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120-453: Metabolic dysfunction–associated steatotic liver disease ( MASLD ), previously known as non-alcoholic fatty liver disease ( NAFLD ), is a type of chronic liver disease . This condition is diagnosed when there is excessive fat build-up in the liver ( hepatic steatosis ), and at least one metabolic risk factor. When there is also increased alcohol intake, the term MetALD, or metabolic dysfunction and alcohol associated/related liver disease

240-563: A transplant . Transplant is required when the liver fails and there is no other alternative. Some studies indicate herbal remedies are useful, but there is not conclusive evidence to support their use. Some support may be found in the orthodox medical use of two of these in acute liver failure: N -acetyl cysteine (NAC) is the treatment of choice for acetaminophen overdose ; both NAC and milk-thistle ( Silybum marianum ) or its derivative silibinin are used in liver poisoning from certain mushrooms, notably Amanita phalloides , although

360-447: A 6-week study with a reduction of NASH induced inflammation and fibrosis, independently from weight loss. Tentative evidence supports dietary interventions in individuals with fatty liver who are not overweight. The EASL recommends energy restriction of 500–1000  kcal per week less than the normal daily diet, a target of 7–10% weight loss for obese/overweight MASLD, a low- to moderate-fat, and moderate- to high-carbohydrate diet, or

480-403: A biopsy but has a contraindication to percutaneous biopsy or needs a hemodynamic evaluation for diagnostic purposes. A transvenous liver biopsy is recommended instead of a percutaneous approach in people with clinically evident ascites, although percutaneous biopsy is an acceptable alternative approach after the removal of ascites. MASLD warrants treatment regardless of whether the affected person

600-583: A change of guidelines to recommend these therapies for MASLD management. Weight loss is associated with improvements in biomarkers, MASLD grade, and reduced chances of NASH, but its effect on long-term health was not known. 2021 meta-analyses of trials over periods of 1 to 28 months found limited evidence to indicate that lifestyle modifications and nutritional supplementation have an effect on mortality, liver cirrhosis, liver decompensation, liver transplantation, and hepatocellular carcinoma in people with non-alcohol-related fatty liver disease; authors said that it

720-777: A genetic component, the American Association for the Study of Liver Diseases (AASLD) does not recommend screening family members as there is not enough confirmation of heritability, although there is some evidence from familial aggregation and twin studies . According to the Asia-Pacific Working Group (APWG) on MASLD, overnutrition is a major factor of MASLD and MASH, particularly for lean MASLD. Diet composition and quantity, in particular omega-6 fatty acid and fructose , have important roles in disease progression from MASL to MASH and fibrosis. Choline deficiency can lead to

840-456: A hand-foot skin reaction and diarrhea . Sorafenib is thought to work by blocking growth of both tumor cells and new blood vessels . Numerous other molecular targeted drugs are being tested as alternative first- and second-line treatments for advanced HCC, such as lenvatinib and regorafenib . Regorafenib increased survival from 7.8 to 10.6 months in those who had tumor progression while on sorafenib compared to placebo. Cabozantinib , which

960-490: A high-intensity pattern on T2-weighted images and a low-intensity pattern on T1-weighted images. The advantage of MRI is that it has improved sensitivity and specificity when compared to ultrasound 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% (95% CI 70–91%) and specificity was 85% (95% CI 77–93%) compared with pathologic examination of an explanted or resected liver as

1080-459: 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 (e.g. cryoablation), or arterial catheter-based therapies (chemoembolization or radioembolization). Surgical resection of HCC tumors is usually the preferred treatment for BCLC stage 0 or A disease. Surgical resection

1200-679: A low-carbohydrate ketogenic or high-protein diet such as the Mediterranean diet, and avoiding all beverages and food containing fructose. Alcohol is an aggravating factor, and the AASLD recommends that people with NAFLD or NASH avoid alcohol consumption. The EASL allows alcohol consumption below 30g/day for men and 20g/day for women. The role of coffee consumption for NAFLD treatment is unclear though some studies indicate that regular coffee consumption may have protective effects. Herbal compounds such as silymarin (a milk thistle seed extract), curcumin,

1320-414: A lower risk of developing MASLD, even after adjusting for BMI. Habitual snoring may be a risk factor for MASLD. Severe snoring often signals the presence of obstructive sleep apnea (OSAS), a much more serious breathing condition. Blockage or narrowing of the airways, even temporarily, can cause the body to experience lowered oxygen levels in the blood . This in turn may cause a variety of changes within

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1440-416: A mechanism for this elevation. Alterations in the composition of the intestinal microbiota may influence NAFLD risk in several ways. These changes appear to increase the permeability of intestinal tissue, thereby facilitating increased liver exposure to harmful substances (e.g., translocated bacteria, bacterial toxins , and inflammatory chemical signals ). The increased transport of these harmful substances to

1560-422: A person where a higher suspicion of HCC exists, 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 to improve detection and accurate classification of any liver lesions. Due to

1680-643: A turmeric extract , and green tea appear to improve NAFLD biomarkers and reduce the grade of NAFLD. Studies suggest an association between microscopic organisms that inhabit the gut (microbiota) and MASLD. Reviews reported the use of probiotics and synbiotics (combinations of probiotics and prebiotics ) were associated with improvement in liver-specific markers of hepatic inflammation, measurements of liver stiffness, and steatosis in persons with MASLD. Vitamin E does not improve established liver fibrosis in those with MASLD but seems to improve certain markers of liver function and reduces inflammation and fattiness of

