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Infection, Inflammation, and Cirrhosis of the Liver - Chapter 31

Terms in this set (65)

Basic Functions of the Liver
Liver is in the right upper quadrant (RUQ) of the abdomen.

The liver has a dual blood supply from the hepatic artery, which is a branch of the aorta, and the portal vein, which drains the veins of the gastrointestinal tract.
Basic Functions of the Liver
The liver synthesizes and secretes bile for fat digestion into the hepatic duct.

Along with the pancreatic duct, the hepatic duct empties into the common bile duct, which carries bile into the intestine.
Basic Functions of the Liver
Hepatocytes, the functional cells of the liver that are capable of regeneration, excrete metabolic substances into small channels called canaliculi.

These canaliculi are responsible for conduction of bile to the hepatic duct.

Sinusoids are vascular spaces located between the hepatocytes that contain a mixture of venous and arterial blood from the hepatic artery and portal vein.

Kupffer cells, specific macrophages of the liver, line the sinusoids and protect the body by detoxifying the bloodstream.

As an accessory organ of digestion, the liver is responsible for bile salt secretion to aid in fat digestion in the small intestine.

Bile, a yellow-green alkaline fluid, is formed in the hepatocytes; some is stored in the gallbladder for later use.

Bile salts continue to the ileum and colon for excretion. Some bile salts are reabsorbed from the ileum into the portal vein, return to the liver, and become resecreted in a process called enterohepatic recycling.
Basic Functions of the Liver
One of the liver's most important functions is the conversion of bilirubin into bile.

Bilirubin, a yellow-colored compound, is derived from the breakdown of aged red blood cells (RBCs).
Hemoglobin (Hgb) Breakdown Bilirubin
Hgb in the RBCs breaks down heme and globin. Heme is further broken down iron and porphyrin. The porphyrin fraction is converted into biliverdin free or unconjugated bilirubin.

Unconjugated bilirubin travels to the liver the process of conjugation takes in the liver, bilirubin is transformed into a water-soluble form.
Basic Functions of the Liver
Conjugated bilirubin excreted in the bile.

Some conjugated bilirubin in the distal ileum and colon is converted to urobilinogen by bacteria.

Most urobilinogen is reabsorbed from the GI tract into the bloodstream and then excreted in urine. Urobilinogen gives urine its yellow color.

Some urobilinogen continues on in the GI tract where bacteria convert urobilinogen to stercobilinogen, which is then excreted in the feces.

Unconjugated bilirubin is also referred to as indirect bilirubin in diagnostic studies, whereas conjugated bilirubin is also referred to as direct bilirubin.
Basic Functions of the Liver
The liver is a major producer of cholesterol.

The liver is capable of both synthesizing and breaking down protein.

In its role as a manufacturer of protein, the liver produces most of the body's albumin.

In breaking down protein, the liver performs deamination—a process that removes nitrogen from proteins and converts it to ammonia (NH3).

Ammonia is absorbed into the bloodstream, becomes integrated into urea, and is then excreted by the kidneys in urine.
Basic Functions of the Liver
Glycogen buildup

Glycogen breakdown

Gluconeogenesis
Basic Functions of the Liver
As part of its hematologic function, the liver synthesizes fibrinogen and coagulation factors I, II, VI, IX, and X and prothrombin for clotting.

It does so with the assistance of vitamin K and bile.
Basic Functions of the Liver
Glucagon from the pancreas stimulates hepatic glycogenolysis and gluconeogenesis.

Glucagon also stimulates lipolysis, converting free fatty acids to ketones in the liver.
Basic Functions of the Liver
Detoxification

After a substance is ingested, it is absorbed by the GI system and then passes into the portal vein.

The portal vein brings all absorbed substances through the liver, where the detoxification processes called biotransformation and the first pass effect occur.

Substances are broken down by the liver into detoxified metabolites.

In the metabolism of drugs, the liver enzymatically processes the compounds by the cytochrome p 450 system.

Hepatocyte injury disrupts the liver's detoxification activity, which results in excess accumulation of drugs, hormones, or metabolites in the blood, tissues, or organs.
Basic Functions of the Liver
The liver stores vitamins A, D, and B12; iron-rich ferritin; and copper, all of which are necessary for efficient cellular functions.

