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Complication of Liver Disease, Treatment, Prevention

Complication of Liver Disease/Liver disease (also called hepatic disease) is a type of damage to or disease of the liver. Whenever the course of the problem lasts long, chronic liver disease ensues. Liver diseases, including hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD) and associated cirrhosis, liver failure (LF) and hepatocellular carcinoma (HCC), are major causes of illness and death worldwide. The foundation of the lobule is composed of hepatocytes, which have physiologically distinct apical and basolateral membranes.

Based on function and perfusion, hepatocytes are divided into 3 zones

Zone I – is considered to be the periportal region of hepatocytes and are the best perfused and first to regenerate due to their proximity to oxygenated blood and nutrients. As predicted, due to its high perfusion, zone I play a large role in oxidative metabolisms such as beta-oxidation, gluconeogenesis, bile formation, cholesterol formation, and amino acid catabolism.
Zone II – is defined as the pericentral region of the hepatocytes and zone II sits between zones I and III.
Zone III – has the lowest perfusion due to its distance from the portal triad. It plays a role in detoxification, biotransformation of drugs, ketogenesis, glycolysis, liponeogenesis, glycogen synthesis, and glutamine formation.

Based on the severity of ACLF, it is stratified into 3 grades

Grade-1 ACLF – is defined as:

Single renal failure
Single liver, coagulation, circulatory, or lung failure that is associated with a serum creatinine level of 1.5 to 1.9 mg/dl and/or hepatic encephalopathy grade 1 or grade 2
A single brain failure with a serum creatinine level of 1.5 to 1.9 mg/dl

Grade 2 ACLF – is diagnosed when there are 2 organ failures of any combination.

Grade 3 ACLF – is diagnosed when there are three or more organ failures of any combination. Grading ACLF helps clinicians assess the prognosis, the usefulness of which has been validated in various studies.

Stages of liver damage

Stage 0 – no fibrosis.
Stage 1 – mild fibrosis without walls of scarring.
Stage 2 – Mild to moderate fibrosis with walls of scarring.
Stage 3 – bridging fibrosis or scarring that has spread to different parts of the liver but no cirrhosis.
Stage 4 – severe scarring, or cirrhosis.

Causes of Liver Disease

There are more than a hundred different kinds of liver disease. These are some of the most common

Fascioliasis – a parasitic infection of the liver caused by a liver fluke of the genus Fasciola, mostly the Fasciola hepatica.^[rx]
Hepatitis inflammation – of the liver, is caused by various viruses (viral hepatitis) also by some liver toxins (e.g. alcoholic hepatitis), autoimmunity (autoimmune hepatitis) or hereditary conditions.^[rx]
Alcoholic liver disease – is a hepatic manifestation of alcohol overconsumption, including fatty liver disease, alcoholic hepatitis, and cirrhosis. Analogous terms such as “drug-induced” or “toxic” liver disease are also used to refer to disorders caused by various drugs.^[rx]
Fatty liver disease – (hepatic steatosis) is a reversible condition where large vacuoles of triglyceride fat accumulate in liver cells.^[rx] Non-alcoholic fatty liver disease is a spectrum of disease associated with obesity and metabolic syndrome.^[rx]
Hereditary diseases – that cause damage to the liver include hemochromatosis,^[rx] involving the accumulation of iron in the body, and Wilson’s disease. Liver damage is also a clinical feature of alpha 1-antitrypsin deficiency ^[rx] and glycogen storage disease type II.^[rx]
In transthyretin-related hereditary amyloidosis – the liver produces a mutated transthyretin protein which has severe neurodegenerative and/or cardiopathic effects. Liver transplantation can give a curative treatment option.^[rx]
Gilbert’s syndrome – a genetic disorder of bilirubin metabolism found in a small percent of the population, can cause mild jaundice.^[rx]
Cirrhosis is the formation of fibrous tissue – (fibrosis) in the place of liver cells that have died due to a variety of causes, including viral hepatitis, alcohol overconsumption, and other forms of liver toxicity. Cirrhosis causes chronic liver failure.^[rx]
Primary liver cancer – most commonly manifests as hepatocellular carcinoma and/or cholangiocarcinoma; rarer forms include angiosarcoma and hemangiosarcoma of the liver. (Many liver malignancies are secondary lesions that have metastasized from primary cancers in the gastrointestinal tract and other organs, such as the kidneys, lungs.)^[rx]
Primary biliary cirrhosis – is a serious autoimmune disease of the bile capillaries.^[rx]
Primary sclerosing cholangitis – is a serious chronic inflammatory disease of the bile duct, which is believed to be autoimmune in origin.^[rx]
Budd–Chiari syndrome – is the clinical picture caused by occlusion of the hepatic vein.^[rx]