1800-503: 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 such as 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, thus are not related to HCC. Methods of diagnosis in HCC have evolved with

1920-745: Is a higher risk of fibrosis for family members where someone was diagnosed with MASH. Asian populations are more susceptible to metabolic syndrome and MASLD than their western counterparts. Hispanic persons have a higher prevalence of MASLD than white individuals, whereas the lowest prevalence is observed in black individuals. MASLD is twice as prevalent in men as in women, which might be explained by lower levels of estrogen in men. Genetic variations in two genes are associated with MASLD: non-synonymous single-nucleotide polymorphisms (SNPs) in PNPLA3 and TM6SF2 . Both correlate with MASLD presence and severity, but their roles for diagnosis remain unclear. Although NAFLD has

2040-486: Is also associated with hormonal disorders ( panhypopituitarism , hypothyroidism , hypogonadism , polycystic ovary syndrome ), persistently elevated transaminases , increasing age, and hypoxia caused by obstructive sleep apnea ; some of these conditions predict disease progression. Most normal-weight people with MASLD ("lean MASLD") have impaired insulin sensitivity, are sedentary, and have increased cardiovascular disease risk and increased liver lipid levels. These are

2160-677: Is an established method that can accurately assess hepatic fibrosis and is recommended by the APASL, AGA, ACR and AASLD. MRE possesses excellent accuracy to detect fibrosis in NAFLD regardless of BMI and inflammation, and is suggested as a more reliable alternative to diagnose NAFLD and its progression to NASH compared to ultrasound and blood tests. A liver biopsy (tissue examination) is the only test widely accepted ( gold standard ) as definitively diagnosing and distinguishing NAFLD (including NAFL and NASH) from other forms of liver disease and can be used to assess

2280-407: Is an inhibitor of multiple tyrosine kinases including VEGFR , hepatocyte growth factor receptor (MET) and AXL and ramucirumab , an antibody directed against VEGF receptor 2 , are second line therapies which have been shown to reduce the risk of death compared to placebo. A host of additional targeted therapies and immune checkpoint inhibitors have been found to be effective. For instance, in

2400-481: Is associated with a greater than 60% survival rate at 5 years and a recurrence rate greater than 70%. Surgical removal of the tumor is associated with better cancer prognosis, but only 5–15% of patients are suitable for surgical resection due to the extent of disease or poor liver function. Surgery is only considered if the entire tumor can be safely removed while preserving sufficient functional liver to maintain normal physiology. Thus, preoperative imaging assessment

2520-515: Is critical to determine both the extent of HCC and to estimate the amount of residual liver remaining after surgery. To maintain liver function, residual liver volume should exceed 25% of total liver volume in a noncirrhotic liver, greater than 40% in a cirrhotic liver. Surgery on diseased or cirrhotic livers is generally associated with higher morbidity and mortality. The Singapore Liver Cancer Recurrence score can be used to estimate risk of recurrence after surgery. Liver transplantation , replacing

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2640-415: Is currently the most common cause of death in people with cirrhosis . HCC is the third leading cause of cancer-related deaths worldwide. HCC most commonly occurs in those with chronic liver disease especially those with cirrhosis or fibrosis, which occur in the setting of chronic liver injury and inflammation. HCC is rare in those without chronic liver disease. Chronic liver diseases which greatly increase

2760-466: Is endemic, such as southeast China, hepatitis B 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 excessive alcohol use. Certain benign liver tumors, such as hepatocellular adenoma , may sometimes be associated with coexisting malignant HCC. Evidence

2880-430: Is examined underneath a microscope. The treatment of chronic liver disease depends on the cause. Specific conditions may be treated with medications including corticosteroids , interferon , antivirals , bile acids or other drugs. Supportive therapy for complications of cirrhosis include diuretics , albumin , vitamin K , blood products , antibiotics and nutritional therapy. Other patients may require surgery or

3000-484: Is extensive and can be categorised in the following way: Viral causes Cytomegalovirus (CMV), Epstein Barr virus (EBV), and yellow fever viruses cause acute hepatitis. Toxic and drugs Paracetamol (acetaminophen) causes acute liver damage. Metabolic Autoimmune response causes Other These differ according to the type of chronic liver disease. Chronic liver disease takes several years to develop and

3120-665: Is greater (from 2.5 to 7.1 times the nondiabetic 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

3240-731: Is increased in MASH compared with simple steatosis, and inflammation is a hallmark of MASH. The degree of inflammation can be correlated to the number of inflammatory foci. Various definitions exist for an inflammatory focus, but one defines it as the presence of more than four mononuclear cells in close proximity inside the hepatic parenchyma. One debated mechanism proposes that hepatic steatosis progresses to steatosis with inflammation following some further injury, or second hit . Oxidative stress , hormonal imbalances, and mitochondrial abnormalities are potential causes of this "second hit" phenomenon. A further nutrigenomics model named multiple hit extends

3360-586: Is increasing due to an increase in hepatitis C virus infections. The incidence of HCC due to NASH has also risen sharply in the past 20 years, with NASH being the fastest growing cause of HCC. This is thought to be due to an increased prevalence of NASH, as well as its risk factors of diabetes and obesity, in higher income countries. It is more than three times as common in males as in females, for unknown reasons. Most cases of HCC occur in people who already have signs and symptoms of chronic liver disease. They may present with worsening symptoms or without symptoms at