The liver also produces insulinlike growth factor 1, a polypeptide protein hormone that plays an important role in childhood growth and has anabolic effects in adults.

The liver synthesizes thrombopoietin, the hormone that regulates the production of platelets by the bone marrow.

The liver also synthesizes angiotensinogen, a hormone that takes part in the renin-angiotensin-aldosterone system (RAAS), which maintains blood pressure.

The liver is responsible for immunological protection; the reticuloendothelial system of the liver contains B lymphocytes and immunoglobulins and also acts as a filter for antigens carried to it via the portal system.
Summary of Liver Functions
Synthesis of bile
Synthesis of albumin
Synthesis of cholesterol
Synthesis of thrombopoietin
Synthesis of insulinlike growth factor
Synthesis of angiotensinogen
Synthesis of coagulation factors
Conjugation of bilirubin
Glycogen buildup, glycogen breakdown
Gluconeogenesis
Immune protection: filters antigens out of blood
Deamination (removes nitrogen from blood)
Detoxification of blood; biotransformation and the first pass effect; uses the cytochrome p 450 system; breaks down medications
Storage of vitamins A, D, and B12; iron-rich ferritin; and copper
Hyperbilirubinemia
a high amount of bilirubin in the bloodstream, causes jaundice, also called icterus.
Hyperbilirubinemia Occurs Because of One of Three Specific Etiologies:
Excessive RBC hemolysis: prehepatic jaundice

Hepatocellular injury: intrahepatic jaundice

Bile duct obstruction: posthepatic jaundice
Inflammation of the Liver
Inflammation of the liver is most often caused by a virus, drugs or toxic substances, or excessive alcohol use.

The most common viruses that infect the liver are hepatitis virus A, B, C, D, and E. Other viruses include cytomegalovirus and Epstein Barr virus.
Hepatitis Liver Cancer
When viral hepatitis lasts longer than 6 months, it can become a chronic, long-term inflammatory condition.

Chronic hepatic inflammation increases the risk of hepatocellular cancer.

Acetaminophen is one of the most common causes of toxic hepatitis.

Alcohol is a common cause of long-term, chronic liver disease.
Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatosis (NASH)
Etiology ?
- Fatty buildup in the liver leads to liver damage
- Hypertriglyceridemia
- Obesity
- Diabetes

NAFLD is a major cause of cirrhosis.
Biliary Obstruction Refers to the Blockage of Any Duct That Carries Bile From the Liver to the Small Intestine.
From the liver, conjugated bilirubin backs up and builds up in the blood; hyperbilirubinemia jaundice and dark urine result.
Diagnostic Tests in Liver Disorder
Liver enzymes: serum alanine transaminase (ALT), serum aspartate transaminase (AST), alkaline phosphatase
Direct (conjugated) and indirect (unconjugated) bilirubin levels
Albumin level
Prothrombin level
Hepatitis serology panel: hepatitis A, B, C, D, or E
Ultrasound
CT scan
MRI
Liver biospy
Management of Liver Disease
Supportive care with rest, fluids, and small high-calorie, high-protein meals

Avoid alcohol or any drugs, unless prescribed

Hepatitis has some treatment regimens that include interferon, nucleoside analogues, protease inhibitors, and other antiviral agents.

Patients with encephalopathy should be monitored in an intensive care setting.

Coagulation parameters, complete blood cell count (CBC), and metabolic panel should be checked frequently.

Serum aminotransferases and bilirubin are generally measured daily to follow the course of infection.

Liver transplantation, in selected cases, is an option if the patient has fulminant hepatic failure.
Hepatitis Is a Systemic Infection Affecting the Liver That Can Be Caused by:
- Hepatitis A (HAV)
- Hepatitis B (HBV)
- Hepatitis C (HCV)
- Hepatitis D (HDV)
- Hepatitis E (HEV)
- Nonviral hepatitis results from exposure to toxic chemicals or certain drugs or autoimmune disease.
- Other hepatitis viruses: cytomegalovirus (CMV) and Epstein Barr.
Hepatitis A Virus (HAV)
HAV is transmitted by the fecal-oral route; it is caused by ingestion of contaminated food or water or contracted from person to person by unsanitary conditions.

The virus is able to live on surfaces at room temperature, but is killed by cooking food thoroughly.