Symptoms of Liver Disease

Some of the signs and symptoms of liver disease are the following

Jaundice
Confusion and altered consciousness caused by hepatic encephalopathy.
Thrombocytopenia and coagulopathy.^[rx]
Risk of bleeding symptoms particularly taking place in the gastrointestinal tract^[rx]
Ascites, the accumulation of fluid in the abdominal cavity.
Abdominal (tummy) pain
Loss of appetite
Fatigue
Feeling sick
Diarrhea
Feeling generally unwell
Behaving differently after drinking
Mental confusion

Advanced Symptoms of Liver Disease

As the liver becomes more severely damaged, more obvious and serious symptoms can develop, such as:

Yellowing of the skin and whites of the eyes (jaundice)
Swelling in the legs, ankles, and feet caused by a build-up of fluid (edema)
Swelling in your abdomen caused by a build-up of fluid known as ascites
A high temperature (fever) and shivering attacks
Very itchy skin
Hair loss
Unusually curved fingertips and nails (clubbed fingers)
Blotchy red palms
Significant weight loss
Weakness and muscle wasting
Confusion and memory problems, trouble sleeping (insomnia) and changes in your personality caused by a build-up of toxins in the brain
Passing black, tarry poo and vomiting blood as a result of internal bleeding
The tendency to bleed and bruise more easily, such as frequent nosebleeds and bleeding gums
Increased sensitivity to alcohol and drugs because the liver cannot process them.

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Diagnosis of Liver Disease

A detailed history delineates possible precipitating factors for the acute hepatic decompensation. The following information should be obtained from the patient’s chart, the patient, or the family:

A known chronic liver condition, the degree of fibrosis or cirrhosis
Any known history of hepatic decompensation
Any concomitant relevant chronic health conditions
The timeline of symptoms the patient presented with regarding systemic features, fluid overload, gastrointestinal bleeding, abdominal pain, altered mental status
Toxic habits or high-risk behavior
Any recent change in medications or recent ingestion of hepatotoxins including herbal products and sedatives/analgesics
Any recent history of travel
Any recent surgeries, including a TIPS procedure

Differential Diagnosis Based on Elevated LFTs

Hepatocellular pattern – Elevated aminotransferases out of proportion to alkaline phosphatase

ALT-predominant – Acute or chronic viral hepatitis, steatohepatitis, acute Budd-Chiari syndrome, ischemic hepatitis, autoimmune, hemochromatosis, medications/toxins, autoimmune, alpha1-antitrypsin deficiency, Wilson disease, Celiac disease
AST-predominant – EtOH-related, steatohepatitis, cirrhosis, non-hepatic (hemolysis, myopathy, thyroid disease, exercise)

Cholestatic pattern elevated alkaline phosphatase + GGT + bilirubin out of proportion to AST and ALT

Hepatobiliary causes – Bile duct obstruction, primary biliary cirrhosis, primary sclerosing cholangitis, medication-induced, infiltrating diseases of the liver (sarcoidosis, amyloidosis, lymphoma, among others), cystic fibrosis, hepatic metastasis, cholestasis
Non-Hepatic causes of elevated alkaline phosphatase – Bone disease, pregnancy, chronic renal failure, lymphoma or other malignancies, congestive heart failure, childhood growth, infection or inflammation

Evaluation should include[rx]:

CBC (Complete blood count) – to rule out the infection, look for complications of cirrhosis, anemia, thrombocytopenia, a leukemoid reaction in alcoholic hepatitis.
LFTs (liver function tests) – AST (aspartate aminotransferase) is markedly raised compared to ALT (alanine aminotransferase) in alcoholic liver disease, albumin is low, bilirubin is elevated. GGTP ( gamma-glutamyl transpeptidase) is usually elevated along with elevated triglyceride levels.
Prothrombin time (PT) and INR (to assess liver synthetic function) – an elevated value indicates more severe disease.
Abdominal imaging (abdominal ultrasonography) – is useful to look for a biliary obstruction and liver tumors.
BMP (basic metabolic profile) – should be ordered to look for renal failure and electrolyte disturbance (low levels of potassium, magnesium, and phosphorus).
Ascitic fluid SAAG (serum-ascites albumin gradient) – should be calculated to assess the reason for ascites if present.
Screening blood tests – for other causes of chronic liver disease, including viral hepatitis.
Endoscopy to look for esophageal varices – due to portal hypertension in patients with cirrhosis.
A liver biopsy – can lead to a definitive diagnosis in cases where the diagnosis is uncertain. It is used more often for evaluation of severity, staging, prognosis, and treatment monitoring. At least 1.5 to 2 cm long sample of liver tissue is necessary for accurate diagnosis of fibrosis. A small sample of liver cells is taken and sent to a laboratory to be examined under a microscope.
Endoscopy – An endoscope is a long, thin, flexible tube with a light and a video camera at one end. During an endoscopy, the instrument is passed down your esophagus (the long tube that carries food from the throat to the stomach) and into your stomach. Pictures of your esophagus and stomach are transmitted to an external screen. The doctor will be looking for swollen veins (varices), which are a sign of cirrhosis.

