency, markedly increase the risk of developing HCC. Metabolic syndrome and NASH are also increasingly recognized as risk factors for HCC.
As with any cancer, the treatment and prognosis of HCC vary depending on the specifics of tumor histology, size, how far the cancer has spread, and overall health.
The vast majority of HCC occurs in Asia and sub-Saharan Africa, in countries where hepatitis B infection is endemic and many are infected from birth. The incidence of HCC in the United States and other developing countries is increasing due to an increase in hepatitis C virus infections. It is more common in male than females for unknown reasons.
- 1 Signs and symptoms
- 2 Risk factors
- 3 Pathogenesis
- 4 Diagnosis
- 5 Prevention
- 6 Treatment
- 7 Prognosis
- 8 Epidemiology
- 9 Research
- 10 Abbreviations
- 11 See also
- 12 References
- 13 Further reading
- 14 External links
Signs and symptoms
Most cases of HCC occur in people who already have symptoms of chronic liver disease. They may present either with worsening of symptoms or may be without symptoms at the time of cancer detection. HCC may directly present with yellow skin, abdominal swelling due to fluid in the abdomen, easy bruising from blood clotting abnormalities, loss of appetite, unintentional weight loss, abdominal pain, nausea, vomiting, or feeling tired.
HCC mostly occurs in people with cirrhosis of the liver, and so risk factors generally include factors which cause chronic liver disease that may lead to cirrhosis. Still, certain risk factors are much more highly associated with HCC than others. For example, while heavy alcohol consumption is estimated to cause 60-70% of cirrhosis, the vast majority of HCC occurs in cirrhosis attributed to viral hepatitis (although there may be overlap). Recognized risk factors include:
- Chronic viral hepatitis (estimated cause of 80% cases globally)
- Congenital disorders:
- Alpha 1-antitrypsin deficiency
- Wilson's disease (controversial; while some theorise the risk increases, case studies are rare and suggest the opposite where Wilson's disease actually may confer protection)
- Hemophilia, although statistically associated with higher risk of HCC, this is due to coincident chronic viral hepatitis infection related to repeated blood transfusions over lifetime.
The significance of these risk factors varies globally. In regions where hepatitis B infection is endemic, such as southeast China, this is the predominant cause. In populations largely protected by hepatitis B vaccination, such as the United States, HCC is most often linked to causes of cirrhosis such as chronic hepatitis C, obesity, and alcohol abuse.
Certain benign liver tumors, such as hepatocellular adenoma, may sometimes be associated with coexisting malignant HCC. There is limited evidence for the true incidence of malignancy associated with benign adenomas; however, the size of hepatic adenoma is considered to correspond to risk of malignancy and so larger tumors may be surgically removed. Certain subtypes of adenoma, particularly those with β-catenin activation mutation, are particularly associated with increased risk of HCC.
Children and adolescents are unlikely to have chronic liver disease, however, if they suffer from congenital liver disorders, this fact increases the chance of developing hepatocellular carcinoma. Specifically, children with biliary atresia, infantile cholestasis, glycogen-storage diseases, and other cirrhotic diseases of the liver are predisposed to developing HCC in childhood.
Young adults afflicted by the rare fibrolamellar variant of hepatocellular carcinoma may have none of the typical risk factors, i.e. cirrhosis and hepatitis.
The risk of hepatocellular carcinoma in type 2 diabetics is greater (from 2.5 to 7.1 times the non diabetic risk) depending on the duration of diabetes and treatment protocol. A suspected contributor to this increased risk is circulating insulin concentration such that diabetics with poor insulin control or on treatments that elevate their insulin output (both states that contribute to a higher circulating insulin concentration) show far greater risk of hepatocellular carcinoma than diabetics on treatments that reduce circulating insulin concentration. On this note, some diabetics who engage in tight insulin control (by keeping it from being elevated) show risk levels low enough to be indistinguishable from the general population. This phenomenon is thus not isolated to diabetes mellitus type 2 since poor insulin regulation is also found in other conditions such as metabolic syndrome (specifically, when evidence of non alcoholic fatty liver disease or NAFLD is present) and again there is evidence of greater risk here too. While there are claims that anabolic steroid abusers are at greater risk (theorized to be due to insulin and IGF exacerbation), the only evidence that has been confirmed is that anabolic steroid users are more likely to have hepatocellular adenomas (a benign form of HCC) transform into the more dangerous hepatocellular carcinoma.
