STUDY TITLE: Genome‐wide association study and meta‐analysis of alcohol‐related liver cirrhosis identifies novel genetic risk factors
SUMMARY: Discovery of a novel region of the genome associated with alcohol-related liver cirrhosis.
OVERVIEW: The liver is a large organ that sits on the right side of the abdomen. It filters blood to detoxify chemicals, including drugs and alcohol. After long periods of heavy alcohol use, healthy liver tissue is replaced by scar tissue. Over time, the build-up of scar tissue can impair the functioning of the liver, leading to a condition called cirrhosis. An estimated 10-20% of heavy drinkers will develop cirrhosis, which can eventually lead to liver failure. This genome-wide association examined about 1,750 individuals of European ancestry to identify genetic factors that may put heavy drinkers at an increased risk for developing liver cirrhosis. The study found one novel genomic region associated with liver cirrhosis. This region harbors the FAF2 gene that plays a role in fat metabolism, in particular how fats are organized within cells.
DID YOU KNOW? The liver is the only internal organ that has the potential to regenerate. As little as 51% of the original liver can regenerate to a full-sized organ. Prolonged alcohol use, though, can affect how well the cells of the liver can regrow. [SOURCE]
SAMPLE RESULTS: Learn more about the Nebula Research Library.
ALCOHOL-RELATED LIVER CIRRHOSIS-ASSOCIATED VARIANTS: rs2294915, rs10401969, rs10433937, rs11134977, rs28929474
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WEEKLY UPDATE: October 5, 2020
Alcohol-related liver cirrhosis and its genetics: further details
|Inflamed liver tissue as seen under a microscope. Image source: Nephron, Wikimedia Commons, CCY-BY-SA 3.0 license|
About alcohol-related liver cirrhosis and genetics
Alcohol-related liver cirrhosis is one of the most severe forms of liver disease. It is one of the advanced stages of chronic liver diseases. A number of environmental and genetic factors reportedly impact the alcohol-related liver cirrhosis. This stage of liver damage is generally considered irreversible. And when not taken care of, cirrhosis can even lead to liver cancer. However, its reversal via a number of treatments might be possible.
Cirrhosis usually involves chronic processes of destruction and regeneration of the liver tissue. In general, alcohol abuse, non-alcoholic fatty liver and chronic viral hepatitis are the few prominent causes of liver cirrhosis. Virus related liver cirrhosis and alcohol related liver cirrhosis are the most common forms of liver disease.
History of liver cirrhosis
The illustration by Leonardo da Vinci (1452-1519) was the first in the history of medicine to show the macroscopic description of liver cirrhosis. This drawing was about the vascular anatomy of the liver of a dead centenarian. And it was the winter of 1508 in Florence, when Leonardo da Vinci was performing an autopsy on this man.
|Comparative overview of a normal and cirrhotic liver morphology. Image source: BruceBlaus, Wikimedia commons, CC-BY-SA 4.0 licence|
GWAS reports have shed light into the genetics of alcohol-related liver-cirrhosis
Various types of cells are responsible for the pathogenesis of liver cirrhosis.
- Necrosis of liver cells by viruses or toxins causes cirrhosis. These cells then release cytokines, which activate liver macrophages and fat storage cells of the liver. Further, this process also activates monocytes and granulocytes from the blood.
- Through these cells, the organ structure is destructively remodeled with parenchymal necrosis, formation of regenerate nodes and connective tissue septums.
These tissue nodes interfere with proper functioning of the liver. And bile flows through the bile ducts to the gallbladder.
- Bile ducts form anew, but end up blind. Then blood congestion occurs between the liver and the digestive tract. And this leads to ascites and enlargement of the spleen. In the worst scenario, esophageal varices bleed.
- Damage in hepatocytes further causes hepatic encephalopathy. Hence, ammonia metabolism reduces by upto 80%. In such a condition, via vascular collaterals, the liver bypasses the ammonia formed in the intestine.
Due to the lack of degradation, the toxin concentration in the blood increases and ammonia passes the blood-brain barrier. The astrocytes in the brain swell possibly reading to brain edema. This can lead to frequent episodic cognitive deficits.
- Ultimately, the inadequate detoxification activity of a cirrhotic liver can lead to hepatic coma. Hepatic encephalopathy is a predictor of a particularly severe form of liver cirrhosis. In one study, almost half of all liver cirrhosis patients with hepatic encephalopathy died within one month of diagnosis.
Under such circumstances, treating hepatic encephalopathy reduces the risk of liver cirrhosis associated complications. For example, hepatic encephalopathy treatments alleviate conditions like spontaneous bacterial peritonitis (SBP) or variceal bleeding.