Treatment of Liver Disease

Non-Pharmacological

It also includes determining prognosis and the need for liver support including possible liver transplantation. All patients should be hospitalized preferably at a center that has facilities and expertise for a liver transplant.[rx][rx]

Prevention of Precipitating Factors Leading to Acute Hepatic Decompensation

To have a high degree of suspicion, evaluate and treat any infection as early as possible.
Attain sustained viral suppression of HBV and HCV
Intravenous administration of albumin in patients with diagnosed spontaneous bacterial peritonitis to prevent accelerated renal dysfunction characterized by hepatorenal physiology. Intravenous albumin has no proven benefit in other bacterial infections
Prophylactic antibiotics for low ascetic albumin
In patients with severe acute alcoholic hepatitis, early initiation of both Pentoxifylline or a combination of prednisolone and intravenous N-acetylcysteine has shown to reduce the incidence of type-1 hepatorenal syndrome.
In patients with severe sepsis, a combination of granulocyte colony-stimulating factor (C-CSF) and Darbepoetin has shown to have improved 1-year survival in decompensated cirrhotics.

Supportive Care

Access hemodynamic stability and the need for intravenous fluids and maintenance of acid-base levels and normal electrolytes. Vasopressors are indicated to maintain a mean arterial pressure of greater than or equal to 75 mm Hg to ensure adequate renal and cerebral perfusion.
Monitor hematocrit for any bleeding, as the patients have coagulopathy and poor platelet functions. Blood products of platelets and fresh frozen plasma for coagulopathy is only indicated in patients with active bleeding or before an invasive procedure. Patients should be empirically started on proton pump inhibitors for prophylaxis of gastrointestinal bleed.
Monitor hepatic encephalopathy and protect the airway (aspiration risk) should the patient show signs of worsening encephalopathy. This patient should be intubated and should be on a protocol to avoid cerebral edema.
Adequate nutrition with 1.0 to 1.5 gm of protein per kilogram per day should be administered
Monitor for hypoglycemia and maintain blood glucose between 160 to 200.
Discontinue all home medications except the ones we identify essential to continue.

Specific Treatment when Etiology is Known

Patients with hepatitis A and E associated ACLF should receive supportive care as no specific anti-virals are known to be effective.
Patients with acute or reactivation of hepatitis C should receive appropriate anti-virals based on the prior treatment administered
Patients with acute or reactivation of hepatitis B should receive nucleos(t)ide analogs.
Patients with acute decompensation in known Wilson’s disease or development of hepatic vein thrombosis as the etiology for ACLF should be considered for a liver transplant.

Some simple strategies that can reduce the risk of liver disease and help the liver rid the body of toxins include

Limiting alcohol intake – Excessive alcohol consumption is a risk factor for liver disease. People with an addiction to alcohol should consider treatment.
Avoiding unnecessary over-the-counter medications – Never exceed the recommended dose, particularly of drugs such as acetaminophen that can harm the liver. Do not mix alcohol and over-the-counter drugs.
Choosing reputable tattoo and piercing salons – Choose a salon that sterilizes their equipment. Unsafe body modifications can transmit hepatitis C.
Getting vaccinated – A person should get vaccinated for hepatitis A and B, and make sure they get appropriate vaccinations before traveling overseas.
Practicing safe sex – This can reduce the risk of transmitting conditions that affect the liver. People should also get tested regularly for sexually transmitted infections (STIs).
Avoiding potentially dangerous chemicals – When painting or using pesticides, wear a mask and ensure the area is well ventilated.
Drinking plenty of water.
Rinsing fruit and vegetables – This can help ensure they are free of pesticides.