3480-438: Is initiated earlier in the disease process. Since the vast majority of HCC cases occur in people with certain chronic liver diseases, especially those with cirrhosis, liver cancer screening is recommended in this population. In the United States, the American Association for the Study of Liver Diseases (AASLD) recommends ultrasound screenings every six months for people with cirrhosis, with or without measurement of blood levels of

3600-476: Is less well established. Treatment of hepatocellular carcinoma varies by the stage of disease, a person's likelihood to tolerate surgery, and availability of liver transplantation: 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

3720-549: Is limited evidence for cirrhosis improvement. A combination of improved diet and exercise, rather than either alone, appears to best help manage NAFLD and reduce insulin resistance. Motivational support, such as with cognitive behavioral therapy , is helpful, as most people with MASLD do not perceive their condition as a disease, and thus have a low motivation to change. Higher-intensity behavioral weight loss therapies (diet and exercise combined) may produce more weight loss than lower-intensity ones. A 2019 systematic review suggested

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3840-488: Is limited 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. Chronic liver disease is rare in children and adolescents; however, congenital liver disorders are associated with an increased

3960-469: 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 noncirrhotic 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 fungi

4080-454: Is more common in children with the disorder. NASH represents a more advanced stage of NAFL and is associated with poor outcomes such as cardiovascular events, cirrhosis, or hepatocellular carcinoma. ICD-11 does not use the term NAFL as it was deemed confusing with the family of disorders NAFLD. The preferred descriptions are instead: NAFLD without NASH or simple steatosis and "NASH". Also, the modifier with or without fibrosis or cirrhosis completes

4200-663: Is not associated with improved survival compared to hepatectomy, but instead is significantly more expensive. Systemic therapy for HCC is indicated in BCLC stage C disease, in which cancer has spread beyond the liver. It is also indicated in BCLC stage B disease with tumor progression after local treatments. In 2007, sorafenib , an oral multikinase inhibitor, was the first systemic agent approved for first-line treatment of advanced HCC. Trials have found modest improvement in overall survival: 10.7 months vs 7.9 months and 6.5 months vs 4.2 months. The most common side effects of Sorafenib include

4320-401: 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

4440-721: 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 HCC 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

4560-579: Is overweight or not. MASLD is a preventable cause of death . Guidelines are available from the American Association for the Study of Liver Diseases (AASLD), American Association of Clinical Endocrinologists (AACE) National Institute for Health and Care Excellence (NICE), the European Association for the Study of the Liver (EASL), and the Asia-Pacific Working Party on NAFLD. Weight loss

4680-503: 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 survive much longer than 6 months. The prognosis for metastatic or unresectable HCC has improved due to

4800-420: Is poorly circumscribed and infiltrates the portal veins, or the hepatic veins (rarely). Microscopically, the four architectural and cytological types (patterns) of hepatocellular carcinoma are: 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

4920-403: Is preferable to moderate training, as only the high-intensity exercise reduced the chances of MASLD developing into NASH or advanced fibrosis. The EASL recommends between 150 and 200 min/week in 3 to 5 sessions of moderate-intensity aerobic physical activity or resistance training. Since both effectively reduce liver fat, a pragmatic approach to the choice of physical activity that accounts for

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5040-799: Is recommended for some clinical situations such as people with known intra-hepatic lesions, previous intra-abdominal surgery who may have adhesions, a small liver that is difficult to percuss, obese people and people with evident ascites. Vital signs must be monitored frequently afterward (at least every 15 minutes in the hour following the biopsy). According to AASLD guidelines, a liver biopsy may be considered in people with NAFLD who are at increased risk of having steatohepatitis with or without advanced fibrosis, but only when all other competing chronic liver diseases are excluded (such as alcoholic liver disease). The presence of metabolic syndrome, NAFLD Fibrosis Score (FIB-4), or liver stiffness (as measured by Vibration-controlled transient elastography or MRE ) can identify

5160-437: Is recommended for the initial assessment of liver fibrosis and cirrhosis and helps to predict complications and prognosis, but the interpretation of results is carefully weighed in the presence of limiting factors such as steatosis, high BMI, low amount of hepatic fibrosis, narrow spaces between the ribs, and portal hypertension . Transient elastography is not a substitute for liver biopsy. Magnetic resonance elastography (MRE)

5280-495: Is recommended particularly for obese or overweight people; similar physical activities and diets are advisable for overweight people with MASLD as for other obese and overweight people. Although physical activity is less important for weight loss than dietary adaptations (to reduce caloric intake), the NICE advises physical activity to reduce liver fat even if there is no overall bodyweight reduction. Weight loss, through exercise or diet,

5400-613: Is some evidence for SGLT-2 inhibitors , GLP-1 agonists , pioglitazone , and vitamin E in the treatment of MASLD. In March 2024, resmetirom was the first drug approved by the FDA for MASH. Those with MASH have a 2.6% increased risk of dying per year. MASLD is the most common liver disorder in the world; about 25% of people have it. It is very common in developed nations, such as the United States, and affected about 75 to 100 million Americans in 2017. Over 90% of obese, 60% of diabetic , and up to 20% of normal-weight people develop MASLD. MASLD

5520-635: Is the most effective treatment for MASLD and MASH. A loss of 5% to 10% body weight is recommended and has shown regression of liver damage, with 10% to 40% weight loss completely reversing MASH without cirrhosis. A weight loss of greater than 10% was associated with resolution of MASH in 90% of people in a biopsy based study. A structured weight loss program helps people with MASLD lose more weight compared with advice alone. This type of program also leads to improvements in NAFLD measured using blood tests, ultrasound, imaging, or liver biopsies. Although fibrosis improves with lifestyle interventions and weight loss, there

