Generally, liver failure related to liver disease and cirrhosis happens slowly. You may not have any symptoms at first. But over time, you might start to notice:. Acute liver failure, on the other hand, happens suddenly, often in response to an overdose or poisoning. Certain things can make you more likely to develop certain liver diseases.

One of the most well-known risk factors is heavy drinking, which the Centers for Disease Control and Prevention CDC defines as more than 8 alcoholic drinks per week for women and more than 15 drinks per week for men.

While not all liver disease or damage can be prevented, lifestyle choices can make a big difference when it comes to keeping your liver healthy. Like the risk factors above, many of the methods around prevention involve dietary decisions and physical activity. The American Liver Foundation says that you can help prevent liver disease by:.

Make sure to also tell them about any prescription or over-the-counter medications you take, including vitamins and supplements. Many liver diseases are chronic, meaning they last for years and may never go away. But even chronic liver diseases can usually be managed.

Depending on the specific liver condition you have, your doctor may recommend other dietary changes. In some cases, you may need surgery to remove all or part of your liver. Generally, a liver transplant is only done when other options have failed.

Many liver diseases are manageable if you catch them early. Without treatment, however, they can cause permanent damage. The complications of untreated or unmanaged liver disease can lead to cirrhosis, severe scarring that cannot be reversed.

If cirrhosis has gone too far, a liver transplant may be your only option. Because some liver diseases can develop without symptoms, making it a point to schedule annual physicals, along with the typical physical blood work, can help you and your doctor stay one step ahead.

Focusing on a nutritious diet, physical exercise, and other healthy lifestyle choices such as limiting alcohol can also help with prevention or management. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available.

VIEW ALL HISTORY. Liver function tests help determine the health of your liver. Learn about the most common liver function tests, why they're used, and more. Type 2 diabetes raises the risk of developing nonalcoholic fatty liver disease and other liver conditions. Take a moment to learn more about the link….

Hepatomegaly is when you have an enlarged liver. Learn about its causes, symptoms, and treatments. Hepatic encephalopathy is a decline in brain function that occurs as a result of liver disease.

In this condition, your liver cannot adequately remove…. Prednisone can increase your risk of NAFLD. If you already have or are at high risk of NAFLD, you might need to take alternative medications.

The gamma-glutamyl transpeptidase test measures the amount of an important liver enzyme in your blood. Read on to learn more about the test and what…. Learn how jaundice appears in people with darker skin tones and what symptoms to look out for.

Bile duct cysts are areas of dilation within the biliary system that connects the liver, gallbladder, and small intestine. Throwing-up blood or having blood in your vomit can be a sign of esophageal varies, gastritis or even cancer.

It is important to seek Upper stomach pain can occur for many reasons, like gastritis, reflux or indigestion. It can also be a sign of a serious condition, like Tua Saúde Health A-Z Diseases and Conditions Cirrhosis.

Updated in January Medical review: Dr. Clarisse Bezerra Family Doctor. Main symptoms Possible causes 1. Viral hepatitis 2. Alcohol abuse 3. Metabolic disorders 4. Fatty liver disease 5. Medication 6. Chronic cholestasis How to diagnose liver inflammation Treatment options Possible complications.

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For determining the nature of the inflammation, the doctor will suggest getting various blood tests done. This is done to check the current enzyme level or even the type of virus present. Various imaging techniques like CT scans, MRI scans, and ultrasound help get a better view of the liver.

A test known as Magnetic Resonance Elastography is done to know about the level of stiffness of the liver. Lastly, in certain cases, the doctor may conduct a liver biopsy to be sent for further testing.

The complications of liver inflammation vary depending on various reasons. If left untreated, it may even lead to a serious medical condition known as liver failure. Thus, it is important to consult the HPB Surgery and Liver Transplant specialist for regular checkups to prevent the situation from getting any worse.

Treatment of an inflamed liver depends on the underlying cause. In the case of a fatty liver, the patient is told to reduce weight, control alcohol, and take Vitamin E supplements. The diet should have a variety of fresh foods, avoid processed foods and eat plenty of fresh fruits and vegetables.

The doctor may recommend surgery to remove any benign cysts that may be present in the liver. In certain severe cases of inflammation of the liver, the doctor may consider one as a candidate for a liver transplant.