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Pharmacological

Corticosteroids – Corticosteroids have been the most extensively studied form of therapy for AH, but their role remains limited [rx]. The rationale for steroid use is to decrease the immune response and pro-inflammatory cytokine response. Most randomized studies have supported the use of corticosteroids in moderate/severe AH [rx],
Pentoxifylline – Pentoxifylline (400 mg 3 times/d for 28 d) is considered as an alternative to corticosteroid treatment in patients with severe alcoholic hepatitis[rx]. The exact mechanism is not understood. However, pentoxifylline inhibits phosphodiesterase and increases the intracellular adenosine 3’,5’-cyclic monophosphate level inducing inhibition of cytokine expression and macrophage inflammatory protein-1a[rx].
Anti-TNF-α therapy – Anti-TNF-α agents have been developed to block TNF-α, a major cytokine involved in alcoholic hepatitis. Two anti-TNF-α agents have been investigated as a therapy for alcoholic hepatitis, infliximab, and etanercept. In a pilot study, combination therapy with infliximab and steroids was reported to be effective[rx]. However, the trial was stopped early by the independent data and safety monitoring board because of a significant excess of severe infections and an insignificant increase in the deaths in the infliximab cohort [rx].
Etanercept – showed an increase in the short-term survival of patients in a pilot study[rx]. However, a subsequent randomized, placebo-controlled trial revealed a worse 6-mo survival rate in the group treated with etanercept than in the placebo group[rx]. Therefore, anti-TNF-α agents are currently not recommended for treating alcoholic hepatitis.
N-acetylcysteine – The combination of N-acetylcysteine, an antioxidant, with prednisolone has been studied. This study enrolled 174 patients who were randomly assigned to receive either prednisolone 40 mg/d for 28 d along with intravenous N-acetylcysteine for 5 d or prednisolone 40 mg/d for 28 d alone. Combination therapy improved the 1-mo survival in patients with alcoholic hepatitis. However, the 6-mo survival, which was the primary endpoint of the study, did not improve[rx,rx]. Further research is needed to evaluate the efficacy of N-acetylcysteine.
Metadoxine – Metadoxine, a combination of 2 antioxidants (pyridoxine and pyrrolidone), is potentially a useful drug in the treatment of ALD. In a large randomized controlled trial, there was a significant improvement in the liver function tests in both groups. The percentage of patients with persistent hepatic steatosis as assessed by ultrasound, was also significantly lower in the methadone group (28% vs 70%)[rx].
Propylthiouracil – Propylthiouracil has also been evaluated for the treatment of acute hepatitis. In some studies, PTU improved the mortality rate by suppressing hypermetabolic activation[rx,rx]. However, in a Cochrane meta-analysis of 6 studies with 710 ALD patients that compared propylthiouracil versus placebo, there was no clear improvement in the liver histology or liver-related or overall mortality rate[rx,rx].
Colchicine – Colchicine affects hepatic fibrogenesis, including the inhibition of collagen production, the enhancement of collagenase activity, and the interference with collagen transcellular trafficking. In addition, colchicine also has favorable effects on cytokine production associated with fibroblast proliferation. In clinical studies involving patients with alcoholic liver cirrhosis, colchicine showed anti-inflammatory and anti-fibrotic effects[rx,rx], and had a positive effect on survival[rx]. However, controlled trials later had conflicting results[rx].
Polyunsaturated lecithin – Polyunsaturated lecithin is extracted from soybeans and is a constituent of cell membranes[rx]. Polyunsaturated lecithin appears to improve histology and reduce the activation of hepatic stellate cells in baboons with alcoholic liver injury[rx]. However, polyenylphosphatidylcholine did not show a clear association with the progression of liver fibrosis in a follow-up randomized controlled study[rx].
Angiotensin II receptor blocker – It has been reported in one randomized controlled trial that combination therapy with candesartan and ursodeoxycholic acid shows greater histologic improvement compared to monotherapy with ursodeoxycholic acid[rx].
Silymarin – Silymarin, a milk thistle extract with anti-oxidative and anti-fibrotic properties, has been evaluated in many studies as a potential treatment agent for ALD[rx,rx]. Although one study reported that silymarin contributes to improved survival, this result has not been confirmed for ALD patients in meta-analyses such as the Cochrane review[rx,rx].
Colchicine – Colchicine has been suggested as a treatment for ALD because of its anti-fibrotic effects. It has many potential therapeutic mechanisms of action including inhibition of collagen production, enhancement of collagenase activity, and anti-inflammatory functions. [rx] Results showed no beneficial effect on either overall mortality or liver-related mortality [rx]. A recent smaller study from Europe also showed no beneficial effects of colchicine [rx]. Thus, despite initial enthusiasm and biochemical rationale for use of this drug, it does not appear to be effective in ALD.
Propylthiouracil (PTU) – Chronic alcohol feeding in experimental animals produces a hypermetabolic state with increased oxygen consumption. This may lead to relative hypoxia, especially in the central lobular area, or zone 3, of the liver. PTU has been postulated to attenuate this hypermetabolic state, to function as an antioxidant, and to improve portal blood flow [rx].
Dilinoleoylphosphatidylcholine – Dilinoleoylphosphatidylcholine (a form of lecithin/soybean extract) has antioxidant, anti-fibrotic, and anti-cytokine activity in experimental rat models of ALD [rx]. However, a recently completed VA Cooperative Study failed to show significant benefit in human ALD [rx][rx].
Anabolic Steroids – ALD is associated with severe muscle wasting. While in part mediated by nutritional deficiencies, decreased functional levels of anabolic and androgenic steroids in alcoholics also occur [rx], which may contribute to the loss of muscle mass. Utilizing the Cochrane database [rx],
S-Adenosylmethionine (SAMe) – SAMe, or AdoMet, is an obligatory intermediate in the conversion of methionine to cysteine in the hepatic transsulfuration pathway. SAMe is a precursor for syntheses of polyamines, choline, and glutathione (GSH), and it is the major methylating agent for a vast number of molecules via specific methyltransferases [rx].
Vitamin E – Vitamin E deficiency has been well documented in ALD [rx]. Vitamin E has been used extensively with hepatoprotective effects in experimental models of liver injury such as that induced by carbon tetrachloride or ischemia. Vitamin E has multiple potential beneficial effects including membrane stabilization [rx], reduced NFκB activation and TNF production [rx], and inhibition of hepatic stellate cell activation and collagen production [rx]. Unfortunately, a major randomized study of vitamin E in ALD showed no benefit but may have used an inadequate dose (500 mg) [rx]. A smaller study with a higher dose (1,000 mg) of vitamin E in AH observed some normalization of serum hyaluronic acid levels but without significant changes in indices of liver damage [rx].
Liver Transplant – A liver transplant may be the only treatment option in severe cases of ALD where the liver has stopped functioning, and there is no improvement even after the patient stops drinking. The consideration for a liver transplant is different, and it is only taken into account when the patient has developed complications of cirrhosis or if the body does not respond to other treatments including medications. However, ALD is one of the most common indications of a liver transplant.