5640-405: Is the most effective way to reduce liver fat and help NASH and fibrosis remission. Exercise alone can prevent or reduce hepatic steatosis, but it remains unknown whether it can improve all other aspects of the liver; hence a combined approach with diet and exercise is advised. Aerobic exercise may be more effective than resistance training, although there are contradictory results. Vigorous training

5760-451: Is the only procedure that can reliably differentiate NAFL from NASH. There are several liver biopsy techniques available to obtain liver tissue. Percutaneous liver biopsy remains the most common practice. Biopsies can also be performed via the transvenous route, either during surgery or by laparoscopy , especially for people with contraindications to a percutaneous approach. The liver biopsy can also be image-guided, in real-time or not, which

5880-738: Is used, and differentiated from alcohol-related liver disease (ALD) where alcohol is the predominant cause of the steatotic liver disease . The terms non-alcoholic fatty liver ( NAFL ) and non-alcoholic steatohepatitis ( NASH , now MASH ) have been used to describe different severities, the latter indicating the presence of further liver inflammation . NAFL is less dangerous than NASH and usually does not progress to it, but this progression may eventually lead to complications, such as cirrhosis , liver cancer , liver failure , and cardiovascular disease . Obesity and type 2 diabetes are strong risk factors for MASLD. Other risks include being overweight , metabolic syndrome (defined as at least three of

6000-553: The prothrombin time . In people with fatty liver with associated inflammatory injury (steatohepatitis) blood tests are usually used to rule out certain types of viral hepatitis and autoimmune diseases . Low thyroid activity is more prevalent in people with NASH, which would be detected by determining the thyroid-stimulating hormone . Some biomarker-based blood tests have been developed and may be useful for diagnosis. Although blood tests cannot diagnose MASLD, circulating serum biomarkers of liver fibrosis can give moderate estimates in

6120-421: The second hit model, suggesting that multiple disease biomarkers and factors such as genes and nutrition influence NAFLD and NASH progression. This model attempts to use these factors to predict the impact of lifestyle changes and genetics for the evolution of the NAFLD pathology. Many researchers describe NAFLD as a multisystem disease, as it impacts and is influenced by organs and regulatory pathways other than

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6240-598: The Fatty Liver Inhibition of Progression (FLIP) algorithm to grade the ballooning and classify MASLD-associated liver injury, and the use of the NAFLD Activity Score (NAS) to grade the severity of NASH rather than for its diagnosis. They also consider the steatosis, activity, and fibrosis (SAF) score to be an accurate and reproducible scoring system. The AASLD recommends the use of the NAS scoring system with or without

6360-488: The Liver (EASL) recommends screening for steatosis whenever NAFLD is suspected as this is a strong predictor of the disease evolution and predicts future type 2 diabetes, cardiovascular events, and hypertension . These non-invasive methods can be used for NAFLD screening but are not accepted as a substitute for liver biopsy in NAFLD nor NASH clinical trials, as only a liver biopsy can define liver pathology. Ultrasound presented average sensitivity and specificity for diagnosing

6480-567: The Milan criteria. Studies from the late 2000s obtained higher survival rates ranging from 67% to 91%. Other estimates of 5 year survival after liver transplantation range from 60-60% with a 50% survival rate at 10 years. The risk of HCC recurrence after liver transplantation is less than 15%. Macrovascular or extrahepatic spread (spread of the cancer to blood vessels or outside the liver, respectively) are contraindications to liver transplantation. The risks of liver transplantation extend beyond risk of

6600-447: The SAF score if deemed appropriate. The Asia-Pacific Working Group disadvises the use of NAS, as it is considered uninformative for NAFLD and inappropriate to diagnose NASH. For liver fibrosis assessment, percutaneous liver biopsy, with or without image guidance, is contraindicated in uncooperative people. Transjugular liver biopsy is indicated for any person with diffuse liver disease who needs

6720-545: The USA; >30 g daily for men and >20 g for women in UK and EU, >140 g/week for men and >70 g/week for women in Asia-Pacific), liver injury caused by drugs or toxins or viruses , nutritional deficiency, or endocrine conditions. In practice, diagnosis was often made simply based on the clinical presentation and a lack of high-volume alcohol consumption reported by

6840-447: The accumulation of toxic fat in the liver in several ways. First, it promotes the release of free fatty acids (FFAs) from adipose tissue into the blood. Typically, adipose tissue stores lipids in the form of triglycerides , slowly releasing them into the bloodstream when insulin is low. In insulin-resistant adipose tissue, such as in people with obesity and type 2 diabetes, more triglycerides are broken down into FFAs and released into

6960-726: The ages of 30 and 50, Hepatocellular carcinoma causes 662,000 deaths worldwide per year about half of them in China. 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 the 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,

7080-515: The approval of Sorafenib (Nexavar®) for advanced HCC. 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

7200-588: 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. Foods infected with Aspergillus flavus (especially peanuts and corns stored during prolonged wet seasons) which produces aflatoxins pose another risk factor for HCC. The most common malignant tumors in

7320-405: The bloodstream (59%), FFAs derived from carbohydrates such as fructose and glucose (26%), and diet (14%). Despite the accumulation of triglycerides in the liver, they are not directly toxic to liver tissue. Instead, alteration of the profile of the other lipid subtypes present in the liver, such as diacylglycerols , phospholipids , ceramides , and free cholesterol , have a more significant role in

