Cirrhosis is the end stage of the chronic liver disease. It starts with chronic inflammation, which starts the wound healing process as well as tissue destruction and replaces it with new fibrous tissue. When the chronic disease stays, a low level of “wound healing” and deposition of fibrous tissue continues. Which in turn builds scar tissue, which becomes reversed and changed into functional tissue.
Once a complication of cirrhosis develops, your 5-year survival rate will decrease with 20%.
Cirrhosis can have many complications:
- High blood pressure in the liver. The blood flow through the portal vein of the liver is decreased due to fibrous tissue. To release the pressure that builds up, new collateral blood vessels are generated, which bypass the liver and send intestinal blood to the organs. The changes in the circulation are dramatic, with serious consequences for the kidneys, lungs, gastrointestinal, and cardiovascular functions.
- Ascites. The most common cause of cirrhosis, 50% of patients will develop this within 10 years. Ascites is an increase of fluid in the abdomen, due to the increased pressure of hepatic circulation that forces the plasma out of the blood vessels into the body cavity.
- Bacterial peritonitis. This is the infection of the fluid in the abdominal cavity and occurs in 30% of people with cirrhosis and ascites.
- Coagulopathy. The main protein factors responsible for blood clotting as well as preventing blood clotting are found in the liver. Patients who suffer from liver disease do not have the ability to clot blood, as these factors are dramatically reduced. This may cause excess bleeding or blood clots. Patients with cirrhosis, have low platelet counts, which further increase the risk of bleeding. This disease could also result in low absorption of fat soluble Vit K which also helps with the blood clotting.
- Gastroesophageal variances. These are abnormally enlarged veins in the lower part of the oesophagus. Gastric variances, are enlarged veins in the stomach. This is a result of high blood pressure. When this rupture or haemorrhage it may cause major complications, which result in a 15-20% mortality rate, with each episode. This is present in 30-40% of patients with compensated cirrhosis, and 60% with decompensated cirrhosis when diagnosed.
- Hepatocellular carcinoma. This is the fifth most common cancer in men, and seventh in the woman.
- Hepatopulmonary syndrome. It is a serious stage of liver cirrhosis. It is present in 10-17% of patients with cirrhosis, due to poor prognosis. Portal hypertension causes the blood to flow from the intestines into the bloodstream. The body responds in secreting excess amount of cellular messengers that cause blood vessels to dilate and cause difficulty in breathing.
- Hepatic encephalopathy. This is when the liver does not metabolise ammonia into urea, thus resulting in a build-up of toxins in the blood, and brain. Patients can have these following symptoms: confusion, sleep disruption, cognitive and intellectual dysfunction, impaired motor activity, slow or slurred speech, as well as in coordination. Coma and death are possible in severe cases.
- Hepatorenal syndrome. This is the functional renal failure when less blood is circulated to the kidneys. This is a result of portal hypertension. Signs and symptoms may be the same as those of liver disease, like nausea, weight gain, and dark urine. But have low blood pressure, increased heart rate, low blood sodium, and increased levels of creatinine and urea in the blood.
- Immune dysfunction. Cirrhosis, reduces the production of immune signalling molecules in the liver, and slows down activity and amounts of innate immune cells, and increase the production of antibacterial antibodies that also have autoimmune activity.
- Malnutrition. This is categorised as loss of skeletal muscle and lean body mass, and fat tissue or both, and does not respond to dietary intake of fats and proteins. Malnutrition has several major complications when diagnosed with cirrhosis, such as sepsis, ascites and hepatic encephalopathy, increased mortality and a reduced quality of life. This can also include micronutrient deficiencies, water soluble vitamin and mineral deficiency, and those that have the disease that affects the bile flow could have difficulty absorbent fat-soluble vitamins such as A, D, E and K.
Other complications of cirrhosis include:
- Hepatic hydrothorax. This is when fluid accumulates in the compartment around the lungs, leading to breathing difficulties.
- Endocrine disorders. Low testosterone levels are common in men with cirrhosis. The liver and adrenal glands have a complex interrelationship. This is common in patients with stable and decompensated cirrhosis.
- Hepatic osteodystrophy. This is a bone disease which occurs in patients with the chronic liver disease, this may also result in osteoporosis, which is the loss of bone density and mass, or softening of bones.