HAV is absorbed by the intestine and travels to the liver, where it damages the hepatocytes.

It is a mild disease with no complications.

Hepatitis A vaccination has made HAV infection uncommon.

Hepatitis A infection is endemic in Asia, Africa, Mexico, and South America.
Hepatitis Signs and Symptoms
Fever, Abdominal pain, Flu-like symptoms, Nausea and vomiting, Fatigue, Malaise, Myalgias, Arthralgias, Mild headache, Anorexia, Loss of taste for food, Smokers often lose their taste for tobacco, Hepatomegaly,
Jaundice, Stool that may have a pale appearance, Dark urine, Pruritus
Diagnosis of HAV
HAV has an incubation period of 2 to 4 weeks.

Liver enzymes will rise after the first 4 weeks.

HAV is apparent in the stool early, within the first 2 to 4 weeks.

IgM anti-HAV antibodies against HAV appear after the first 4 weeks.

IgG anti-HAV antibodies rise after 8 to 12 weeks.

IgG anti-HAV antibodies remain elevated and provide long-term immune protection.
HAV Immunization
HAV endows immunity with one dose as prevention of HAV.

Passive immunization with HAV Ig is available for contacts of patients with HAV infection.
Hepatitis B Virus (HBV)
HBV is a stable virus spread by blood products, body fluids, or sexual contact.
HBV Antigens and Antibodies
Hepatitis surface antigen (HBsAg) is a surface protein used to measure the number of viral particles.

The antibody to this protein is anti-HBsAg.

The protein expressed by the viral DNA is called hepatitis B core antigen (HBcAg).

The corresponding antibody is anti-HBcAg.

HBeAg: marker of active viral replication.

The best indication of active viral replication is the presence of HBV DNA in the serum.
Risk for HBV
- Non-Hispanic black ethnicity
- Cocaine use
- High number of sexual partners
- Unprotected sexual activity
- Sexually transmitted infection
- Human immunodeficiency virus (HIV) positive status
- Handling of blood products
- Intravenous drug use or use of unsterile needles
- Men who have sex with men (MSM)
- Household contact with someone with HBV
- Hemodialysis
- Travel to regions with high rates of HBV, such as Africa, Central and Southeast Asia, and Eastern Europe, places a person at risk.
- Perinatal transmission is possible.
- Oral passage of the virus is uncommon, but possible.
Hepatitis B Virus (HBV) - Four different stages have been identified in the viral life cycle of hepatitis B:
Stage 1: Stage 1 is the incubation period; no signs or symptoms; however, the patient can pass the virus to others; duration is 2 to 4 weeks.

Stage 2: Inflammatory reaction of the hepatocytes occurs. The patient may experience flu-like symptoms, and jaundice begins. HBeAg, HBsAg, and HBV DNA can be detected in the bloodstream. Liver enzymes begin to increase; duration is 3 to 4 weeks.

Stage 3: Immune system reacts against HBV. Viral replication slows. The HBV DNA levels are lower or undetectable, and liver enzyme levels decrease to normal.

Stage 4: The virus cannot be detected and antibodies to HBsAg, HBcAg, and HBeAg have been produced.
HBV Signs and Symptoms
Anorexia, Nausea and vomiting, Fatigue, Flu-like symptoms: fever, malaise, myalgias, Jaundice, Hepatomegaly, Splenomegaly, Lymphadenopathy, Spider angiomata, Palmar erythema, Jaundice can last for months, Patients with severe cases of infection may show signs of hepatic encephalopathy—somnolence, confusion, stupor, or coma.
Diagnosis of HBV
Diagnosis of HBV is usually made by the presence of HBsAg in the bloodstream.
Acute or Chronic HBV?
IgM-type anti-HBc antibodies are present in acute infection, whereas IgG-type anti-HBc antibodies are present in chronic infection.
Did the Patient Receive the HBV Vaccine or Did the Patient Endure and Recover From HBV Disease?
Antibody to HBcAg is only detected in those with actual previous infection with HBV.

Those with vaccination do not obtain the HBcAg in the vaccine.
Hepatitis B Immunoglobulin (HBIg)
Contacts can obtain HBIg, which can provide rapid passive immunity against HBV.
HBV
The course of HBV is variable and may run from a moderate illness to fulminant hepatitis.

Most individuals with HBV do not recover completely.