Hepatocellular carcinoma, like any other cancer, develops when there is a mutation to the cellular machinery that causes the cell to replicate at a higher rate and/or results in the cell avoiding apoptosis. In particular, chronic infections of hepatitis B and/or C can aid the development of hepatocellular carcinoma by repeatedly causing the body's own immune system to attack the liver cells, some of which are infected by the virus, others merely bystanders. While this constant cycle of damage followed by repair can lead to mistakes during repair which in turn lead to carcinogenesis, this hypothesis is more applicable, at present, to hepatitis C. Chronic hepatitis C causes HCC through the stage of cirrhosis. In chronic hepatitis B, however, the integration of the viral genome into infected cells can directly induce a non-cirrhotic liver to develop HCC. Alternatively, repeated consumption of large amounts of ethanol can have a similar effect. The toxin aflatoxin from certain Aspergillus species of fungus is a carcinogen and aids carcinogenesis of hepatocellular cancer by building up in the liver. The combined high prevalence of rates of aflatoxin and hepatitis B in settings like China and West Africa has led to relatively high rates of hepatocellular carcinoma in these regions. Other viral hepatitides such as hepatitis A have no potential to become a chronic infection and thus are not related to hepatocellular carcinoma.
Methods of diagnosis in HCC have evolved with the improvement in medical imaging. The evaluation of both asymptomatic patients and those with symptoms of liver disease involves blood testing and imaging evaluation. Although historically a biopsy of the tumor was required to prove the diagnosis, imaging (especially MRI) findings may be conclusive enough to obviate histopathologic confirmation.
Due to the fact that HCC most commonly occurs in the setting of chronic liver disease (e.g. viral hepatitis) and cirrhosis (about 80%),[medical citation needed] screening by ultrasound (US) is commonly advocated in this population. Surveillance recommendations vary, but the American Association of Liver Diseases recommends screening Asian men over the age of 40, Asian women over the age of 50, people with HBV and cirrhosis, and African and North American blacks. These people are screened with ultrasound every 6 months. Additional evaluation may include measurement of blood levels of AFP, which is a tumor marker. Elevated levels of AFP are associated with active HCC disease. At levels >20 sensitivity is 41-65% and specificity is 80-94%. However, at levels >200 sensitivity is 31, specificity is 99%.
Ultrasound (US) is often the first imaging and screening modality used. On US, HCC often appears as a small hypoechoic lesion with poorly defined margins and coarse irregular internal echoes. When the tumor grows, it can sometimes appear heterogeneous with fibrosis, fatty change, and calcifications. This heterogeneity can look similar to cirrhosis and the surrounding liver parenchyma. A systematic review found that the sensitivity was 60 percent (95% CI 44-76%) and specificity was 97 percent (95% CI 95-98%) compared with pathologic examination of an explanted or resected liver as the reference standard. The sensitivity increases to 79% with AFP correlation.
Higher risk people
In a person where there is higher suspicion of HCC, such as a person with symptoms or abnormal blood tests (i.e. alpha-fetoprotein and des-gamma carboxyprothrombin levels), evaluation requires imaging of the liver by CT or MRI scans. Optimally, these scans are performed with intravenous contrast in multiple phases of hepatic perfusion in order to improve detection and accurate classification of any liver lesions by the interpreting radiologist. Due to the characteristic blood flow pattern of HCC tumors, a specific perfusion pattern of any detected liver lesion may conclusively detect an HCC tumor. Alternatively, the scan may detect an indeterminate lesion and further evaluation may be performed by obtaining a physical sample of the lesion.
Ultrasound, CT scan, and MRI may be used to evaluate the liver for HCC. On CT and MRI, HCC can have three distinct patterns of growth:
- A single large tumor
- Multiple tumors
- Poorly defined tumor with an infiltrative growth pattern
A systematic review of CT diagnosis found that the sensitivity was 68 percent (95% CI 55-80%) and specificity was 93 percent (95% CI 89-96%) compared with pathologic examination of an explanted or resected liver as the reference standard. With triple-phase helical CT, the sensitivity 90% or higher, but this data has not been confirmed with autopsy studies.