Any chronic liver disease can change into cirrhosis. The most common cause is 30% caused by the Hepatitis B virus infection. And 27% of chronic hepatitis C virus infection. This is generally caused because of intravenous drug use, unprotected intercourse, blood transfusions, and tattoos. Alcoholic liver disease is also a worldwide contributor for cirrhosis. Non-alcoholic fatty liver disease is common causes of cirrhosis, and are associated with obesity and metabolic syndrome.
Hepatitis C often has the same symptoms, and may not be detected until cirrhosis is already diagnosed. This is common in USA and affects over 3 million people. Hepatitis C viral infections can be detected with blood tests, thus can be treated before it progresses to cirrhosis.
There are also less common chronic liver diseases which could lead to cirrhosis:
Autoimmune hepatitis: A disease which attacks the body’s own hepatocytes.
Cholestatic liver diseases. These are disease which interfere with the flow of bile.
- Primary Biliary cirrhosis: Chronic and slow progressive liver disease which is autoimmune in origin and results from damage to small bile ducts.
- Primary sclerosing cholangitis: Condition associated with bowel disease which results in inflammation and fibrosis, and can cause narrowing and dilation of the bile ducts.
- Cystic fibrosis: A condition that is characterized by the secretion that affect the lungs, pancreas, intestines and liver.
- Biliary atresia: Is the malformation of bile ducts.
Inherited metabolic disorders:
- Alpha 1 antitrypsin deficiency: genetic disease which can cause liver disease, cirrhosis, and hepatocellular carcinoma.
- Wilson’s disease: Inherited copper storage disease.
- Hereditary hemochromatosis: excessive glycogen storage in the liver.
- Abetalipoproteinemia: Inability to build lipoproteins and to absorb fats and fat soluble vitamins.
Proper management and treatment of liver disease and decompensated liver disease, may improve the outcome and lead to either regression or fibrosis, in some cases. Hepatitis C with early diagnosis and treatment could be cured, and may prevent cirrhosis entirely, and treatment of autoimmune hepatitis, no alcohol consumption with alcoholic liver disease.
Alcoholic liver disease. No alcohol intake and reduce other risk factors such as obesity and smoking. Promoting abstinence would be beneficial.
Hepatitis B. Standard public health measures are to be vaccinated. Hep B is treated with interferon drugs and nucleoside analogues. This has a relatively high rate of side effects.
Hepatitis C. Pegylated interferon combined with ribavirin is the standard treatment for Hep C, and results have shown a complete virus clearance in some cases.
Hemochromatosis.
Primary Biliary cirrhosis. A prescription of isolated and concentrated bile acid.
Wilson’s disease. Copper chelators
Budd-Chiari syndrome. Anticoagulants, beta blockers and balloon stents
Autoimmune hepatitis. Immunosuppressants or modulators example Prednisone
Clinical signs and symptoms include:
- Fatigue, weakness, loss of appetite, weight loss, nausea, abdominal pain and itching are the most common symptoms
- An enlarged spleen, which can be felt during a physical exam
- Spider veins are occasionally seen
Cirrhosis can also result in distinctive symptoms in individuals with advanced disease:
- Abdominal distention – Abdomen fills with ascetic fluid
- Jaundice - A yellowing of the skin and white of the eyes. This is due to a build-up of a yellow waste pigment from the breakdown of old red blood cells that are usually removed from the blood by the liver
- Bruising or excessive bleeding – Lack of the clotting protein, which coagulates the blood
- Melena – Dark stools resulting from blood in the faeces, and “coffee ground” emesis, which is vomiting of digested blood, caused from portal hypertension
- Pale or grey coloured stools – caused from lack of bile secretion
- Altered mental state – confusion, personality change, slow or slurred speech, memory loss, trouble concentrating, change in sleep habits
- Flapping Tremors – involuntary muscle contractions, usually at the wrists or hips, can also be caused from encephalopathy
- Lower extremity swelling/peripheral oedema – Low albumin in the blood leads to abnormal fluid collection in tissues
- Recurrent infections – immune dysfunction
- Difficulty breathing – due to hepatopulmonary syndrome
- Hypogonadism – Low testosterone and libido, impotence and shrinkage of the testes, can cause male breast enlargement
- Bone loss or fracture – metabolic bone disease
There are both invasive and non-invasive ways to test for Cirrhosis
Biochemical tests
This can be measured from blood samples. Alanine transaminase and aspartate transaminase are released by damaged hepatocytes, gamma-glutamyl transferase and bilirubin indicate whether the liver fails to excrete bile. All of these may increase with liver disease. Patients who have cirrhosis, have increased alkaline activity.