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7440-503: The bloodstream, promoting uptake by the liver. Second, insulin promotes the production of new FFAs in the liver via de novo lipogenesis ; this production of liver fats continues to be stimulated by insulin, even when other tissues are insulin-resistant. These FFAs are combined back into triglycerides in the liver, forming the major constituent of the accumulated fat in the liver. The three sources of free fatty acids that contribute to liver triglyceride accumulation include FFAs circulating in

7560-401: The body such as tissue inflammation , increased insulin resistance , and liver injury. A prospective cohort study found the association between habitual snoring and MASLD development to be significant, and the trend was noted to be most prominent in lean individuals. The primary characteristic of MASLD is the accumulation of lipids in the liver, largely in the form of triglycerides . However,

7680-411: The burden of the fibrosis in the liver, and previous studies have confirmed that these scores can predict future development of mortality and liver cancer. A liver ultrasound scan or magnetic resonance imaging (MRI) can diagnose steatosis, but not fibrosis, and confirmation of early cirrhosis detection by ultrasound by other diagnostic methods is recommended. The European Association for the Study of

7800-553: The cancer at a later age than those with classic symptoms. Patients with acute hepatic porphyrias should be monitored for HCC. The incidence of HCC is relatively lower in the Western Hemisphere than in Eastern Asia. However, despite the statistics being low, the diagnosis of HCC has increased since the 1980s and it is continuing to increase, making it one of the rising causes of death due to cancer. The common risk factor for HCC

7920-434: The case of patients with cirrhosis, alcohol consumption is to be avoided. Also, screening for hemochromatosis may be beneficial for some patients. HCC surveillance in those with chronic liver disease with cirrhosis is indicated and generally consists of a twice-yearly ultrasound with or without Alpha-fetoprotein lab testing. The utility of HCC surveillance or screening in those with chronic liver disease without cirrhosis

8040-522: The cause. Note that other diseases can involve the liver and cause hepatomegaly but would not be considered part of the spectrum of chronic liver disease. Some examples of this would include chronic cancers with liver metastases , infiltrative haematological disorders such as chronic lymphoproliferative conditions, chronic myeloid leukaemias, myelofibrosis and metabolic abnormalities such as Gaucher's disease and glycogen storage diseases . The list of conditions associated with chronic liver disease

8160-447: The chance of developing HCC. 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, such as cirrhosis and hepatitis. The risk of hepatocellular carcinoma in type 2 diabetics

8280-475: 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 biopsy 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 systematic review of CT diagnosis found that

8400-401: The condition may not be recognised unless there is clinical awareness of subtle signs and investigation of abnormal liver function tests . Testing for chronic liver disease involves blood tests, imaging including ultrasound , and a biopsy of the liver. The liver biopsy is a simple procedure done with a fine thin needle under local anaesthesia. The tissue sample is sent to a laboratory where it

8520-489: The consequences of a decreased capacity for storing fat and reduced mitochondrial function in fat and increased hepatic de novo lipogenesis . A recent systematic review reported an increased risk of severe COVID-19 infection in MASLD patients, but no difference in mortality was observed between MASLD and non-MASLD patients. Two-thirds of families with a history of diabetes type 2 report more than one family member having MASLD. There

8640-404: The cytoplasm. In poorly differentiated forms, malignant epithelial cells are discohesive, pleomorphic , anaplastic , and giant. The tumor has a scant stroma and central necrosis because of the poor vascularization. A fifth form – lymphoepithelioma like hepatocellular carcinoma – has also been described. Barcelona Clinic Liver Cancer (BCLC) Staging System The prognosis of HCC is affected by

8760-503: The development of MASLD. Higher consumption of processed , red , and organ meats have been associated with higher risk of developing MASLD. Some research also suggests eggs are also associated with developing MASLD. On the other hand, studies have found healthful plant foods such as legumes and nuts , to be associated with a lower risk of developing MASLD. Two different studies have found healthy plant-based diets rich in healthy plant foods and low in animal foods to be associated with

8880-470: 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. Activated immune-system inflammatory cells release free radicals, such as reactive oxygen species and nitric oxide reactive species , which in turn can cause DNA damage and lead to carcinogenic gene mutations. Reactive oxygen species also cause epigenetic alterations at

9000-557: The diagnosis of liver fibrosis and cirrhosis. The ratio of the transaminase liver enzyme aspartate aminotransferase (AST) to platelets in the blood, known as the AST/platelet ratio index (APRI score), and Fibrotest are recommended as the preferred noninvasive tests for cirrhosis by the Asian-Pacific Association for Study of the Liver (APASL). Several other scores such as FIB-4 score and NAFLD fibrosis score can also reflect

9120-497: The diagnostic description. Following the renaming of NAFLD to MASLD, these definitions are being updated. Liver function tests may be abnormal, but they often remain within the normal range even in advanced disease. Other blood tests that may be useful to confirm the diagnosis include erythrocyte sedimentation rate , serum glucose , and albumin . Because the liver is important for making proteins used in blood clotting , coagulation-related studies are often carried out, especially

9240-513: The disease in children, while in the adult population, sensitivity and specificity were significantly higher. Proton density fat fraction magnetic resonance imaging has been increasingly used for the diagnosis of steatosis in pediatric patients. Ultrasound elastography is an effective tool for staging liver fibrosis and discriminating NASH in children. Computerized tomography and magnetic resonance imaging are more accurate in detecting cirrhosis than conventional ultrasound. Transient elastography