The doctor will recommend medicine for liver inflammation depending on the symptoms. There is no medical therapy in general for an inflamed liver. Chronic hepatitis B may be treated with an antiviral agent along with interferon alfa. Chronic hepatitis C may be treated with antivirals or ribavirin or ribavirin along with interferon alfa.

Autoimmune hepatitis may be treated with corticosteroids. Liver inflammation is not a life-threatening disease if treated properly at the right time.

If left untreated, it can cause serious medical issues such as acute liver failure. Liver inflammation disease affects many individuals all across the globe.

This is caused mainly due to an unhealthy lifestyle. Certain changes in one's diet, regular exercise, healthy food swaps, controlling the alcohol intake, checking the medicines one takes and regular checkups with the doctor can help appropriately manage the condition. To book an appointment with some of the best hepatologists in Hyderabad , call Gleneagles Global Hospital, Lakdi-ka-pul.

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The extra collagen stiffens around the tissue like it is supposed to in the healthy liver; but, instead of a signal being released to stop the inflammation and discard the extra collagen, the inflammation continues, and even more collagen is deposited, leading to more stiffening.

This is how fibrosis develops. Learn more about Fibrosis. Cirrhosis is where your liver is severely scarred and permanently damaged. While the word cirrhosis is most commonly heard when people discuss alcohol-induced liver disease , cirrhosis is caused by many forms of liver disease.

Learn more about Cirrhosis. Liver cancer is cancer that begins in the cells of your liver. While several types of cancer can form in the liver, the most common type of liver cancer is hepatocellular carcinoma , or HCC, which begins in the main type of liver cells hepatocytes.

Learn more about Liver Cancer. Liver transplantation is a surgical procedure performed to remove a diseased or injured liver from one person and replace it with a whole or a portion of a healthy liver from another person, called the donor.

Learn more about Liver Transplantation. The best thing anyone can do for their health is to stay engaged in their healthcare. Be an active member of your care team by regularly visiting your healthcare provider, undergoing routine surveillance when needed, making the most of your appointments by asking questions and learning more about your health.

Learn what to ask your doctor. How Liver Diseases Progress. What is Liver Disease? How Many People Have Liver Disease? Your liver performs essential, life-sustaining functions In America, liver disease affects millions and is on the rise. Learn more about which foods are good for your liver.

Depending on the symptoms, the doctor may also prescribe the use of some medications, such as diuretics, high blood pressure remedies or creams for skin itchiness, in order to improve the patient's quality of life.

In more advanced stages, when there are many lesions to the liver, the only form of treatment may be a liver transplant, which is done by removing the affected liver and replacing it with a healthy liver from a compatible donor.

Possible complications of liver cirrhosis include portal hypertension, enlarged spleen , increased risk of infection, hemorrhage, accumulation of fluid in the abdomen, hepatorenal syndrome, spontaneous bacterial peritonitis or hepatic encephalopathy.

Please follow the instructions in that email so that we can continue to contact you and respond to your inquiry. Right side abdominal pain is typically not serious and is usually just a sign of built-up gas in the intestine. However, it can be a Pain under the left rib cage is commonly caused by pancreatitis, kidney stones, or stomach inflammation.

It can be treated with diet There are many reasons for belly button pain that can very from gas and bloating to infections and other more serious illnesses. Symptoms can vary, however, depending on Tingling throughout the body may be a result of poor circulation, a herniated disc, a nutritional deficiency, nervous system problems or Yellow diarrhea is typically a sign of stress, but it can also be indicate an intestinal infection, gallbladder issue or pancreatic issue Throwing-up blood or having blood in your vomit can be a sign of esophageal varies, gastritis or even cancer.

It is important to seek Upper stomach pain can occur for many reasons, like gastritis, reflux or indigestion. It can also be a sign of a serious condition, like Tua Saúde Health A-Z Diseases and Conditions Cirrhosis.

Updated in January Medical review: Dr. Clarisse Bezerra Family Doctor. Main symptoms Possible causes 1. Viral hepatitis 2. Alcohol abuse 3. Metabolic disorders 4.

Fatty liver disease 5. Medication 6. Chronic cholestasis How to diagnose liver inflammation Treatment options Possible complications. Was this information helpful? Yes No. Email where you want to receive the reply: Check the confirmation email we sent you.