However, MRI has the advantage of delivering high-resolution images of the liver without ionizing radiation. HCC appears as a high-intensity pattern on T2 weighted images and a low-intensity pattern on T1 weighted images. The advantage of MRI is that is has improved sensitivity and specificity when compared to US and CT in cirrhotic patients with whom it can be difficult to differentiate HCC from regenerative nodules. A systematic review found that the sensitivity was 81 percent (95% CI 70-91%) and specificity was 85 percent (95% CI 77-93%) compared with pathologic examination of an explanted or resected liver as the reference standard. The sensitivity is further increased if gadolinium contrast-enhanced and diffusion-weighted imaging are combined.
Liver Image Reporting and Data System (LI-RADS) is a classification system for the reporting of liver lesions detected on CT and MRI. Radiologists use this standardized system to report on suspicious lesions and to provide an estimated likelihood of malignancy. Categories range from LI-RADS (LR) 1 to 5, in order of concern for cancer. A biopsy is not needed to confirm the diagnosis of HCC if certain imaging criteria are met.
Macroscopically, liver cancer appears as a nodular or infiltrative tumor. The nodular type may be solitary (large mass) or multiple (when developed as a complication of cirrhosis). Tumor nodules are round to oval, gray or green (if the tumor produces bile), well circumscribed but not encapsulated. The diffuse type is poorly circumscribed and infiltrates the portal veins, or the hepatic veins (rarely).
Microscopically, there are four architectural and cytological types (patterns) of hepatocellular carcinoma: fibrolamellar, pseudoglandular (adenoid), pleomorphic (giant cell) and clear cell. In well-differentiated forms, tumor cells resemble hepatocytes, form trabeculae, cords, and nests, and may contain bile pigment in the cytoplasm. In poorly differentiated forms, malignant epithelial cells are discohesive, pleomorphic, anaplastic, giant. The tumor has a scant stroma and central necrosis because of the poor vascularization.
The prognosis of HCC is affected by the staging of the tumor as well as the liver's function due to the effects of liver cirrhosis.
There are a number of staging classifications for HCC available; however, due to the unique nature of the carcinoma in order to fully encompass all the features that affect the categorization of the HCC, a classification system should incorporate; tumor size and number, presence of vascular invasion and extrahepatic spread, liver function (levels of serum bilirubin and albumin, presence of ascites and portal hypertension) and general health status of the patient (defined by the ECOG classification and the presence of symptoms).
Out of all the staging classification systems available the Barcelona Clinic Liver Cancer (BCLC) staging classification encompasses all of the above characteristics. This staging classification can be used in order to select people for treatment.
Important features that guide treatment include the following:
- spread (stage)
- involvement of liver vessels
- presence of a tumor capsule
- presence of extrahepatic metastases
- presence of daughter nodules
- vascularity of the tumor
MRI is the best imaging method to detect the presence of a tumor capsule.
The most common sites of metastasis are the lung, abdominal lymph nodes, and bone.
Since hepatitis B or C is one of the main causes of hepatocellular carcinoma, prevention of this infection is key to then prevent hepatocellular carcinoma. Thus, childhood vaccination against hepatitis B may reduce the risk of liver cancer in the future.
It is unclear if screening those with chronic liver disease for hepatocellular carcinoma improves outcomes.
Treatment of hepatocellular carcinoma varies by the stage of disease, a person's likelihood to tolerate surgery, and availability of liver transplant:
- Curative intention: for limited disease, when the cancer is limited to one or more areas of within the liver, surgically removing the malignant cells may be curative. This may be accomplished by resection the affected portion of the liver (partial hepatectomy) or in some cases by orthotopic liver transplantation of the entire organ.
- "Bridging" intention: for limited disease which qualifies for potential liver transplantation, the person may undergo targeted treatment of some or all of the known tumor while waiting for a donor organ to become available.
- "Downstaging" intention: for moderately advanced disease which has not spread beyond the liver, but is too advanced to qualify for curative treatment. The person may be treated by targeted therapies in order to reduce the size or number of active tumors, with the goal of once again qualifying for liver transplant after this treatment.
- Palliative intention: for more advanced disease, including spread of cancer beyond the liver or in persons who may not tolerate surgery, treatment intended to decrease symptoms of disease and maximize duration of survival.
Loco-regional therapy (also referred to as liver-directed therapy) refers to any one of several minimally-invasive treatment techniques to focally target HCC within the liver. These procedures are alternatives to surgery, and may be considered in combination with other strategies, such as a later liver transplantation. Generally, these treatment procedures are performed by interventional radiologists or surgeons, in coordination with a medical oncologist. Loco-regional therapy may refer to either percutaneous therapies, such as microwave or cryoablation, or arterial catheter-based therapies, such as chemoembolization and radioembolization.