9360-520: The diseased liver with a cadaveric or a living donor liver, plays an increasing role in treatment of HCC. Although outcomes following liver transplant were initially poor (20%–36% survival rate), outcomes have significantly improved with improvement in surgical techniques and adoption of the Milan criteria at transplantation centers. Expanded Shanghai criteria in China have resulted in overall survival and disease-free survival rates similar to those achieved using

9480-454: The five following medical conditions: abdominal obesity, high blood pressure , high blood sugar , high serum triglycerides , and low serum HDL cholesterol ), a diet high in fructose , and older age. Obtaining a sample of the liver after excluding other potential causes of fatty liver can confirm the diagnosis. Treatment for MASLD is weight loss by dietary changes and exercise; bariatric surgery can improve or resolve severe cases. There

9600-464: 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 nonalcoholic fatty liver disease or NAFLD is present) and again evidence of greater risk exists here, too. While there are claims that anabolic steroid abusers are at greater risk (theorized to be due to insulin and IGF exacerbation ),

9720-538: The gut microbiota. In particular, diet diversity may play a role that was overlooked in animal studies, since they often compare a Western high-fat, low-diversity diet against a low-fat but higher-diversity chow. The health benefits after bariatric surgery may also involve changes in the gut microbiota by increasing gut permeability. NAFLD was defined by the presence of excess fat in the liver that cannot be explained by another factor, such as excessive alcohol use (>21 standard drinks /week for men and >14 for women in

9840-562: The improvement in medical imaging. The evaluation of both asymptomatic patients and those with symptoms of liver disease involves blood testing and imaging evaluation. Historically, a biopsy of a tumor was required to prove an HCC diagnosis. However, imaging (especially MRI) findings may be conclusive enough without histopathologic confirmation. HCC remains associated with a high mortality rate, in part because initial diagnosis commonly occurs at an advanced stage of disease. As with other cancers, outcomes are significantly improved if treatment

9960-434: The individual's preferences for what they can maintain in the long-term is preferred. Any engagement in physical activity or increase over previous levels is better than remaining sedentary. Chronic liver disease Signs of chronic liver disease detectable on clinical examination can be divided into those that are associated with the diagnosis of chronic liver disease, associated with decompensation, and associated with

10080-420: The individuals who are at higher risk of steatohepatitis or advanced fibrosis. The AASLD and ICD-11 consider that clinically useful pathology reporting distinguishes "between NAFL (steatosis), NAFL with inflammation and NASH (steatosis with lobular and portal inflammation and hepatocellular ballooning)" with the presence or absence of fibrosis being described and optionally comment on severity. The EASL recommends

10200-467: The liver (hepatic steatosis ). A liver can remain fatty without disturbing liver function (MASL), but by various mechanisms and possible insults to the liver, it may also progress into steatohepatitis (MASH), a state in which steatosis is combined with inflammation and sometimes fibrosis . MASH can then lead to complications such as cirrhosis and hepatocellular carcinoma . The new name, metabolic dysfunction-associated steatotic liver disease (MASLD),

10320-509: The liver , risk factors generally include factors which cause chronic liver disease that may lead to cirrhosis. Certain risk factors are 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: The significance of these risk factors varies globally. In regions where hepatitis B infection

10440-484: The liver by stimulating de novo lipogenesis in the liver and reducing the beta-oxidation of fat. Unlike the sugar glucose , the enzyme fructokinase rapidly metabolizes fructose. This leads to a decreased level of intracellular adenosine triphosphate (ATP). The decrease in ATP increases oxidative stress and impairments in proper protein synthesis and mitochondrial function in the liver. Insulin resistance contributes to

10560-418: The liver in some people with MASLD. The Asia-Pacific Work Group advises that Vitamin E may improve liver condition and aminotransferase levels, but only in adults without diabetes or cirrhosis who have NASH. The NICE guidelines recommend Vitamin E as an option for children and adults with NAFLD with advanced liver fibrosis, regardless of whether the person has diabetes mellitus. Weight loss may improve MASLD and

10680-575: The liver in the absence of secondary causes of fatty liver, such as significant alcohol use, viral hepatitis , or medications that can induce fatty liver, was the definition of NAFLD. However, the term MASLD accepts there may be other conditions present, but focuses on the metabolic abnormalities contributing to the disorder. MASLD encompasses a continuum of liver abnormalities, from metabolic dysfunction–associated steatotic liver (MASL, simple steatosis) to Metabolic dysfunction-associated steatohepatitis (MASH). These diseases begin with fatty accumulation in

10800-430: The liver promotes liver inflammation, enhances nutrient and calorie absorption, and alters choline metabolism. Higher levels of intestinal bacteria that produce butyrate may be protective. Excessive macronutrient intake contributes to gut inflammation and perturbation of homeostasis, and micronutrients may also be involved. In addition to reducing weight and risk factors, lifestyle changes may prompt positive changes in

10920-476: The liver represent metastases (spread) from tumors which originate elsewhere in the body. Among cancers that originate from liver tissue, HCC is the most common primary liver cancer. In the United States, the US surveillance, epidemiology, and end results database program, shows that HCC accounts for 65% of all cases of liver cancers. As screening programs are in place for high-risk persons with chronic liver disease, HCC

