Liver Disease

The Liver

2007-06-29T12:36:00.000-07:00

Liver
From Wikipedia, the free encyclopedia

Liver of a sheep: (1) right lobe, (2) left lobe, (3) caudate lobe, (4) quadrate lobe, (5) hepatic artery and portal vein, (6) hepatic lymph nodes, (7) gall bladder.

Position of the liver (red) in the human abdomen.
Gray's subject #250 1188
Artery: hepatic artery
Vein: hepatic vein, portal vein
Nerve: celiac ganglia, vagus[1]
Precursor: foregut
MeSH: Liver

The liver is an organ present in vertebrates and some other animals. It plays a major role in metabolism and has a number of functions in the body, including glycogen storage, plasma protein synthesis, and detoxification. This organ also is the largest gland in the human body. It lies below the diaphragm in the thoracic region of the abdomen.[2] It produces bile, an alkaline compound which aids in digestion, via the emulsification of lipids. It also performs and regulates a wide variety of high-volume biochemical reactions requiring specialized tissues.

Medical terms related to the liver often start in hepato- or hepatic from the Greek word for liver, hēpar (ήπαρ[3]).

Contents [hide]
1 Anatomy
1.1 Flow of blood
1.2 Flow of bile
1.3 Regeneration
1.4 Traditional (Surface) anatomy
1.4.1 Peritoneal ligaments
1.4.2 Lobes
1.5 Modern (Functional) anatomy
2 Physiology
3 Diseases of the liver
4 Liver transplantation
5 Development
5.1 Fetal blood supply
6 Liver as food
7 Cultural allusions
8 Further reading
9 See also
10 References
11 Additional images
12 External links

Anatomy
The adult human liver normally weighs between 1.7 - 3.0 kilograms (3.5 - 6.5 pounds), and it is a soft, pinkish-brown "boomerang shaped" organ. It is the second largest organ (the largest organ being the skin) and the largest gland within the human body.It is the heaviest organ in the body. It is located on the right side of the upper abdomen below the diaphragm. The liver lies on the right of the stomach and makes a kind of bed for the gallbladder (which stores bile).

Flow of blood
The splenic vein, joins the inferior mesenteric vein, which then together join with the superior mesenteric vein to form the portal vein, bringing venous blood from the spleen, pancreas, small intestine, and large intestine, so that the liver can process the nutrients and byproducts of food digestion.

The hepatic veins drain directly into the inferior vena cava.

The hepatic artery is generally a branch from the celiac trunk, although occasionally some or all of the blood can be from other branches such as the superior mesenteric artery.

Approximately 60% to 80% of the blood flow to the liver is from the portal venous system, and 1/4 is from the hepatic artery.

Flow of bile
The bile produced in the liver is collected in bile canaliculi, which merge to form bile ducts.

These eventually drain into the right and left hepatic ducts, which in turn merge to form the common hepatic duct. The cystic duct (from the gallbladder) joins with the common hepatic duct to form the common bile duct.

Bile can either drain directly into the duodenum via the common bile duct or be temporarily stored in the gallbladder via the cystic duct. The common bile duct and the pancreatic duct enter the duodenum together at the ampulla of Vater.

The branchings of the bile ducts resemble those of a tree, and indeed the term "biliary tree" is commonly used in this setting.

Regeneration
The liver is among the few internal human organs capable of natural regeneration of lost tissue; as little as 25% of remaining liver can regenerate into a whole liver again.

This is predominantly due to the hepatocytes acting as unipotential stem cells (i.e. a single hepatocyte can divide into two hepatocyte daughter cells). There is also some evidence of bipotential stem cells, called oval cells, which can differentiate into either hepatocytes or cholangiocytes (cells that line the bile ducts).

Traditional (Surface) anatomy

Peritoneal ligaments
Apart from a patch where it connects to the diaphragm, the liver is covered entirely by visceral peritoneum, a thin, double-layered membrane that reduces friction against other organs. The peritoneum folds back on itself to form the falciform ligament and the right and left triangular ligaments.

These "ligaments" are in no way related to the true anatomic ligaments in joints, and have essentially no functional importance, but they are easily recognizable surface landmarks.

Lobes
Traditional gross anatomy divided the liver into four lobes based on surface features.

The falciform ligament is visible on the front (anterior side) of the liver. This divides the liver into a left anatomical lobe, and a right anatomical lobe.

If the liver flipped over, to look at it from behind (the visceral surface), there are two additional lobes between the right and left. These are the caudate lobe (the more superior), and below this the quadrate lobe.

From behind, the lobes are divided up by the ligamentum venosum and ligamentum teres (anything left of these is the left lobe), the transverse fissure (or porta hepatis) divides the caudate from the quadrate lobe, and the right sagittal fossa, which the inferior vena cava runs over, separates these two lobes from the right lobe.

Each of the lobes is made up of lobules, a vein goes from the centre of each lobule which then joins to the hepatic vein to carry blood out from the liver.