Diagnostic imaging. Ultrasound is non-invasive and not expensive to do. It can be used to assess several liver parameters that are consistent with hepatic fibrosis. Doppler ultrasound can measure the amount of blood flow in the liver, and can detect changes in the portal vein’s flow and arterial resistance in the liver, which can be visible through portal hypertension. Contrast-enhanced ultrasound involves injecting microbubbles intravenously prior to imaging, which enhances the signals and allows more detailed measurements of blood flow. Computed tomography (CT) is a 3 dimensional x-ray, for visualising internal structures. Magnetic resonance imaging (MRI) produces cross sectional images using radio waves in powerful magnetic fields.
They are used to for visualising advanced liver disease and hepatocellular carcinoma in cirrhosis patients, also can be found this way are surface nodules, prominent fibrous bands, shrinkage of liver volume, and enlarged portal vein system. But are not efficient enough to diagnose early stages of cirrhosis.
Elastography. Ultrasound based method which measures liver stiffness for fibrosis, thus not diagnosing liver fibrosis in the early stages, before surface nodules may become present.
Liver biopsy. The best way to assess liver fibrosis, as it allows direct examination of the liver to guide the treatment needed as you can see at what stage the disease is. The biopsy is invasive and has its own complications. Because of the samples that are used are very small, a sampling error may occur. Three biopsy methods are used, Percutaneous biopsies a hollow cutting needle inserted through the skin into the liver to take samples. Laparoscopic biopsy minimally invasive surgical technique used to get samples from a specific area in the liver, to avoid disrupting a tumour or site of infection.
Transjugular biopsy is used with patients that have a clotting disorder or ascites. A biopsy needle is threaded down the neck through the jugular vein into the liver, where a sample is taken with x-ray guidance.
Other diagnostic techniques
- Upper GI endoscopy. Direct visualisation of ruptured or damaged blood vessels in the stomach or oesophagus via a camera.
- Autoantibody testing. An anti-mitochondrial antibody is located in the blood, patients with primary biliary cirrhosis a condition where there is an obstruction in the bile ducts, and leads to cirrhosis.
- Molecular analysis. This is for inherited disorders, which increase the risk for cirrhosis. This includes the Wilson’s disease (copper storage disease) and cystic fibrosis
- Ferritin and transferrin saturation testing. These iron transport proteins are increased in patients with hereditary hemochromatosis, which is a risk for cirrhosis.
Prognostic scores
This is a method for estimating the survival of a cirrhosis patient within a given time period. Two systems are in use – Child-Pugh score works out the clotting time and degree of ascites and encephalopathy in its scoring system. Model for end-stage liver disease score is a more accurate predictor of survival. It’s used to predict short term survival in patients with liver disease. This method also prioritises patients for liver transplants depending on their results found post testing.
Conventional treatments
Through cirrhosis management prevention of progressing of underlying chronic liver disease and reduce the risk of decompensated cirrhosis. Once this occurs, it changes from treatment for cirrhosis and its complications, to the option of liver transplantation.
Management of cirrhosis complications include:
- Ascites – Includes treatment for the underlying disorder, alcohol abuse, treatment of hepatitis, sodium restrictions, and diuretics.
- Portal hypertension – Beta blockers and nitrates may be recommended, along with diuretics in cases of ascites. This method is less invasive than traditional surgery.
- Spontaneous bacterial peritonitis – Treatment with broad spectrum oral or intravenous antibiotics.
- Hepatorenal syndrome - Treatment to increase circulation and oxygenation of the kidneys
- Hepatic Hydrothorax - Treatment has dietary sodium restriction and diuretics
- Oesophageal and gastrointestinal varices – Screening by endoscopy is used to check for varices, this also may reduce the risk of rupture and haemorrhage of fragile varices.
- Hepatic ensephalopathy – Can be treated with non-absorbable carbohydrates, which are fermented by colon bacteria thus reducing excess ammonia.
- Hepatocellular carcinoma – When the tumour is a more important clinical concern than cirrhosis. Common treatment techniques include ethanol injection and radiofrequency ablation.