11040-443: The liver. The accumulation of senescent cells in the liver is seen in persons with NAFLD. In mice, liver senescent hepatocytes result in increased liver fat deposition. Treatment of NAFLD mice with senolytic agents has been shown to reduce hepatic steatosis. Based on gene knockout studies in murine models, it has been suggested that, among many other pathogenic factors, TGF beta signals may be crucially involved in promoting

11160-427: The liver. These properties include improved liver fat metabolism, decreased de novo lipogenesis, decreased glucose production in the liver , anti-inflammatory properties, and anti-fibrotic properties. Skeletal muscle insulin resistance may also play a role in MASLD. Insulin-resistant skeletal muscle is not as efficient at taking up glucose from the bloodstream after a meal. This inefficient glucose uptake promotes

11280-414: The lung, abdominal lymph nodes, and bone. Since hepatitis B and C are some of the main causes of hepatocellular carcinoma, prevention of infection is key to then prevent HCC. Thus, childhood vaccination against hepatitis B may reduce the risk of liver cancer in the future. In those with chronic hepatitis C infection, treatment of the hepatitis C using medications reduces the risk of developing HCC. In

11400-622: The mechanisms by which triglycerides accumulate and the reasons that accumulation can lead to liver dysfunction are complex and incompletely understood. MASLD can include steatosis along with varied signs of liver injury: either lobular or portal inflammation (a form of liver injury) or ballooning degeneration . Similarly, NASH can include histological features such as portal inflammation, polymorphonuclear cell infiltrates, Mallory bodies , apoptotic bodies, clear vacuolated nuclei, microvesicular steatosis , megamitochondria , and perisinusoidal fibrosis . Hepatocyte death via apoptosis or necroptosis

11520-474: The most effective screening protocols. For example, while some data support decreased mortality related to screening people with hepatitis B infection, the AASLD notes, “There are no randomized trials [for screening] in Western populations with cirrhosis secondary to chronic hepatitis C or fatty liver disease, and thus there is some controversy surrounding whether surveillance truly leads to a reduction in mortality in this population of patients with cirrhosis.” In

11640-494: The only evidence that has been confirmed is that anabolic steroid users are more likely to have the benign hepatocellular adenomas transform into the more dangerous hepatocellular carcinoma. Hepatocellular carcinoma, like any other cancer, develops when epigenetic alterations and mutations affecting the cellular machinery cause the cell to replicate at a higher rate and/or result in the cell avoiding apoptosis . In particular, chronic infections of hepatitis B and/or C can aid

11760-431: The pathogenesis of MASLD. Once MASLD progresses in severity to the point of NASH, this promotes further insulin resistance in the adipose tissue and liver, which results in a harmful cycle of insulin resistance, liver fat accumulation, and inflammation. Adipose tissue dysfunction also decreases secretion of the insulin-sensitizing adipokine adiponectin in people with NAFLD. Adiponectin has several properties that protect

11880-521: The patient (defined by the ECOG classification ) and the presence of symptoms. Of all the staging classification systems available, the Barcelona Clinic Liver Cancer staging classification encompasses all of the above characteristics. This staging classification can be used to guide treatment decisions. Important features that guide treatment include: The most common sites of metastasis are

12000-564: The patient, but this is an unreliable method of diagnosis. NAFLD comprises two histological categories: NAFL, and the more aggressive form NASH. The presence of at least 5% fatty liver is common to both NAFL and NASH, but the features of substantial lobular inflammation and hepatocyte injuries such as ballooning or Mallory hyaline only occur in NASH. The majority of NAFL cases show minimal or no inflammation. Pericentral and perisinusoidal fibrosis occur more often in adult-onset NASH, whereas portal fibrosis

12120-531: The procedure itself. The immunosuppressive medication required after surgery to prevent rejection of the donor liver also impairs the body's natural ability to combat dysfunctional cells. If the tumor has spread undetected outside the liver before the transplant, the medication effectively increases the rate of disease progression and decreases survival. Liver transplantation can be a curative approach for patients with advanced HCC without extrahepatic metastasis. Among patients with compensated cirrhosis, transplantation

12240-498: The progression of NASH. Non-alcoholic and alcoholic fatty liver disease share similar histological features, which suggests that they might share common pathogenic pathways. Fructose can cause liver inflammation and addiction similarly to ethanol by using similar metabolic pathways, unlike glucose. Therefore, some researchers argue that non-alcoholic and alcoholic fatty liver diseases are more alike than previously thought. Furthermore, high fructose consumption promotes fat accumulation in

12360-766: The promoter of TERT lead to a constitutively active telomerase which maintains telomere length and contributes to cell immortality. Mutations in the tumor suppressor gene TP53 are seen in about 30% of cases of HCC. And mutations in Wnt signalling (which is responsible for embryogenesis and cell homeostasis) are also seen in HCC, specifically CTNNB1 mutations seen in 30% of cases and AXIN1 mutations seen in 10% of cases. Mutations of genes involved in chromatin remodeling such as ARID1A and ARID2 are also seen in 10% and 5% of HCC cases respectively. While this constant cycle of damage followed by repair can lead to mistakes during repair, which in turn lead to carcinogenesis, this hypothesis

12480-475: The recent phase III trial IMBrave 150, the combination of atezolizumab and bevacizumab was found to improve both overall and progression-free survival compared to sorafenib alone. Tremelimumab (Imjudo) was approved for medical use in the United States in October 2022. It is indicated , in combination with durvalumab , for the treatment of adults with unresectable hepatocellular carcinoma. The usual outcome