Reason for your visit: Choose your reason Disease Live better Help someone else Gain knowledge. Are you a healhtcare professional? No Doctor Pharmaceutical Nurse Nutritionist Biomedical Scientist Physiotherapist Beautician Other.

Click here to send us a question. Thanks for your message. Your suggestions are always welcome. We sent you an email. We regularly update our content with the latest scientific information to maintain an exceptional level of quality.

Updated by Daisy Oliveira - Registered Nurse.

Genetic liver diseases include:. Complications of liver disease depend on the cause of the liver problems. Without treatment, liver disease may progress to liver failure. Liver failure can be fatal. Liver disease care at Mayo Clinic. Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission.

Check out these best-sellers and special offers on books and newsletters from Mayo Clinic Press. This content does not have an English version. This content does not have an Arabic version. Overview The liver Enlarge image Close. The liver The liver is the largest internal organ in the body.

Liver problems Enlarge image Close. Liver problems Liver problems that can occur include fatty liver disease and cirrhosis. More Information Liver disease care at Mayo Clinic Liver cysts: A cause of stomach pain?

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By Mayo Clinic Staff. Show references Loscalzo J, et al. Approach to the patient with liver disease. In: Harrison's Principles of Internal Medicine.

McGraw-Hill; Accessed Nov. How liver disease progresses. American Liver Foundation. Metabolic and alcohol-associated liver disease adult. Mayo Clinic; Cirrhosis adult. Feldman M, et al. Liver disease caused by anesthetics, chemicals, toxins, and herbal and dietary supplements.

In: Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. Elsevier; Elsevier Point of Care. Clinical Overview: Nonalcoholic fatty liver disease. Neshat SY, et al. Liver disease: Induction, progression, immunological mechanisms, and therapeutic interventions.

International Journal of Molecular Sciences. Malnick SDH, et al. Fatty liver disease — alcoholic and nonalcoholic: Similar but different. People with chronic hepatitis B can be treated with antiviral drugs and should be monitored regularly for signs of liver disease progression.

People who test positive for hepatitis C should be treated with medication right away. Treatment is typically taking pills for 8 — 1 2 weeks. The sooner the treatment starts the better it will be at preventing liver damage and further spread. Experts recommend not waiting until a person already has liver damage.

ABC Table What causes it? Hepatitis A Hepatitis B Hepatitis C Hepatitis A virus Hepatitis B virus Hepatitis C virus Number of U.

cases Hepatitis A Hepatitis B Hepatitis C About 11, estimated infections in About 13, estimated new infections in Estimated , adults with chronic hepatitis B About 69, estimated new infections in Estimated 2.

Hepatitis C is a leading cause of liver transplants and liver cancer How long does it last? Hepatitis A Hepatitis B Hepatitis C Hepatitis A can last from a few weeks to several months.

Hepatitis A Hepatitis B Hepatitis C Hepatitis A virus is spread when someone ingests the virus even in microscopic amounts too small to see through close, personal contact with an infected person, or through eating contaminated food or drink. Hepatitis A Hepatitis B Hepatitis C People can be sick for a few weeks to a few months Most recover with no lasting liver damage Although very rare, death can occur Acute hepatitis B is a short-term illness that occurs within the first 6 months after someone is exposed to the hepatitis B virus.

Hepatitis A Hepatitis B Hepatitis C Screening for prior hepatitis A is not routinely recommended. People who test positive for hepatitis C should be treated with medication right away Treatment is typically taking pills for 8 — 1 2 weeks.

Last Reviewed: October 2, Source: Division of Viral Hepatitis , National Center for HIV, Viral Hepatitis, STD, and TB Prevention. Facebook Twitter LinkedIn Syndicate.

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For more information on CDC's web notification policies, see Website Disclaimers. Cancel Continue. Damaged hepatocytes can transfer their danger signals by regulating inflammasome activation in immune cells Figure 1.

In fact, molecules such as ATP and uric acid, which are released from injured hepatocytes, cause inflammasomes in liver Kupffer cells in murine models of ASH and NASH 28 , Because the liver is exposed to gut-derived microbial products, liver inflammation is modified by the microbiota in the gut.