- Hepatic Osteodystrophy – Calcium, Vit D, K is often prescribed for osteoporosis.
- Transplantation – Standard treatment for end stage cirrhosis and chronic liver disease. There are several medical contraindications to liver transplantation:
- Cardiac and pulmonary diseases
- Sepsis/active infection
- Cancer outside the liver
- Poorly controlled HIV infection
- Physciatric disorders
- Active substance abuse
- Obesity
- Old age
- Malnutrition
- Poor medication compliance
Post transplantation, requires a person to be on a lifetime immunosuppressive drug therapy, to prevent rejection of the transplanted organ by the body.
Novel and emerging therapies
These types of therapies mainly target the pathways that cause hepatic fibrosis.
PPAR Activators
This is a nuclear receptor that is found in the liver as well as adipose tissue. When sensing fatty-acids around it, it will become active, and activate genes that regulate lipid metabolism and fat cell growth. This is a target for medication which restore insulin in diabetics and promote breaking down of fatty acids in high cholesterol, and also plays an important role in liver repair.
Ursodeoxycholic Acid
It is a natural constituent of bile, this is the only approved treatment for a disease that may cause liver cirrhosis. Over a long term trial on patients, it was shown that there were reduced indigestion symptoms, common in cirrhosis, lowered amount of fat in the stools, and improved fat digestion, and significantly lower levels of AST in the blood.
Pentoxifylline
This is an effective therapy to reduce the risk of hepatorenal syndrome in alcoholic hepatitis, without an improvement in the overall survival. This is recommended by many as a second-line therapy for severe alcoholic hepatitis where corticosteroids are contraindicated.
Angiotension II receptor blockers
This is a treatment for hypertension and congestive heart failure, as it helps regulate blood volume and pressure. During a chronic liver injury there is an overproduction of hypertensive hormone angiotension II which stimulates the activation of hepatic stellate cells as well as their overproduction of fibrous tissue in the liver. This receptor blocker may block this interaction.
Lysyl Oxidase Inhibitors
This is an enzyme that helps with th cross-linking of collagen fibrils, the final step that occurs in the fibrous matrix produced during liver fibrosis. Lysyl oxidase also helps to break down the fibrous matrix, preventing the reversal of fibrosis.
Stem cell therapy
Due to a shortage of liver transplant donors, stem cell therapy proves to be a useful alternative for replenishing hepatocytes – reducing inflammation, reversing liver fibrosis inn people who have cirrhosis or liver failure.
Liver dialysis
Similar to kidney dialysis. It filters the blood through an external device through the liver for a short-term support mechanism for the liver.
The blood toxins are tightly bound to the albumin molecules in circulation, liver dialysis devices must separate these toxins from the albumin. But still preserve the albumin levels in the blood. This treatment can be used while waiting for a transplant to become available.
Metformin continuation in diabetics with cirrhosis
Patients with cirrhosis have a five times higher chance of having diabetes, than those without cirrhosis. These patients are at more risk of liver-related complications and death compared to the people without diabetes.
Metformin is a commonly spread antibiotic drug, associated with a reduced risk of some forms of cancer, including liver cancer, in diabetics. Studies have proved that using Metformin after cirrhosis diagnosis, reduced the risk of death by 75%. None of these patients developed lactic acidosis during the follow ups. It has been concluded that diabetic patients with cirrhosis should keep using Metformin if they do not have any contraindications.
- Abstain from alcohol
- Avoid tobacco use
- Adjust prescription drug doses
- Reduce medication dosages in general
- Opioid analgesics, anxiolytics and sedatives can worsen the symptoms
- Non-steroidal anti- inflammatory drugs, can cause internal bleeding and renal failure
- Anticancer and immunomodulation drugs – lower dosages
- Antimicrobials, should be avoided
- Proton pump inhibitors/ histamine blockers – lead to serious infections
- Antidepressants half- lives and clearances may be altered
- Cardiovascular drugs – dose adjustment might be needed
- Coffee – May reduce the risk of fibrosis by lowering the blood levels growth factors that are associated with liver damage and cirrhosis. By drinking coffee it has been proven to reduce the risk of liver cancer.