Surgical resection to remove the tumor while preserving enough remaining healthy liver to maintain normal physiologic function. Surgical removal results in favorable prognosis, but only 10-15% of patients are suitable for surgical resection.[medical citation needed] This is often because of extensive disease or poor underlying liver function. For example, resection in cirrhotic patients is associated with higher morbidity and mortality. Preoperative evaluation for resection must include imaging of the liver in order to estimate the amount of residual liver remaining after surgery; in order to preserve normal function, the residual liver volume should be more than 25% of the total size in a non-cirrhotic liver, and more than 40% of the total size for a cirrhotic liver. The overall recurrence rate after resection is 50-60%. The Singapore Liver Cancer Recurrence (SLICER) score can be used to estimate risk of recurrence after surgery.
Liver transplantation to replace the diseased liver with a cadaveric liver or a living donor graft has historically low survival rates (20%-36%). During 1996–2001 the rate had improved to 61.1%, likely related to adoption of the Milan criteria at US transplantation centers. Expanded Shanghai criteria in China resulted in overall survival and disease-free survival rates similar to the Milan criteria. Studies from the late 2000 obtained higher survival rates ranging from 67% to 91%. If the liver tumor has metastasized, the immuno-suppressant post-transplant drugs decrease the chance of survival. Considering this objective risk in conjunction with the potentially high rate of survival, some recent studies conclude that: "LTx can be a curative approach for patients with advanced HCC without extrahepatic metastasis". For those reasons, and others, it is considered nowadays that patient selection is a major key for success.
- Radiofrequency ablation (RFA) uses high-frequency radio waves to destroy tumor by local heating. The electrodes are inserted into the liver tumor under ultrasound image guidance using percutaneous, laparoscopic or open surgical approach. It is suitable for small tumors (<5 cm). RFA has the best outcomes in patients with a solitary tumor less than 4 mm. Since it is a local treatment and has minimal effect on normal healthy tissue, it can be repeated multiple times. Survival is better for those with smaller tumors. In one study, In one series of 302 patients, the three-year survival rates for lesions >5 cm, 2.1 to 5 cm, and ≤2 cm were 59, 74, and 91 percent, respectively. A large randomized trial comparing surgical resection and RFA for small HCC showed similar 4 year survival and less morbidities for patients treated with RFA.
- Cryoablation: Cryoablation is a technique used to destroy tissue using cold temperature. The tumor is not removed and the destroyed cancer is left to be reabsorbed by the body. Initial results in properly selected patients with unresectable liver tumors are equivalent to those of resection. Cryosurgery involves the placement of a stainless steel probe into the center of the tumor. Liquid nitrogen is circulated through the end of this device. The tumor and a half inch margin of normal liver are frozen to -190 °C for 15 minutes, which is lethal to all tissues. The area is thawed for 10 minutes and then re-frozen to -190 °C for another 15 minutes. After the tumor has thawed, the probe is removed, bleeding is controlled, and the procedure is complete. The patient will spend the first post-operative night in the intensive care unit and typically is discharged in 3 – 5 days. Proper selection of patients and attention to detail in performing the cryosurgical procedure are mandatory in order to achieve good results and outcomes. Frequently, cryosurgery is used in conjunction with liver resection as some of the tumors are removed while others are treated with cryosurgery.
- Percutaneous ethanol injection (PEI) well tolerated, high RR in small (<3 cm) solitary tumors; as of 2005, no randomized trial comparing resection to percutaneous treatments; recurrence rates similar to those for postresection. However a comparative study found that local therapy can achieve a 5-year survival rate of around 60% for patients with small HCC.
Arterial catheter based treatment
- Transcatheter arterial chemoembolization (TACE) is usually performed for unresectable tumors or as a temporary treatment while waiting for liver transplant. TACE is done by injecting an antineoplastic drug (e.g. cisplatin) mixed with a radio-opaque contrast (e.g. Lipiodol) and an embolic agent (e.g. Gelfoam) into the right or left hepatic artery via the groin artery. The goal of the procedure it to restrict the tumor’s vascular supply while supplying a targeted chemotherapeutic agent. TACE has been shown to increase survival and to downstage HCC in patients who exceed the Milan criteria for liver transplant. Patients who undergo the procedure may are followed with CT scans and may need additional TACE procedures if the tumor persists. As of 2005, multiple trials show objective tumor responses and slowed tumor progression but questionable survival benefit compared to supportive care; greatest benefit seen in people with preserved liver function, absence of vascular invasion, and smallest tumors. TACE is not suitable for big tumors (>8 cm), the presence of portal vein thrombus, tumors with a portal-systemic shunt, and patients with poor liver function.