Gut dysbiosis has been demonstrated in obesity 30 , 31 , metabolic syndrome 32 , diabetes 33 , 34 , cardiovascular diseases, and NAFLD Boursier and colleagues evaluated gut dysbiosis in NAFLD patients and found that Bacteroides abundance was independently associated with NASH and Ruminococcus with fibrosis Thus, both endogenous ligands generated from injured cells and exogenous ligands generated from the gut microbiota activate inflammatory pathways.

Kupffer cells. Kupffer cells play a central role in liver inflammation. In the late stage of embryonic development and postnatally, these cells proliferate and differentiate into Kupffer cells, which are characterized by peroxidase activity in the nuclear envelope and rough ER Although Kupffer cells were previously believed to be unable to self-renew and were instead derived from bone marrow—derived monocytes 40 — 43 , recent evidence suggests that Kupffer cells are either a self-renewing population or are derived from local progenitors 39 , In response to hepatocyte injury, Kupffer cells become activated and express cytokines and signaling molecules.

Additionally, activated Kupffer cells display markers of M1-like macrophages or M2-like macrophages depending on the signals they receive from their environment.

Inflammation in the liver is regulated by the balance of proinflammatory M1 Kupffer cells and antiinflammatory M2 Kupffer cells Kupffer cells are exposed to various substances such as nutrients and gut-derived bacterial products via the portal circulation and they function to sense and remove pathogens and danger molecules via pattern-recognition receptors PRRs.

PRRs comprise at least two families of sensing proteins: TLRs and NLRs, which detect danger signals including pathogen-associated molecular patterns and alarmins.

TLRs recognize gut microbiota-derived bacterial products such as LPS and peptidoglycan. In turn, activation of many of these mediators worsen insulin resistance and metabolic syndrome. Recruited macrophages. Recruited bone marrow—derived macrophages are a key component of both acute and chronic liver inflammation and are involved in regression of liver disease.

Traditionally, macrophages are divided into proinflammatory M1 , wound-healing M2 , and immunosuppressive regulatory macrophages phenotypes M1 macrophages, which are induced by IFN-γ, LPS, and TNF-α and express proinflammatory cytokines such as TNF-α, IL-6, and IL-1, are implicated in the pathogenesis of chronic liver inflammation.

M2 macrophages, which are induced by IL-4, IL, IL and produce IL, TGF-β, PDGF, and EGF, have antiinflammatory effects and promote wound healing 47 , In addition to distinct functions and gene expression profiles, M1 and M2 macrophages exhibit distinct metabolic activities 49 , M1 macrophages are associated with increased glycolysis and production of NO from arginine by inducible NOS In contrast, M2 macrophages rely on fatty acid oxidation and metabolize arginine through arginase 1 ARG1 However, extensive transcriptome analysis for recruited macrophages in response to various stimuli revealed a spectrum of macrophage activation between the M1 and M2 poles These macrophages are responsible for tissue remodeling This invasion was dependent on CD44 and ATP and resulted in rapid replication and switching of macrophages toward an alternatively activated phenotype.

Another macrophage recruitment pathway was described by Xu and colleagues 49 , in which NOTCH1 signaling is required for the migration of blood monocytes into the liver and subsequent M1 differentiation.

Furthermore, monocyte infiltration into the liver is primarily controlled by CCR2 and its ligand CCL2 also known as MCP-1 54 — 57 , providing another potential target for the treatment of NASH.

Figure 2. Interaction of immune cells and the liver. The initiation of inflammation results in the trafficking and localization of immune cells to the site of injury, including neutrophils, recruited macrophages, and Tregs.

Generation of an intravascular chemokine gradient e. HMGB1 released by necrotic hepatocytes also mediates the recruitment of neutrophils through interaction with the HMGB1 receptor RAGE.

Monocyte infiltration into the liver is primarily controlled by CCR2 and its ligand CCL2, which may serve as therapeutic targets in nonalcoholic steatohepatitis NASH. Serum amyloid P binds to neutrophils and decreases TNF-α— and IL-8—induced neutrophil adhesion to extracellular matrix proteins, attenuates profibrotic macrophages, activates the complement pathway, and promotes phagocytosis of cell debris.

Oral administration of an anti-CD3 mAb induces Tregs and has been shown to be effective in a NASH animal model; this antibody is currently in clinical trials. Although recruited macrophages and Kupffer cells exhibit similarities, they can be distinguished by several markers.