- Eventually, the liver shrinks, its surface becomes wrinkled and knotty. Microscopically, active and inactive cirrhosis can be distinguished. The preliminary stage of liver cirrhosis is liver fibrosis.
Cirrhosis-disease progression and genetics of alcohol-related and non-alcoholic cirrhosis
Typically, cirrhosis is a gradual process and develops over years to decades. Liver cirrhosis seldom progresses faster in a matter of less than one year. But in the end, almost all chronic liver diseases lead to cirrhosis.
–The first step is liver inflammation. Usually, liver inflammation is treatable.
–If left untreated, scarring of the liver tissue or fibrosis occurs.
–Next, abdominal swellings follow the scarring of the liver. At this stage there is a reduction of the blood flow via portal veins. And this results in portal hypertension and subsequently high blood pressure.
–Finally, the end stage of liver disease occurs. This may be fatal to the patient.
Incidence and genetics of alcohol related liver cirrhosis and non-alcoholic cirrhosis
The incidence, i.e. the number of new cases, in industrialized countries is 250 per 100,000 inhabitants per year. Regarding the cirrhosis related deaths, the ratio of men to women is 2:1. According to a 2015 study, 0.29% of the adult population had developed cirrhosis in the United States. The genetics of alcohol-related liver cirrhosis is an important aspect in order to delineate the mechanism of alcohol-related liver cirrhosis.
Environment and ethnicity reveals more about the genetics of alcohol-related liver cirrhosis
When it comes to the genetics of alcohol-related liver cirrhosis, a study indicates that at least “50% of an individual susceptibility ” is due to genetic factors. In both the non-alcohol and alcohol-related liver cirrhosis, environmental and genetic factors interact to impact the diseases.
Genetic factors such as PNPLA3, TM6SF2, and MBOAT7 determine the alcohol-related liver cirrhosis and the non-alcoholic cirrhosis. All of these genetic modifiers participate in lipid metabolism and worsen the condition in alcohol-related liver cirrhosis. In addition to genetics, epigenetics also contributes towards the alcohol-related liver cirrhosis.
Next, another type of disorder, cryptogenic cirrhosis is a non-alcohol related liver cirrhosis, where the influence of genetic factors is witnessed via mutation in keratin genes. Association of ethnicity with the genetics of alcohol-related liver cirrhosis is a crucial point in disentangling liver disease related mechanisms. For instance, among several populations, Hispanics, Native Alaskans and Native Americans have higher cirrhosis related mortality.
Causes of liver cirrhosis
(the genetics of alcohol-related liver cirrhosis and non-alcoholic cirrhosis)
Fatty liver disease
Globally, fatty liver is the most common issue of liver health. A distinction is made between two forms of fatty liver diseases. They are alcoholic fatty liver disease (AFLD) and non-alcoholic fatty liver disease (NAFLD).
Alcoholic fatty liver disease (AFLD)
Alcoholism is the most common cause of liver cirrhosis in industrialized countries and it accounts for about 50% of cases. Next to hepatitis, alcohol related fatty liver cirrhosis is the major cause of fatty liver. In this disease, excessive alcohol consumption results in the conversion of ethanal from ethanol. And this, in turn, leads to a sharp increase in the NADH/NAD ratio in the body.
Increase in the redox potential of these pyridine nucleotides inhibits the citric acid cycle. In this situation fatty acid synthesis increases markedly. Finally, accumulation of triglycerides (fat) takes place.
One of the long term effects of alcohol consumption is AFLD. In alcohol related fatty liver cirrhosis, the damage gets worse with increased consumption of alcohol. One of the mechanisms that cause scarring is elevation of the Interleukin-8 in liver tissue. This resultantly allows the accumulation of neutrophils in the liver.
Another mechanism behind alcohol related liver cirrhosis is the formation of leukotriene B4 from arachidonic acid, which also attracts inflammatory cells.
The degeneration of the liver in alcohol related liver cirrhosis is initially fully reversible. However, continued alcohol consumption leads to fatty liver and ultimately to the development of liver cirrhosis.
Non-alcoholic fatty liver disease (NAFLD)
This liver disease is characterized by fat storage in the liver cells, which is reversible in its initial course.
Non alcoholic fatty liver can be of two types.
-A simple fatty liver that does not yet lead to liver damage.
-Non-alcoholic steatohepatitis that is the inflammation and damage of the liver.
Eventually, both forms can lead to scarring of the liver, which increases the risk of developing liver cirrhosis.