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Here are 10 foods you can add to your diet to cleanse your liver

Garlic – Garlic contains selenium, a mineral that helps to detoxify the liver. It also has the ability to activate liver enzymes that can help your body naturally flush out toxins.
Citrus Fruits – Fruits like grapefruit, oranges, limes, and lemons all boost the liver’s cleansing ability. Even consumed in small amounts (we know some of these can be tart!), citrus fruits help the liver to produce the detoxifying enzymes that flush out pollutants.
Vegetables – Cruciferous vegetables like broccoli and cauliflower contain glucosinolate, which helps the liver to produce detoxifying enzymes. They also contain sulfur compounds that aid with liver health. Leafy vegetables are high in chlorophyll, which leaches toxins out of the bloodstream. They can neutralize heavy metals to protect the liver.
Turmeric – This herb works wonders for the liver—it helps the enzymes that flush out toxins and contains antioxidants that repair liver cells. It also assists the liver in detoxing metals, while boosting bile production.
Walnuts – Walnuts are high in the amino acid arginine and assist the liver in detoxifying ammonia. They’re high in glutathione and omega-3 fatty acids, which all provide support to natural liver cleansing.
Beets – Beets assist with increasing oxygen by cleansing the blood, and can break down toxic wastes to help them be excreted quicker. They stimulate bile flow and boost enzymatic activity. Beets also contain fiber and Vitamin C, which both are natural cleansers for the digestive system.
Carrots – Carrots are very high in plant-flavonoids and beta-carotene, which stimulates and supports liver function overall. They also contain Vitamin A, which prevents liver disease.
Green Tea – If you’re thirsty from all the liver-benefiting foods, try some green tea. This beverage contains catechins, plant-based antioxidants known to improve liver function. Be careful to stick to green tea and not green tea extract, which can potentially negatively impact liver health.
Apples – Apples contain high levels of pectin, a chemical that helps the body cleanse and release toxins from the digestive tract. With fewer toxins in the digestive tract, the liver can better manage its toxin load, being able to better cleanse the rest of the body.
Avocado – Avocados are basically a superfood. In addition to cleansing your arteries, they help the body naturally produce glutathione, the compound that helps the liver rid itself of toxins.