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Alcohol-related liver cirrhosis (Schwantes‐An, 2020)

STUDY TITLE: Genome‐wide association study and meta‐analysis on 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 sample results


ALCOHOL-RELATED LIVER CIRRHOSIS-ASSOCIATED VARIANTS: rs2294915, rs10401969, rs10433937, rs11134977, rs28929474

ADDITIONAL RESOURCES:
What does the liver do? (Video)
Cirrhosis

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WEEKLY UPDATE: September 7, 2020

More about liver cirrhosis

inflammed fatty liver
Inflamed liver tissue as seen under a microscope. Image source: Nephron, Wikimedia Commons, CCY-BY-SA 3.0 license

Introduction

Liver cirrhosis is referred to as the scarring of liver tissues. It is one of the advanced stages of chronic liver disease. Liver cirrhosis is generally considered irreversible. However, its reversal via a number of treatments have been reported.

Cirrhosis involves chronic processes of destruction and regeneration of the liver tissue. Generally, alcohol abuse, non-alcoholic fatty liver and chronic viral hepatitis are few common causes of cirrhosis.

History

The first macroscopic description of liver cirrhosis in the history of medicine is found in the drawing by Leonardo da Vinci (1452-1519). The drawing was about the vascular anatomy of the liver of an over 100-year-old man. It was 1508  and Leonardo da Vinci, in Florence, was performing an autopsy on this man. 

healthy and cirrhotic liver
Comparative overview  of a normal and cirrhotic liver morphology. Image source: BruceBlaus, Wikimedia commons, CC-BY-SA 4.0 licence

Pathogenesis

  • The cause of cirrhosis is necrosis  of liver cells caused by viruses or toxins. The cells release cytokines, which activate liver macrophages and fat storage cells of the liver. In addition, monocytes and granulocytes are activated 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 are formed 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. Ammonia metabolism is reduced by up to 80%. By this, the ammonia formed in the intestine is bypassed by the liver via vascular collaterals. 

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 considered a predictor of a particularly severe course of liver cirrhosis. In one study,  almost half of all liver cirrhosis patients with hepatic encephalopathy died within one month of diagnosis. 

Treating hepatic encephalopathy reduces the risk of liver cirrhosis complications. For example, conditions like spontaneous bacterial peritonitis (SBP) or variceal bleeding are alleviated when hepatic encephalopathy is treated.       .

  •   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

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. Eventually in the end, almost all chronic liver diseases lead to cirrhosis.

–The first step is liver inflammation. This stage is treatable.

–If left untreated, scarring of the liver tissue occurs. This stage is usually known as fibrosis.

–Scarring is followed by abdominal swellings. At this stage blood flow via portal veins is reduced. And this results in portal hypertension and subsequently high blood pressure.

–End stage liver disease occurs. This may be fatal to the patient.

Incidence

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.    

Causes of liver 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. It accounts for about 50% of cases. Excessive alcohol consumption results in the conversion of ethanal from ethanol. 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. Liver 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 is the formation of leukotriene B4 from arachidonic acid, which also attracts inflammatory cells. 

The fatty degeneration of the liver 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.

–Other causes

A number of other factors responsible for 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

-Autoimmune hepatitis

Rare forms of cirrhosis with defined etiology

-Hemochromatosis

-Wilson’s disease

-Galactosemia

-Hereditary fructose intolerance

-Cystic Fibrosis

-Glycogen storage disease

-Cholangiodysplastic cirrhosis of the liver

-Primary sclerosing cholangitis

-Budd-Chiari Syndrome

-Tropical diseases

-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.

Symptoms

  • 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 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, 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 the 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.

 As an example, patients in stage C  have a very poor prognosis regarding survival time. Hepatic encephalopathy and ascites are assessed in only three grades of severity, resulting in more or less subjective, 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 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. A cirrhosis patient with a MELD of 40 is most likely to die in three months.       

Diagnosis

Liver cirrhosis is diagnosed through a number of ways. Diagnosis ranges from checking the medical history to scanning the liver using rays.