Patients with chronic HBV can be healthy carriers without any evidence of active disease.

Chronic HBV can lead to hepatocellular cancer.
Treating and Preventing HBV
Interferon alfa and drugs that inhibit viral polymerase, such as lamivudine, telbivudine, adefovir, entecavir, and tenofovir, are used to treat HBV.

Prevention is the key to disease control. Hepatitis B vaccine is recommended for all people.

During the course of the disease, close contacts of the patient can receive HBIg for short-acting immediate immunity.

For unvaccinated individuals who are exposed to HBV, postexposure prophylaxis with a combination of HBIg and HBV vaccine is recommended.
Hepatitis C Virus (HCV)
HCV is a virus that targets hepatocytes and B lymphocytes.

Acute HCV infection is usually mild and chronic hepatitis results in at least 75% of patients.

The mode of transmission is via blood as in intravenous drug use; sexual transmission is not as likely.

HCV can live dormant in the patient for years before symptoms develop.

There are many different genotypes of hepatitis C because of the virus's great potential to mutate.
Transmission of HCV
Transmission of HCV occurs mainly via blood.

People who inject illegal drugs with nonsterile needles or who use cocaine with shared straws are at highest risk for HCV.

The risk of transfusion-associated HCV is fewer than 1 case in 230,000 donations.

Health-care providers can contract HCV via needlestick injuries or other occupational exposures.

Nosocomial patient-to-patient transmission may occur by means of contaminated instruments.

Tattooing, sharing razors, and acupuncture may transmit the disease.

Uncommon routes include high-risk sexual activity and maternal-fetal transmission.

Co-infection with HIV type 1 appears to increase the risk of both sexual and maternal-fetal transmission of HCV.

After contraction of HCV, the long incubation period can vary from 2 weeks to 8 months.

During this time, the patient is asymptomatic and can spread the virus.

HCV-RNA can be detected weeks to months before antibody development and remains detectable indefinitely.

Acute HCV becomes chronic in 70% of patients.

Chronic HCV can lead to hepatocellular cancer.
Diagnostic Test
HCV-RNA assay is the best blood test.

Genotyping of the virus can direct the type of treatment.
Treatment of HCV
Pegylated interferon-A by intramuscular injection once weekly accompanied by administration of riboflavin orally twice daily is used.

Interferon in combination with protease inhibitors such as tenofovir has proven to be effective treatment for HCV.

No vaccine has been developed because of rapid HCV viral
mutations.

Immunoglobulin is ineffective in preventing HCV and is not recommended for postexposure prophylaxis.

Health-care personnel who sustain a needlestick injury involving an HCV-infected patient should undergo HCV-RNA assay immediately and then every 2 months for 6 months. If positive, treatment should be commenced.
HDV and HEV
HDV is a defective RNA virus that requires the helper function of HBV for its replication, expression, and duration. Mode of transmission is parenteral drug use or sexual contact.

HEV, which is clinically similar to HAV, is spread by the oral-fecal route. It is the most common cause of hepatitis in India, Asia, Africa, and Central America. Its actions are similar to those of HAV.

Patients with HBV or HCV are considered carriers and may transmit the disease.
Nonalcoholic Fatty Liver Disease (NAFLD)
NAFLD: the most common cause of chronic liver disease in the United States

Etiology: unclear

Hepatocytes show an accumulation of triglycerides.

In some patients, fatty liver is accompanied by hepatic inflammation and scarring of the liver; called nonalcoholic steatohepatitis (NASH).
Nonalcoholic Steatohepatitis (NASH)
NASH is the most extreme form of NAFLD, and is regarded as a major cause of cirrhosis of the liver.
NAFLD Pathophysiology
NAFLD is linked to metabolic syndrome: insulin resistance, obesity, and hyperlipidemia.

Under normal conditions, insulin enhances free fatty acid storage in adipose tissue. However, when insulin resistance occurs, storage of fat is shifted to nonadipose tissues, such as the liver.

When 5% to 10% of the liver contains fat, this is steatosis, also called fatty degeneration. Steatosis is the abnormal accumulation of lipids within a cell. Large accumulations can disrupt cellular organelles, and in severe cases the cell can rupture.

As organelles rupture, mitochondrial dysfunction causes the release of free radicals, which results in inflammation and progression of liver damage.