Generally, high expression of CX3CR1 and low expression of the myeloid marker Ly6c characterize patrolling monocytes Kupffer cells are characterized by a lack of CX3CR1 expression Using CX3CR1-GFP transgenic mice, a gene expression analysis of recruited macrophages and Kupffer cells 60 revealed that both Kupffer cells and recruited macrophages highly express TGF-β, suggesting that both cells contribute to liver fibrogenesis.

Further, the infiltrating macrophages are Ly6c hi and differentiate into Ly6c lo macrophages in acetaminophen-induced liver injury Similar trans-differentiation is observed in alcoholic liver injury In NAFLD and alcoholic liver injury, inflammation is predominantly mediated by recruited macrophages, and Kupffer cells exhibit an antiinflammatory M2 phenotype 45 , Similarly, the increased hepatic macrophage population in diet-induced obesity is from infiltrating bone marrow—derived macrophages Neutrophils are rapidly recruited to sites of acute inflammation.

Despite the central role of neutrophils in a variety of liver diseases, the molecular mechanisms that allow these cells to home to the liver and their functions within the liver are not well understood.

Unlike neutrophil trafficking mechanisms in other organs, the adhesion of neutrophils within the liver is independent of selectins In one study, a heat-induced liver injury model demonstrated a neutrophil recruitment pathway via the following three steps 25 : a ATP released by necrotic hepatocytes activated NLRP3 inflammasome via P2X7 receptor signaling; b generation of an intravascular chemokine gradient e.

Furthermore, the TLR4 ligand SA9 protein secreted in NASH was a key regulator of hepatic CXCL2 expression and neutrophil recruitment Surprisingly, this study determined that impaired neutrophil recruitment did not aggravate or inhibit liver fibrosis. Another alarmin, HMGB1, which is released by necrotic hepatocytes, also mediates the recruitment of neutrophils in an acetaminophen-induced liver injury model, through interaction with receptor for advanced glycation end products RAGE Hyaluronan expressed by the liver sinusoidal endothelial cells LSECs interacts with CD44 on the surface of neutrophils, and this interaction plays a critical role in the recruitment of neutrophils to the liver Neutrophil infiltration is associated with inflammation induced by the dietary carbohydrates and cholesterol, whereas the non-metabolic triggers LPS and IL-1β mainly induce intrahepatic accumulation of mononuclear cells, suggesting that different inducers may elicit different inflammatory responses It has been suggested that increased myeloperoxidase secreted by neutrophils may cause oxidative damage to hepatocytes and contribute to the development of NASH 67 , Additionally, high neutrophil elastase activity and low α-1 antitrypsin determine the severity of experimental NASH Thus, there are several lines of evidence that neutrophils contribute to the metabolic syndrome and, in particular, to the pathogenesis of NASH.

DCs are professional antigen-presenting cells that capture and process antigens, migrate to lymphoid organs, and secrete cytokines to initiate both innate and adaptive immune responses. However, liver DCs have tolerogenic functions, including induction of Tregs and deletion of active T cells 70 , thereby minimizing autoimmune reactions.

DCs are divided into classical type 1 DCs cDC1 , cDC2, and plasmacytoid DCs pDCs , and their markers have been identified in both mice and humans 71 , In humans and mice, the cDC2 cells are most abundant in the liver and they exhibit tolerogenic capacity.

pDCs secrete type I IFNs during viral infections 73 , while cDC1s present antigens to T cells. After liver injury, DCs gain the capacity to induce hepatic stellate cells, NK cells, and T cells to mediate inflammation DCs are also involved in the regression of fibrosis after liver injury through their production of MMP9 Although the role of DC migration in liver pathology has not been explored in detail, extrahepatic DCs affect liver inflammation in the context of NAFLD pathogenesis.

T lymphocytes. Unlike other organs, inflammation in the liver is mainly sterile non-infectious , excluding parasite-induced fibrosis. Th17 cells are proinflammatory cells that produce IL cytokines, which have been implicated in the promotion of liver inflammation and fibrosis 77 — Based on evidence from mouse models, IL has a strong profibrogenic effect through two independent mechanisms First, IL stimulates Kupffer cells and macrophages to express inflammatory cytokines IL-6, IL-1β, and TNF-α, as well as the major fibrogenic cytokine TGF-β1.