–Chemical assays

Usually blood tests are commonly performed in liver cirrhosis. Enzymes such as transaminases, alkaline phosphatases are measured to test the liver damage. Besides, bilirubin and other blood proteins are assayed for diagnosing cirrhosis.

For instance, in the laboratory, reduced values for cholinesterase, albumin and some coagulation factors are noticeable due to the liver’s limited synthesis capacity. 

The liver enzymes 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.

–Imaging

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 shape and structure of the liver, blood flow in the hepatic portal veins are diagnosed using CT scans and MRI. 
  • Ultrasound examines the structural homogeneity of the liver. The edge of the liver is wavy and the internal vessels are rare. The caudate lobe may be enlarged. Ultrasound can very well detect ascites and splenomegaly. 
  • An improved form of sonography is the so-called fibroscan, also known as 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
Fatty liver diagnosis via CT. Image source: James Heilman, MD, Wikimedia Commons, CC-BY-SA 3.0 license

–Biopsy

The definitive diagnosis is made by a liver biopsy. A part of the liver tissue is extracted with a needle. Using microscopy, this tissue is examined for cirrhosis. 

Therapy

–Nutritional therapeutic measures

The basis of the therapy is formed by general nutritional-therapeutic measures. A liver cirrhosis diet encompasses balanced amounts of carbohydrates, proteins, vitamins, calcium, phenols.  

Omission of all potentially liver-toxic substances like alcohol is one such way. Compensation for a vitamin deficiency (e.g. vitamin B1 in the case of alcoholism) and  adequate energy supply are also used in therapy. 

 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 kilogram body weight.

 If the liver cirrhosis is at its final stage, the patient’s life is acutely threatened. Due to complications of cirrhosis, liver transplantation is the last possible treatment option to save the patient. A suitable donor organ replaces the cirrhotic liver.

Carbohydrate intake

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. Diabetics with liver cirrhosis are advised against carbohydrate-reduced diets.       

Protein consumption

A daily protein amount of 1.2-1.5 g protein per kg body weight is recommended. 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.

Osteoporosis prophylaxis

Osteoporosis prophylaxis should be started early in all patients. This is done by calcium substitution (1200-1500 mg/d). In patients with cholestatic liver disease, vitamin D3 is additionally substituted (400-800 IU/d). In patients of advanced age (> 65 years), underweight patients and smokers, a basic diagnosis should be made early on.

Vitamin substitution

Vitamin K substitution is indicated for increased risk of bleeding. The absorption of this lipophilic vitamin is reduced in cholestasis. The substitution here should be performed orally or parenterally in increased doses (10 mg every 10 weeks). 

In alcoholic patients 50% of patients have a vitamin B1 deficiency. This should also be substituted – especially in the case of continued alcohol consumption for the prophylaxis of Wernicke’s encephalopathy.

Caffeine

There is evidence that the consumption of caffeine can protect the liver from the formation of cirrhosis or delay its development. Polyphenols, a group of plant substances that are found in particularly high quantities in coffee, could play a major role in this. 

–Non-nutritional therapeutic measures

The underlying cause for the disease is generally treated using this measure. However, regular examinations for early detection of liver carcinoma are important. A last resort in many cases is a liver transplant.

  • In case of alcohol dependence withdrawal treatment is tried. Patients with autoimmune hepatitis are treated by immunosuppression. In case of chronic hepatitis B, virus elimination with interferons can be tried. In hepatitis C, antiviral therapy leads to virus elimination in over 90% of patients (no viruses detectable in the blood). 
  • Complications of liver cirrhosis are treated with specific measures. In the case of bleeding from esophageal varices, the primary goal is hemostasis. Otherwise there is a risk of fatal blood loss. If there is a severe form of ascites, the abdominal fluid can be drained by a specific puncture. 
  • Hepatic encephalopathy is treated with medication. The primary goal is to reduce the further production of ammonia and other toxins. 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. Hence, 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. This in turn suppresses the growth of ammonia-forming intestinal bacteria. 
  • For the treatment of hepatic encephalopathy, L-ornithine L-aspartate can also be used, which promotes the conversion of ammonia to harmless urea. The urea then gets excreted out in the urine.


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