Proinflammatory cytokines, such as tumor necrosis factor, cause progression of liver damage to cirrhosis.

NASH cirrhosis is a risk factor for the development of hepatocellular carcinoma (HCC).
NAFLD and NASH Signs and Symptoms
NAFLD may show no symptoms.
NASH symptoms:
- Fatigue
- Weakness
- Loss of appetite
- Nausea
- RUQ abdominal pain
- Spiderlike blood vessels
- Yellowing of the skin and eyes (jaundice)
- Ascites
- Ankle edema
- Mental confusion
Diagnosing NAFLD
There are no biomarkers or blood tests yet developed that can diagnose NAFLD with absolute accuracy.

Liver biopsy is a key test in the diagnosis of NASH, but false negative results occur if the sample is not obtained from an area of the liver with high fat content.

Clinicians should assume that the patient with elevated liver enzymes, metabolic syndrome, or type 2 diabetes also has probable NAFLD.

There is a NAFLD fibrosis score consisting of age, hyperglycemia, body mass index (BMI), platelet count, albumin level, and ratio of AST to ALT.

This assessment tool is available for NAFLD diagnosis and helps to avoid liver biopsies.
Treatment of NAFLD
- Weight loss
- Exercise
- Bariatric surgery for patients with morbid obesity
- Medications: Biguanides such as metformin and glitazones such as pioglitazone lower liver enzymes, enhance cellular insulin sensitivity, and improve histological findings in NAFLD.
- Medication: lipid-lowering agents (monitor for liver toxicity)
Alcoholic Liver Disease
Alcoholic hepatitis is an acute disorder that causes a distinct syndrome of reversible and transient symptoms; it can resolve if ingestion of alcohol ceases, but long-term effects often remain.

Alcoholic liver disease, also known as alcoholic cirrhosis, develops over a long period of time and is permanent.

Diagnosis: liver biopsy
How Much Alcohol Causes Cirrhosis?
Men who ingest greater than 60 to 80 grams of alcohol per day for 10 years usually develop cirrhosis.

Women who ingest 20 to 40 grams of alcohol per day for 10 years usually develop cirrhosis.

Ingestion of 160 grams of alcohol per day 25-fold increased risk of developing alcoholic liver disease.

[one beer = 12 g]
Alcoholic Liver Disease Signs and Symptoms - Acute alcoholic hepatitis:
- RUQ pain and tenderness
- Nausea
- Malaise
- Low-grade fever
- Jaundice
- Darkened urine
- Hepatomegaly
Alcoholic Liver Disease Signs and Symptoms - Severe alcoholic hepatitis:
- Hepatic encephalopathy—confusion, disorientation, or stupor
- Coagulation dysfunction; spontaneous bruising and bleeding
- Hyperbilirubinemia
- Jaundice
- Hematemesis
Alcoholic Liver Disease Signs and Symptoms - Chronic alcohol liver disease:
- Hepatomegaly
- Splenomegaly
- Portal hypertension: esophageal varices hematemesis
- Ascites is demonstrated by bulging flanks with shifting abdominal dullness with the patient in the supine position.
- Spider angiomata
- Proximal muscle wasting
- Altered hair distribution
- Gynecomastia in males
- Withdrawal symptoms of restlessness, mood disturbance, tremors called delirium tremens, and, possibly, seizures.
Alcoholic Cirrhosis Diagnosis
- AST and ALT liver enzymes are elevated.
- Hypertriglyceridemia
- Hypercholesterolemia
- Hyperbilirubinemia
- Hypoalbuminemia
- Coagulation disturbances
- Ultrasound of the liver is useful to detect fatty infiltration of the liver.
- Liver biopsy can confirm alcoholic liver disease.
Recovery From Alcohol Abuse
Cirrhosis of the liver and liver failure may be the outcome of alcoholic liver disease.

Patients with alcoholic hepatitis may have improvement of liver function if there is 6 months of abstinence from alcohol.
Most Common Causes of Cirrhosis of the Liver
HCV
Alcoholism
NAFLD

Cirrhosis of the liver is the third most common cause of death in people aged 45 to 65, after heart disease and cancer.
Portal Hypertension Is a Complication of Cirrhosis
The portal vein drains the whole GI system.

The portal vein then delivers blood to the liver for detoxification.