Second, IL directly stimulates hepatic stellate cells to express collagen type I and promotes their differentiation into fibrogenic myofibroblasts via STAT3. Levels of ILA are elevated in serum of patients with alcoholic liver disease, chronic hepatitis B and chronic hepatitis C and are correlated with increased numbers of circulating Th17 cells and histologic manifestations of liver fibrosis 77 , IL—expressing cells, including Th17 cells, have been linked to progressive NAFLD Anti—IL biological therapies are currently in clinical trials for autoimmune inflammatory diseases and may be applicable in liver inflammation and fibrosis Mucosal-associated invariant T MAIT cells are innate-like T cell populations characterized by the invariant TCR chain Vα7.

MAIT cells reside in peri-biliary areas of portal tracts in healthy adults, but are reduced in blood and liver in patients with autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic liver disease and NASH A recent study of MAIT cells in obese individuals and patients with type 2 diabetes demonstrated a marked reduction in circulating MAIT cells in both patient groups compared with controls MAIT cells, which are prominent producers of IL, were enriched in adipose tissue compared with the peripheral blood of obese patients.

A direct role of MAIT cells in NASH has not been demonstrated but will be an important area for future exploration. NKT cells can recognize both exogenous and endogenous lipid antigens in the context of the major histocompatibility complex-like molecule CD1d.

NKT cells are classified into two main subsets; type I or invariant NKT cells and type II or diverse NKT cells. Murine alcoholic liver injury models exhibit an increased number of activated type I NKT cells, but not type II cells, in the liver Type II NKT cells have protective roles in alcoholic liver injury models Tregs are antiinflammatory regulators of obesity-related metabolic dysregulation Tregs have been found to be reduced in the blood of obese individuals Accordingly, Tregs have been studied in the context of NASH pathogenesis.

While the word cirrhosis is most commonly heard when people discuss alcohol-induced liver disease , cirrhosis is caused by many forms of liver disease. Learn more about Cirrhosis.

Liver cancer is cancer that begins in the cells of your liver. While several types of cancer can form in the liver, the most common type of liver cancer is hepatocellular carcinoma , or HCC, which begins in the main type of liver cells hepatocytes.

Learn more about Liver Cancer. Liver transplantation is a surgical procedure performed to remove a diseased or injured liver from one person and replace it with a whole or a portion of a healthy liver from another person, called the donor.

Learn more about Liver Transplantation. The best thing anyone can do for their health is to stay engaged in their healthcare. Be an active member of your care team by regularly visiting your healthcare provider, undergoing routine surveillance when needed, making the most of your appointments by asking questions and learning more about your health.

Learn what to ask your doctor. How Liver Diseases Progress. What is Liver Disease? NAFLD often has no symptoms. When it does, they may include:. Possible symptoms of NASH and cirrhosis, or severe scarring, include:.

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You will also receive emails from Mayo Clinic on the latest health news, research, and care. Experts don't know exactly why fat builds up in some livers and not others. They also don't fully understand why some fatty livers turn into NASH.

NAFLD and NASH are both linked to the following:. These combined health problems may contribute to a fatty liver. However, some people get NAFLD even if they do not have any risk factors.

Many diseases and health problems can increase your risk of NAFLD , including:. It is hard to tell apart NAFLD from NASH without a clinical evaluation and testing. A healthy liver, at left, shows no signs of scarring. In cirrhosis, at right, scar tissue replaces healthy liver tissue. Esophageal varices are enlarged veins in the esophagus.

They're often due to blocked blood flow through the portal vein. The portal vein carries blood from the intestine, pancreas and spleen to the liver. Liver cancer begins in the liver cells.

The most common type of liver cancer starts in cells called hepatocytes and is called hepatocellular carcinoma. Severe liver scarring, or cirrhosis, is the main complication of NAFLD and NASH. Cirrhosis happens because of liver injury, such as the damage caused by inflammation in NASH.

As the liver tries to stop inflammation, it creates areas of scarring, also called fibrosis. With ongoing inflammation, fibrosis spreads and takes up more liver tissue.

have NAFLD , and about 1. Nonalcoholic fatty liver disease care at Mayo Clinic. Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission. Check out these best-sellers and special offers on books and newsletters from Mayo Clinic Press.

This content does not have an English version. This content does not have an Arabic version. Overview Nonalcoholic fatty liver disease Enlarge image Close. Nonalcoholic fatty liver disease Compared with a healthy liver top , a fatty liver bottom appears bigger and discolored.