12600-409: The redistribution of consumed carbohydrates from glucose destined for use in glycogen stores in the skeletal muscles to being used as a substrate for de novo lipogenesis in the liver. Disruptions in the intestinal microbiota seem to influence NAFLD risk in several ways. People with NASH can have elevated levels of blood ethanol and Pseudomonadota (which produce alcohol), with dysbiosis proposed as

12720-540: The reference standard. The sensitivity is further increased if gadolinium contrast-enhanced and diffusion-weighted imaging are combined. MRI is more sensitive and specific than CT. 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

12840-425: The risk of HCC include hepatitis infection such as ( hepatitis B , C or D ), non-alcoholic steatohepatitis (NASH), alcoholic liver disease , or exposure to toxins such as aflatoxin , or pyrrolizidine alkaloids . Certain diseases, such as hemochromatosis and alpha 1-antitrypsin deficiency , markedly increase the risk of developing HCC. The five-year survival in those with HCC is 18%. As with any cancer,

12960-430: The sensitivity was 68% (95% CI 55–80%) and specificity was 93% (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 was 90% or higher, but these data have 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

13080-555: The severity of the inflammation and resultant fibrosis. However, since most people affected by NAFLD are likely to be asymptomatic, liver biopsy presents too high a risk for routine diagnosis, so other methods are preferred, such as liver ultrasonography or liver MRI . For young people, guidelines recommend liver ultrasonography, but biopsy remains the best evidence. Liver biopsy is also the gold standard to detect hepatic fibrosis and assess its progression. Routine liver function blood tests are not sensitive enough to detect MASLD, and biopsy

13200-410: The sites of DNA repair. Many genes responsible for cell proliferation, apoptosis or cell senescence and differentiation are commonly mutated in HCC and are implicated in tumor formation. Mutations in the telomerase reverse transcriptase ( TERT ) promoter are seen in 47-60% of HCC cases. The HBV genome commonly inserts into hepatocytes' TERT promoter site contributing to oncogenesis. These mutations in

13320-459: The skin may occur, although this is rare. MASH can severely impair liver function, leading to cirrhosis , liver failure , and liver cancer . The condition is strongly associated with or caused by type 2 diabetes, insulin resistance, and metabolic syndrome (defined as at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein). It

13440-600: The staging of the tumor, the liver's function due to the effects of chronic liver disease and cirrhosis as well as the person's physical performance status. A number of staging classifications for HCC are available. However, due to the unique nature of the carcinoma 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

13560-527: The time of cancer detection. HCC may present with non-specific symptoms such as abdominal pain , nausea , vomiting , or feeling tired . Some symptoms that are more closely associated with liver disease include yellow skin (also called jaundice), abdominal swelling due to fluid in the abdominal cavity , easy bruising from blood clotting abnormalities , loss of appetite , unintentional weight loss, abdominal pain , nausea , vomiting , or feeling tired . Since HCC mostly occurs in people with cirrhosis of

13680-532: The treatment and prognosis of HCC varies depending on tumor histology, size, how far the cancer has spread , and overall health of the person. The vast majority of HCC cases and the lowest survival rates after treatment occur 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 higher income countries

13800-633: 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% and specificity was 97% as compared with pathologic examination of an explanted or resected liver as the reference standard. The sensitivity increases to 79% with AFP correlation. Hepatic nodules that are less than 1 centimeter in size on surveillance ultrasound require serial imaging to ensure stability and to monitor for potential transformation to HCC. Controversy remains as to

13920-429: The tumor marker alpha-fetoprotein (AFP). Elevated levels of AFP are associated with active HCC disease, though their reliability can be inconsistent. At levels >20, sensitivity is 41–65% and specificity is 80–94%. However, at levels >200, sensitivity is 31% and specificity is 99%. On ultrasound, HCC often appears as a small hypoechoic lesion with poorly defined margins and coarse, irregular internal echoes. When

14040-409: The use of milk-thistle is controversial. Some common herbs are known or suspected to be harmful to the liver, including black cohosh , ma huang , chaparral , comfrey , germander , greater celandine , kava , mistletoe , pennyroyal , skull cap and valerian . Hepatocellular carcinoma Hepatocellular carcinoma ( HCC ) is the most common type of primary liver cancer in adults and

14160-453: Was proposed after 70% of a panel of experts expressed support for this name. This new name was adopted in 2023. People with MASLD often have no noticeable symptoms, and it is often only detected during routine blood tests or unrelated abdominal imaging or liver biopsy . In some cases, it can cause symptoms related to liver dysfunction such as fatigue, malaise , and dull right-upper-quadrant abdominal discomfort . Mild yellow discoloration of

14280-494: Was the leading cause of chronic liver disease and the second most common reason for liver transplantation in the United States and Europe in 2017. MASLD affects about 20 to 25% of people in Europe. In the United States, estimates suggest that 30% to 40% of adults have MASLD, and about 3% to 12% of adults have MASH. The annual economic burden was about US$ 103 billion in the United States in 2016. An abnormal accumulation of fat in

14400-446: Was unlikely that differences in clinical outcomes would become apparent in trials with less than 5 years to 10 years of follow‐up, and that sample sizes needed to be much larger than had been used. Treatment of NAFLD typically involves counseling to improve nutrition and calorie restriction . People with NAFLD can benefit from a moderate to low-carbohydrate diet and a low-fat diet. The Mediterranean diet also showed promising results in

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