- Selective internal radiation therapy (SIRT) can be used to destroy the tumor from within (thus minimizing exposure to healthy tissue). Similar to TACE, this is a procedure in which an interventional radiologist selectively injects the artery or arteries supplying the tumor with a chemotherapeutic agent. The agent is typically Yttrium-90 (Y-90) incorporated into embolic microspheres that lodge in the tumor vasculature causing ischemia and delivering their radiation dose directly to the lesion. This technique allows for a higher, local dose of radiation to be delivered directly to the tumor while sparing normal healthy tissue. While not curative, patients have increased survival. No studies have been done to compare whether SIRT is superior to TACE in terms of survival outcomes, although retrospective studies suggest similar efficacy. There are currently two products available, SIR-Spheres and TheraSphere. The latter is an FDA approved treatment for primary liver cancer (HCC) which has been shown in clinical trials to increase the survival rate of low-risk patients. SIR-Spheres are FDA approved for the treatment of metastatic colorectal cancer but outside the US SIR-Spheres are approved for the treatment of any non-resectable liver cancer including primary liver cancer.
Systemic therapy is considered in people with advanced HCC which has spread beyond the liver to other areas of the body. Currently, the multikinase inhibitor sorafenib is the only chemotherapy shown to be effective against HCC.
- Portal Vein Embolization (PVE): Using a percutaneous transhepatic approach, an interventional radiologist embolizes the portal vein supplying the side of the liver with the tumor. Compensatory hypertrophy of the surviving lobe can qualify the patient for resection. This procedure can also serve as a bridge to transplant.
- High intensity focused ultrasound (HIFU) (not to be confused with normal diagnostic ultrasound) is a technique uses powerful ultrasound to treat the tumor.
- A systematic review assessed 12 articles involving a total of 318 patients with hepatocellular carcinoma treated with Yttrium-90 radioembolization. Excluding a study of only one patient, post-treatment CT evaluation of the tumor showed a response ranging from 29 to 100% of patients evaluated, with all but two studies showing a response of 71% or greater.
The usual outcome is poor, because only 10–20% of hepatocellular carcinomas can be removed completely using surgery. If the cancer cannot be completely removed, the disease is usually deadly within 3 to 6 months. This is partially due to late presentation with tumors, but also the lack of medical expertise and facilities in the regions with high HCC prevalence. However, survival can vary, and occasionally people will survive much longer than 6 months. The prognosis for metastatic or unresectable hepatocellular carcinoma has recently improved due to the approval of sorafenib (Nexavar®) for advanced hepatocellular carcinoma.
HCC is one of the most common tumors worldwide. The epidemiology of HCC exhibits two main patterns, one in North America and Western Europe and another in non-Western countries, such as those in sub-Saharan Africa, central and Southeast Asia, and the Amazon basin. Males are affected more than females usually and it is most common between the age of 30 to 50, Hepatocellular carcinoma causes 662,000 deaths worldwide per year about half of them in China.
Africa and Asia
In some parts of the world, such as sub-Saharan Africa and Southeast Asia, HCC is the most common cancer, generally affecting men more than women, and with an age of onset between late teens and 30s. This variability is in part due to the different patterns of hepatitis B and hepatitis C transmission in different populations - infection at or around birth predispose to earlier cancers than if people are infected later. The time between hepatitis B infection and development into HCC can be years, even decades, but from diagnosis of HCC to death the average survival period is only 5.9 months according to one Chinese study during the 1970-80s, or 3 months (median survival time) in Sub-Saharan Africa according to Manson's textbook of tropical diseases. HCC is one of the deadliest cancers in China where chronic hepatitis B is found in 90% of cases. In Japan, chronic hepatitis C is associated with 90% of HCC cases. Food infected with Aspergillus flavus (especially peanuts and corns stored during prolonged wet seasons) which produces aflatoxin poses another risk factor for HCC.
In the Eastern Asian hemisphere, hepatocellular carcinoma (HCC) is the most common type of cancer. The common risk factor for HCC in Asia is the high diagnosis of Hepatitis B. However, in Japan the common risk factor is hepatitis C. Another factor is that causes HCC is a mycotoxin called aflatoxin. This mycotoxin is found among many areas in Asia with Southern China being the Asian country with the highest amount of aflatoxin. Thus, China is the country with the highest diagnosis of HCC in Eastern Asia.