The liver Enlarge image Close. The liver The liver is the largest internal organ in the body. Request an appointment.

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The multicomponent NADPH oxidase NOX complexes and the mitochondrial respiratory pathway are the two major producers of endogenous ROS. NOX play an important role in liver fibrogenesis. NOX2 induces the oxidative burst required by neutrophils to kill pathogenic bacteria , while NOX1 and NOX4 are expressed in hepatocytes, Kupffer cells, and hepatic stellate cells NOX1 is catalytically activated by pro-fibrogenic agonists including angiotensin II Ang II , LPS, and PDGF, which induce hepatic stellate cell activation and proliferation NOX4 is a TGF-responsive gene and is regulated at the level of transcription NOX1- or NOX4-deficient hepatic stellate cells produce less ROS in response to Ang II compared with cells that express these enzymes Both NOX1 KO and NOX4 KO mice exhibit attenuated liver fibrosis mediated by decreased hepatic stellate cell activation.

Importantly, NOX1 and NOX4 are elevated in mouse models of NASH, and NOX inhibition decreases inflammation and fibrosis in NASH models TLR4 activation can lead to ROS signaling, and ROS may modulate signaling downstream of TLR4 via NOX activation.

Kupffer cells and macrophages are targets for the TLR4 ligand LPS, and these cells express profibrogenic cytokines that activate hepatic stellate cells 46 , which also express TLR4 , In response to LPS, hepatic stellate cells express chemokines MCP-1, MIP-1α, MIP-1β, RANTES, KC, MIP-2, and IP and adhesion molecules ICAM-1, VCAM-1, and E-selectin to recruit Kupffer cells and circulating macrophages LPS also enhances TGF-β signaling in hepatic stellate cells via down regulation of bambi, a TGF-β pseudo receptor that drives hepatic fibrosis through activation of hepatic stellate cells refs.

In most liver injury diseases such as NASH, chronic liver inflammation precedes liver fibrosis. Various liver fibrosis models in rodents also evoke inflammation. On the other hand, overexpression of PDGF-B in hepatocytes causes liver fibrosis with minimal liver inflammation , Additionally, hemochromatosis is characterized by liver cirrhosis with minimal inflammation , and the murine hemochromatosis model also shows minimal inflammation with massive fibrosis.

In iron overload, ferritin released from damaged hepatocytes contributes to the local hepatic ferritin concentration. A murine model of hereditary hemochromatosis HH; Hfe KO mice exhibits attenuated inflammatory responses to Salmonella infection and LPS induction These results suggest a role of iron in the regulation of the inflammatory response leading to liver fibrosis.

However, about half of patients with HH show histologic evidence of portal inflammation. Hepatic venous outflow obstruction also causes liver fibrosis without massive liver inflammation.

Right heart failure cardiac hepatopathy and Budd-Chiari syndrome thrombosis of the hepatic veins are the representative pathology. Further, outflow obstruction histology shows minimal inflammation in the liver Finally, advanced stages of NASH may have less inflammation than earlier stages, and the NASH activity score does not correlate with the stage of fibrosis.

Thus, NASH may progress from an inflammatory, steatotic early phase driven by metabolic syndrome to a predominantly fibrotic later stage, where fibrogenic stimuli such as TGF-β perpetuate scarring.

NASH and NAFLD are characterized by decreased consumption and secretion of lipids. Therefore, enhancement of lipid secretion and consumption may be a promising therapeutic strategy for NAFLD.

PPAR stimulation facilitates oxidation of lipids by upregulating acyl-CoA oxidase and medium-chain acyl-CoA dehydrogenase MCAD. Thus, PPARs are possible therapeutic targets in NASH Figure 1. In fact, PPAR agonists have been reported and are now in clinical trials for the treatment of NASH , FXR signaling is also a potential target because it facilitates secretion of bile acids , resulting in decreased hepatic storage of triglycerides and fatty acid esters Figure 1.

Moreover, FXR signaling caused decreased hepatic lipid synthesis and enhanced peripheral clearance of VLDL. As a result, it promotes insulin sensitivity, decreases hepatic gluconeogenesis and circulating triglycerides Based on these metabolic effects, pharmacologic activation of FXR has been proposed as a target for the treatment of NASH.