Liver cirrhosis increases portal vein blood pressure.

Venous congestion of the GI tract occurs.
Signs of Portal Hypertension
- Esophageal varices hematemesis
- Rectal varices (hemorrhoids) rectal bleeding
- Ascites
- Hepatomegaly
- Splenomegaly
- Caput medusa = dilated veins around the umbilicus
Liver Failure Multiple Complications
Portal hypertension leads to esophageal varices which leads to hematemesis

Portal hypertension leads to venous congestion of GI system which leads to hepatic congestion, splenic congestion, ascites

Decreased bile synthesis leads to decreased fat digestion then leads to steatorrhea

Decreased coagulation factor synthesis which leads to bruising, bleeding

Decreased albumin synthesis resulting in loss of colloid oncotic pressure leading to edema

Lack of thrombopoieitin resulting in low platelets

Loss of detoxification process resulting in high level of drugs circulate

Decreased conjugation of bilirubin; bilirubin backs up resulting in hyperbilirubinemia leading to dark urine and jaundice

Loss of deamination process high nitrogen in blood lyses RBCs and platelets anemia and thrombocytopenia

Decreased fat-soluble vitamins absorbed vitamin A, D, E, K lack of vitamin D lack of calcium absorption hypocalcemia tetany, muscle cramps, bone breakdown

Hepatic encephalopathy leads to confusion, stupor, asterixis

Hepatorenal syndrome
Other Side Effects of Liver Failure
- Spider angiomata
- Skin telangiectasias
- Palmar erythema
- Finger clubbing
- Pruritus often develops because of accumulation of bile salts in the bloodstream.
- Muscle wasting is caused by protein loss.
- Males may develop gynecomastia and impotence.
- Loss of axillary and pubic hair is noted in both men and women.
Biliary Cirrhosis
Biliary cirrhosis: Bile production is dysfunctional.

Prolonged obstruction of the intrahepatic or extrahepatic biliary system causes biliary cirrhosis.

Inflammation and fibrous destruction of the intrahepatic bile ductules are the tissue evidence of primary biliary cirrhosis (PBC).

The exact etiology is unknown, but an autoimmune mechanism is theorized.
Crigler-Najjar Syndrome
Deficiency of the enzyme glucuronyl transferase lack of conjugation processing of bilirubin in the liver. Bilirubin backs up into the bloodstream.

Type I Crigler-Najjar syndrome is very rare and found in neonates.

Type II Crigler-Najjar syndrome is more common and is caused by an inherited gene mutation.

The patient has a reduced amount of glucuronyl transferase enzyme.

Patients live into adulthood with elevated serum bilirubin levels.

Kernicterus encephalopathy caused by excessive bilirubin in the blood can occur when the patient is under stress.

If bilirubin levels in the blood become too high, brain damage, also called kernicterus, can occur.
Gilbert's Syndrome
Decreased activity of the enzyme glucuronyl transferase, which conjugates bilirubin in the liver.

Mild, chronic disorder in which patients have elevated serum bilirubin levels and jaundice during periods of stress, infection, or fasting.

Individuals may have problems with liver detoxification of certain drugs.

In Gilbert's syndrome, hyperbilirubinemia usually resolves with removal of the stressful event.

Treatment is unnecessary.
Hemochromatosis
It is a genetic disorder that is caused by an accumulation of iron in the liver from excessive absorption of iron from the intestine.

Primary hemochromatosis is inherited

Secondary hemochromatosis is a side effect of excessive RBC breakdown associated with thalassemia, sideroblastic anemia, or multiple blood transfusions.
Wilson's Disease
Wilson's disease is a rare, inherited metabolic disorder characterized by excessive copper deposits in the liver, brain, and eye. Excessive copper in the liver leads to fibrosis and destruction of the hepatocytes.

The patient demonstrates symptoms of hepatic dysfunction, difficulty speaking, tremor, arthritis, excessive salivation, clubbing, ataxia, masklike facies, clumsiness, and personality changes.

Diagnosis: copper rings in the cornea called Kayser-Fleischer rings, low levels of a serum copper transport protein (ceruloplasmin), and increased levels of hepatic and urinary copper.

Treatment involves chelation with penicillamine. If left untreated, Wilson's disease leads to cirrhosis and liver failure.
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