A number of other factors responsible for alcohol related liver cirrhosis and non-alcoholic cirrhosis are as follows:
-Chronic viral hepatitis such as Hepatitis B and Hepatitis C
-Cryptogenic liver cirrhosis (without detectable etiology)
-Congestive cirrhosis (Cirrhosis cardiaque), typical in right heart failure
Rare forms of cirrhosis with defined etiology
-Hereditary fructose intolerance
-Glycogen storage disease
-Cholangiodysplastic cirrhosis of the liver
-Primary sclerosing cholangitis
-Cirrhosis in Alpha-1-Antitrypsin Deficiency
-Primary biliary cholangitis (formerly: primary biliary cirrhosis)
-Secondary biliary cirrhosis
-Hepatopathy in celiac disease (gluten-sensitive enteropathy)
-Cirrhosis of the liver caused by substances toxic to the liver. It can be a xenobiotic compound like tetrachloromethane or a drug such as methotrexate.
A genetic disorder, hereditary hemochromatosis is another example linked to liver damage in general. However, whether such damage is specific to alcohol-related liver cirrhosis or the non-alcoholic cirrhosis, still remains to be clarified. Damage in hemochromatosis occurs due to excessive absorption of iron. In majority, this disorder is linked with p.Cys282Tyr (c.845G > A) HFE variant. Diagnosis happens by means of identification of the biallelic HFE pathogenic variants.
Symptoms of alcohol related liver cirrhosis and non-alcoholic liver cirrhosis
- Early, but unspecific symptoms of liver cirrhosis can be reduced performance, lack of concentration and fatigue.
- In addition, the so-called “hepatic skin “ signs can occur. These are characterized by red coloration of hand palms, yellowish skin and spider nevi.
- Cirrhosis of the liver often affects the subjective sensation of the affected patient but only at a very late stage of the disease.
- Liver function can be impaired in a variety of ways with regards to synthesis and detoxification. Until complications develop, this is referred to as compensated liver cirrhosis.
- Decompensated liver cirrhosis is accompanied by clinically relevant complications such as portal hypertension, ascites, or splenomegaly.
- Hepatic encephalopathy is a brain dysfunction that increases toxic metabolites causing the brain cells to swell. Symptoms of hepatic encephalopathy also include dizziness, disorientation, fatigue, concentration difficulties, memory loss, changes in personality up to hepatic coma.
- Other typical symptoms are reddening of the palms, caput medusae, swollen blood vessels, varnished tongue and edema.
Clinical measure: for alcohol related liver disease and non-alcoholic liver disease
In the so-called Child-Pugh Score Classification, several of the above factors are included and a score is calculated. These factors encompass bilirubin, time required for blood clotting, albumin, hepatic encephalopathy and ascites. The resulting classification into stages A to C allows a statement about the prognosis of the disease. For instance, patients in stage C have a very poor prognosis regarding survival time.
As much as this score is useful clinically, it also has a major drawback. For example, hepatic encephalopathy and ascites are assessed in only three grades of severity. This results in more or less subjective and inaccurate scores.
For this reason, since 2002, the MELD-Score has been used. It is calculated according to a certain formula from laboratory parameters (creatinine, bilirubin and INR). The MELD-Score then provides information on survival over the next three months.
As an example, a patient in hospital with a score of 20-30 has a 25% risk of dying in the next three months. While a cirrhosis patient with a MELD of 40 is most likely to die in three months.
Liver cirrhosis is diagnosed through a number of ways. Diagnosis ranges from checking the medical history to scanning the liver using rays. These are the classic testing methods to diagnose liver cirrhosis.
Blood test is a common chemical procedure for diagnosing liver cirrhosis. Enzymes such as transaminases and alkaline phosphatases are of clinical importance in liver disease diagnosis. These enzymes are the signs of liver damage.
By and large, liver enzymes like AST (GOT), ALT (GPT) as well as γ-GT, bilirubin and ammonia may be elevated in cirrhosis. However, the level of ammonia alone does not indicate the presence of hepatic encephalopathy.
Cirrhosis can also be diagnosed by further measuring bilirubin and many other blood proteins. For instance, in the laboratory, reduced values for cholinesterase, albumin and some coagulation factors are noticeable due to the liver’s limited synthesis capacity.
Imaging is a non-invasive method that captures a detailed image of the liver. X-rays, radio waves, ultrasound scans are few ways of diagnosing cirrhosis.
- While CT scan uses X-rays to capture the image of the liver, MRI uses magnet and radio waves for the diagnosis. Other than the shape and structure of the liver, CT scans and MRI diagnose blood flow in the hepatic portal veins.
- Ultrasound examines the structural homogeneity of the liver. In cirrhosis the edge of the liver is wavy and the internal vessels exhibit some form of obstruction. Ultrasound can very well detect ascites and splenomegaly.