Cholic acids and obeticholic acid are reported as agonists of FXR, and both are now in clinical trials refs. CCR2 and CCR5 and their ligands CCL2 and CCL5 are implicated in the pathogenesis of liver inflammation and fibrosis, especially in NASH.

In response to hepatocyte injury, Kupffer cells secrete CCL2, which recruits monocytes to the liver. New targets for treating chronic liver diseases with fibrosis can be analyzed in the context of recent insights into the mechanisms of liver inflammation.

Serum amyloid P SAP; also known as pentraxin-2 is a kDa protein that is produced by the liver and secreted into the blood and circulates as stable kDa pentamers SAP binds to neutrophils and decreases TNF-α— and IL-8—induced neutrophil adhesion to ECM proteins, attenuates profibrotic macrophages, activates the complement pathway, and promotes phagocytosis of cell debris — After activation, Kupffer cells and recruited macrophages produce TGF-β1, which induces differentiation of hepatic stellate cells into myofibroblasts.

Local suppression of TGF-β1 activity remains a major challenge of antifibrotic therapy. Neutralization of TGF-β in animal models inhibits liver fibrosis and reduces the risk of developing cholangiocarcinoma Fresolimumab GC , a human anti—TGF-β1 mAb that neutralizes all isoforms of TGF-β, has demonstrated an acceptable safety profile and preliminary evidence of antitumor activity in patients with advanced malignant melanoma and renal cell carcinoma — Fresolimumab also exhibits antiinflammatory and anti-fibrotic effects in systemic sclerosis patients , suggesting that therapeutic targeting of TGF-β1 is a potential strategy in fibrotic liver disease.

Because oxidative stress mediates hepatocyte death and hepatic stellate cell activation, regulation of ROS is a promising strategy for liver fibrosis therapy PPARδ is a key metabolic regulator with pleiotropic actions in various tissues including fat, skeletal muscle, and liver.

PPARδ agonists protect hepatocytes from cell death by reducing ROS generation in hepatocytes, leading to decreased liver fibrosis The cellular membrane component phosphatidylcholine PC is generated by a transmethylation reaction from phosphatidylethanolamine PE via a metabolic pathway that utilizes S-adenosylmethionine SAMe as a methyl donor Furthermore, the formation of PC is reduced in various chronic liver diseases including intrahepatic cholestasis, cholestasis of pregnancy, and alcoholic liver disease — There have been few randomized controlled trials to assess the efficacy of SAMe in chronic liver diseases , , but in studies conducted thus far, SAMe treatment improved pruritus.

Tregs are important for the pathogenesis of NAFLD and NASH. Therefore, enhancement of Treg function may be a therapeutic strategy for the treatment of NASH. Oral administration of an anti-CD3 mAb induces Tregs and has been shown to be effective in a NASH animal model; this antibody is currently in clinical trials refs.

In conclusion, the cellular and molecular mechanisms of liver inflammation and fibrosis are being investigated extensively. Liver inflammation and fibrogenesis are controlled by complex immunologic pathways that implicate many possible therapeutic targets. Enhancement of our understanding of the mechanisms underlying inflammation should be translated into clinical therapies.

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View PDF Download citation information Send a comment Terms of use Standard abbreviations Need help? Email the journal. Top Abstract Introduction From metabolism to liver injury Inflammatory cells in the liver From liver inflammation to fibrosis No fibrosis without inflammation?

Perspectives Acknowledgments Footnotes References Version history. School of Medicine, UCSD, La Jolla, California, USA. Published in Volume , Issue 1 on January 3, J Clin Invest. Copyright © , American Society for Clinical Investigation.

Published January 3, - Version history. Abstract Chronic liver inflammation leads to fibrosis and cirrhosis, which is the 12th leading cause of death in the United States. Figure 1 An overview of lipid metabolism in hepatocytes. Figure 2 Interaction of immune cells and the liver. This article is supported by NIH grants to DAB AA, ES, and AA Conflict of interest: The authors have declared that no conflict of interest exists.

Reference information: J Clin Invest. Centers for Disease Control and Prevention. Health, United States, Web Site. CDC Web site. htm Updated April 27, Accessed November 11, Mokdad AA, et al. Liver cirrhosis mortality in countries between and a systematic analysis.

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