North America and Western Europe
The most common malignant tumors in the liver represent metastases (spread) from tumors which originate elsewhere in the body. Among cancer that originate from liver tissue, HCC is the most common primary liver cancer. In the United States, the US surveillance, epidemiology, and end results (SEER) database program, shows that HCC accounts for 65% of all cases of liver cancers. As there are screening programs in place for high risk persons with chronic liver disease, HCC is often discovered much earlier in Western countries than in developing regions such as Sub-Saharan Africa.
Acute and chronic hepatic porphyrias (acute intermittent porphyria, porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria) and tyrosinemia type I are risk factors for hepatocellular carcinoma. The diagnosis of an acute hepatic porphyria (AIP, HCP, VP) should be sought in patients with hepatocellular carcinoma without typical risk factors of hepatitis B or C, alcoholic liver cirrhosis or hemochromatosis. Both active and latent genetic carriers of acute hepatic porphyrias are at risk for this cancer, although latent genetic carriers have developed the cancer at a later age than those with classic symptoms. Patients with acute hepatic porphyrias should be monitored for hepatocellular carcinoma.
The incidence of HCC is relatively lower in the Western hemisphere than in Eastern Asia. However, despite the statistics being low, there is an increase of HCC in the West. The diagnosis of HCC has increased since the 1980s and it is continuing to increase, making it one of the rising cause of death due to cancer. The common risk factor for HCC is hepatitis C, along with other health issues.
Current research includes the search for the genes that are disregulated in HCC, anti-heparanase antibodies, protein markers, non-coding RNAs (such as TUC338) and other predictive biomarkers. As similar research is yielding results in various other malignant diseases, it is hoped that identifying the aberrant genes and the resultant proteins could lead to the identification of pharmacological interventions for HCC.
HCC, hepatocellular carcinoma; TACE, transarterial embolization/chemoembolization; PFS, progression-free survival; PS, performance status; HBV, hepatitis B virus; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation; RR, response rate; MS, median survival.
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Diabetes is associated with an increased risk for HCC. However, more research is required to examine issues related to the duration and treatment of diabetes, and confounding by diet and obesity
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Recent studies in our laboratory have identified several potential factors that may contribute to the pathogenesis of HCC...For example, oxyradical overload diseases such as Wilson disease and hemochromatosis result in the generation of oxygen/nitrogen species that can cause mutations in the p53 tumour suppressor gene
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As copper has been shown to protect against chemically induced hepatocellular carcinoma in rats, this may be the reason for the extreme rarity of hepatocellular carcinoma in patients with Wilson's disease and possibly in other liver diseases with hepatic copper overload
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Diabetes appears to increase the risk of HCC, and such risk is correlated with a long duration of diabetes. Relying on dietary control and treatment with sulfonylureas or insulin were found to confer the highest magnitude of HCC risk, whereas treatment with biguanides or thiazolidinediones was associated with a 70% HCC risk reduction among diabetics.
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Our study confirms that type 2 diabetes mellitus is an independent risk factor for HCC and pre-exists in the majority of HCC patients. Moreover, in male patients with type 2 diabetes mellitus, our data shows a direct association of HCC with insulin and sulphanylureas treatment and an inverse relationship with metformin therapy.
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The majority of 'cryptogenic' HCC in the United States is attributed to nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome... It is predicted that metabolic syndrome will lead to large increases in the incidence of HCC over the next decades. A better understanding of the relation between these 2 diseases ultimately should lead to improved screening and treatment options for patients with HCC.
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Based on the known association of NAFLD with IR and MS, approximately two-thirds of the patients were obese and/or diabetic, 4 and a remarkable 25% of these patients had no cirrhosis... Therefore, it is particularly worrying that the most persuasive evidence for an association between NAFLD and HCC derives from studies on the risk of HCC in patients with metabolic syndrome
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Our data indicate that loss of autocrine/paracrine IGFBP-3 loops may lead to HCC tumor growth and suggest that modulating production of the IGFs, IGFBP-3, and IGF-IR may represent a novel approach in the treatment of HCC.
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This is the first reported case of hepatic adenoma re-growth with recidivistic steroid abuse, complicated by life-threatening hemorrhage.
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