- Maintain adequate nutrient intake – malnutrition increase your risk of cirrhosis
- Calories – patients should try to fulfil an energy intake of 35-40kcal/kg/day
- Protein – Restriction of protein in the diet is not recommended, unless it’s not tolerated. The diet should include protein of 1,2-1,5g/kg/day to avoid muscle waste
- §Vitamins – Patients who suffer from alcohol and non-alcohol related cirrhosis, may have a lack of water soluble vitamins such as, Vitamin B12, and folate as well as Thiamine. Patients with cholestatic liver disease will have a lack of fat-soluble vitamins such as, Vitamin A, D, E and K
- §Minerals – Patients with cirrhosis, have low levels of zinc
Integrative interventions
Nutrients for viral hepatitis
Viral hepatitis B and C are the leading risk factors for cirrhosis and liver failure. Several nutrients have been on trial to help minimize the effects if Hepatitis B viral infection such as, green tea extract, selenium, coffee, zinc, whey protein astragalus and milk thistle. These next few have been trialed on Hepatitis C, N-Acetyl cysteine, alpha lipoic acid, whey protein, milk thistle, liquorice Vitamin D, coffee, zinc, curcumin and L-Carnitine.
Nutrients for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis
Vitamin E, Omega-3 fatty acids, and N-Acetyl cysteine plus metformin have been studied to help with the treatment of the above diseases.
Nutrients for Iron overload
High iron stores are a risk factor for liver disease. Nutrients that have shown a deduction in iron load are, pectin, milk thistle, and green tea.
Nutrients specifically investigated in the context of cirrhosis or its complications are:
- Milk thistle/ Silymarin – have shown antioxidant effects against some types of liver damage.
- Branched-chain amino acids – These are nutritionally essential amino acids that are not metabolized into energy in the liver, but they are taken up by the skeletal muscles where they have multiple purposes. The breakdown products are used to form glutamate, which absorbs toxic ammonia in skeletal muscles and converts it into glutamine.
- Vitamin D – 66% of patients with moderate severe cirrhosis, and 96% of patients waiting for a transplant have a Vit D deficiency. Bone fractures are more common in people with chronic liver disease, therefore a calcium and Vit D supplement is recommended, as their bone density is very low. In studies, it has shown that a low vit D level in patients with cirrhosis, are more likely to have bacterial infections.
- Vitamin C – In a study intravenous Vit C was given to patients, which lowered the oxidative stress and venous pressure in the liver. Vit C increased the liver fat and blood proteins, caused by decreased bile flow.
- Vitamin E – Low levels are found in people who have cirrhosis. Especially in those with alcoholic cirrhosis. These patients show higher levels of oxidative stressPeople with Hepatitus C, normal levels of Vit e were discovered.
- Probiotics – The wrong kind of bacteria in the intestines, can cause complications with cirrhosis.
- The right bacteria causes increased ammonia production, which in turn helps the migration of bacteria across the intestinal wall that has been implicated in both spontaneous bacterial peritonitis and bleeding due to oesophageal varices.
- Prebiotics – Fermentable natural fibres, beta-glucan, inulin, pectin and resistant starch together with probiotics showed a lower ammonia level in blood with patients who have cirrhosis.
- Zinc – Studies have shown that there was a cognitive function improvement when compared to baseline measurements. A reduction in ammonia blood levels, improved quality of life scores, and reduced child-pugh scores post 6 months of supplementation.
- S-Adenosylmethionine – It helps with the making of the important liver protectant glutathione, that is less in people with cirrhosis
- Polyenylphosphatidylcholine (PPC) – Soyabeans contain the lipid mixture that helps to protect the integrity of cell membranes, especially in the liver.PPC helps to prevent lipid peroxidation, caused by excessive alcohol intake.
- Curcumin – It has a protective effect against chemically induced cirrhosis. Curcumin inhibits metabolic pathways that stimulate fibrosis. It also reduces the protein that promotes liver stellate cell activation and fibrosis.
- Glyccyrrhizic acid – Is an extract from the root of liquorice plant, for its anti-inflammatory and anti-viral effects.
- Coenzyme Q10 – “Catches” all the free radicals in cell membranes. People with liver cirrhosis, have 70% lower levels as those who do not have the disease.
- Berberine – Is a plant alkaloid used for its bacteriostatic and bactericidal properties. For now until further studies, only short term use is recommended.
- Green tea extract – The anti-inflammatory antioxidant and anti-fibrotic properties, make it a natural therapy for hepatitis and liver fibrosis.