- An improved form of sonography is the so-called fibroscan. The alternative term for fibroscan is transient elastography. With this method, the fibrosis, i.e. the connective tissue remodeling of the liver, can be determined. This provides a very reliable result for diagnosis and could replace liver biopsy in the future.
|Fatty liver diagnosis via CT. Image source: James Heilman, MD, Wikimedia Commons, CC-BY-SA 3.0 license|
Liver biopsy is the definitive diagnosis in cirrhosis. A part of the liver tissue is extracted with a needle. Using microscopy, this tissue is examined for cirrhosis.
Therapy (as prescribed for both alcohol related liver cirrhosis and non-alcoholic form)
–Nutritional therapeutic measures
General nutritional-therapeutic measures form the basis of liver cirrhosis related diseases. The liver cirrhosis diet encompasses balanced amounts of carbohydrates, proteins, vitamins, calcium, phenols. Measures such as managing blood sugar levels, limiting salt intake, avoiding drinking alcohol etc. can be helpful in tackling the liver cirrhosis progression.
Usually, a registered dietitian prescribes a balanced diet and lifestyle measures for improving the liver conditions. Omission of all potentially liver-toxic substances like alcohol is one such way. Further, this therapy also uses other methods such as compensation for a vitamin deficiency (e.g. vitamin B1 in the case of alcoholism) or adequate energy supply.
Nutritional intake should preferably take the form of oral sip feeds. Patients with advanced liver cirrhosis in particular also benefit from parenteral nutrition. The energy intake should be about 145-167 kJ (35-40 kcal) per kg body weight.
At its final stage, liver cirrhosis acutely threatens the patient’s life. Due to complications of cirrhosis, liver transplantation is the last possible treatment option to save the patient. At this phase, a suitable donor organ replaces the cirrhotic liver.
An insufficient carbohydrate supply can worsen an existing metabolic situation. This can be explained by the fact that in this situation not only fats but also proteins are metabolized for energy production. Hence, carbohydrate-reduced diets are harmful for diabetics with liver cirrhosis.
A daily protein amount of 1.2-1.5 g protein per kg body weight is useful in this treatment. Protein restriction should only be applied in patients with refractory chronic hepatic encephalopathy. If necessary, leucine, isoleucine and valine should be substituted in their diet.
The general recommendation is to start the osteoporosis prophylaxis early on, in all patients. And calcium substitution (1200-1500 mg/d) is the common procedure for the prophylaxis. Additionally, patients with cholestatic liver disease get vitamin D3 substitutions (400-800 IU/d). Further, in patients of advanced age (> 65 years), underweight patients and smokers, a basic diagnosis should be made early on.
Substitution with Vitamin K can be a solution during the increased risk of bleeding. This vitamin is lipophilic in nature. The condition of cholestasis reduces its absorption. Hence, the general recommendation is vitamin substitution in increased doses, orally or parenterally (10 mg every 10 weeks).
In alcoholic patients 50% of patients have a vitamin B1 deficiency. So, vitamin B1 substitution is the recommended treatment in continued alcohol consumption for the prophylaxis of Wernicke’s encephalopathy.
There is evidence that the consumption of caffeine can protect the liver from the formation of cirrhosis or delay its development. By and large, polyphenols could play a major role in this. Polyphenols are a group of plant substances and found in particularly high quantities in coffee.
–Non-nutritional therapeutic measures
In general, this measure treats the underlying cause for the disease. However, regular examinations for early detection of liver carcinoma are important. For people with cirrhosis, the last resort in many cases is a liver transplant.
- Withdrawal treatment is a tried measure in case of alcohol related liver cirrhosis. Patients with autoimmune hepatitis are treated by immunosuppression. Virus elimination with interferons is the preferred method in chronic hepatitis B. Whereas, in hepatitis C, antiviral therapy leads to virus elimination in over 90% of patients (no viruses detectable in the blood).
- Sometimes the doctor may use specific measures to treat particular complications. For example, in the case of bleeding from esophageal varices, the primary goal is achieving hemostasis. Otherwise there is a risk of fatal blood loss. In case there is a severe form of ascites, the abdominal fluid can be drained by a specific puncture.
Generally, medication is helpful in treating hepatic encephalopathy. The primary goal is to reduce the further production of ammonia and other toxins. Hence, as a possible therapy option, the intestinal selective antibiotic Rifaximin is available for recurrence.
Among other things, it kills the ammonia-producing bacteria in the intestine. As a result, the relative risk of recurrent episodes of hepatic encephalopathy reduces.
- Another drug is lactulose, a synthetic disaccharide that influences the intestinal flora in favor of lactic acid-forming bacteria. Therefore, this in turn suppresses the growth of ammonia-forming intestinal bacteria.
- Other treatments of hepatic encephalopathy utilizes L-ornithine or L-aspartate. Mainly, these drugs promote the conversion of ammonia to harmless urea. The urea then gets excreted out in the urine.