On the surface of the lobules there are ducts, veins and arteries that carry fluids to and from them.

Modern (Functional) anatomy
The central area where the common bile duct, portal vein, and hepatic artery enter the liver is the hilum or "porta hepatis". The duct, vein, and artery divide into left and right branches, and the portions of the liver supplied by these branches constitute the functional left and right lobes.

The functional lobes are separated by a plane joining the gallbladder fossa to the inferior vena cava. This separates the liver into the true right and left lobes. The middle hepatic vein also demarcates the true right and left lobes. The right lobe is further divided into an anterior and posterior segment by the right hepatic vein. The left lobe is divided into the medial and lateral segments by the left hepatic vein. The fissure for the ligamentum teres (the ligamentum teres becomes the falciform ligament) also separates the medial and lateral segmants. The medial segment is what used to be called the quadrate lobe. In the widely used Couinaud or "French" system, the functional lobes are further divided into a total of eight subsegments based on a transverse plane through the bifurcation of the main portal vein. The caudate lobe is a separate structure which receives blood flow from both the right- and left-sided vascular branches.[4][5]

The subsegments corresponding to the anatomical lobes are as follows:

Segment*...Couinaud segments
Caudate..........................1
Lateral.......................2, 3
Medial....................4a, 4b
Right..................5, 6, 7, 8

*or lobe in the Caudate's case.
Each number in the list corresponds to one in the table.

..1. Caudate
..2. Superior subsegment of the lateral segment
..3. Inferior subsegment of the lateral segment
..4.
.........a. Superior subsegment of the medial segment
.........b. Inferior subsegment of the medial segment
..5. Inferior subsegment of the anterior segment
..6. Inferior subsegment of the posterior segment
..7. Superior subsegment of the posterior segment
..8. Superior subsegment of the anterior segment

Physiology
The various functions of the liver are carried out by the liver cells or hepatocytes.

The liver produces and excretes bile (a greenish liquid) required for emulsifying fats. Some of the bile drains directly into the duodenum, and some is stored in the gallbladder.
The liver performs several roles in carbohydrate metabolism:

Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or
glycerol)
Glycogenolysis (the breakdown of glycogen into glucose) (muscle tissues can also do this)
Glycogenesis (the formation of glycogen from glucose)
The breakdown of insulin and other hormones
The liver is responsible for the mainstay of protein metabolism.

The liver also performs several roles in lipid metabolism:

Cholesterol synthesis
The production of triglycerides (fats).

The liver produces coagulation factors I (fibrinogen), II (prothrombin), V, VII, IX, X and XI, as well as protein C, protein S and antithrombin.
The liver breaks down hemoglobin, creating metabolites that are added to bile as pigment (bilirubin and biliverdin).
The liver breaks down toxic substances and most medicinal products in a
process called drug metabolism. This sometimes results in toxication, when the
metabolite is more toxic than its precursor.
The liver converts ammonia to
urea.
The liver stores a multitude of substances, including glucose in the form of glycogen, vitamin B12, iron, and copper.
In the first trimester fetus, the liver is the main site of red blood cell production. By the 32nd week of gestation, the bone marrow has almost completely taken over that task.
The liver is responsible for immunological effects- the reticuloendothelial system of the liver contains many immunologically active cells, acting as a 'sieve' for antigens carried to it via the portal system.

Currently, there is no artificial organ or device capable of emulating all the functions of the
liver. Some functions can be emulated by liver dialysis, an experimental treatment for liver failure.

Diseases of the liver
Many diseases of the liver are accompanied by jaundice caused by increased levels of bilirubin in the system. The bilirubin results from the breakup of the hemoglobin of dead red blood cells; normally, the liver removes bilirubin from the blood and excretes it through bile.

Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons, autoimmunity or hereditary conditions.
Cirrhosis is the formation of fibrous tissue in the liver, replacing dead liver cells. The death of the liver cells can for example be caused by viral hepatitis, alcoholism or contact with other liver-toxic chemicals.
Haemochromatosis, a hereditary disease causing the accumulation of iron in the body, eventually leading to liver damage.
Cancer of the liver (primary hepatocellular carcinoma or cholangiocarcinoma and metastatic cancers, usually from other parts of the gastrointestinal tract).
Wilson's disease, a hereditary disease which causes the body to retain copper.
Primary sclerosing cholangitis, an inflammatory disease of the bile duct, autoimmune in nature.
Primary biliary cirrhosis, autoimmune disease of small bile ducts.
Budd-Chiari syndrome, obstruction of the hepatic vein.
Gilbert's syndrome, a genetic disorder of bilirubin metabolism, found in about 5% of the population.
Glycogen storage disease type II,The build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, liver and nervous system.
There are also many pediatric liver disease, including biliary atresia, alpha-1 antitrypsin deficiency, alagille syndrome, and progressive familial intrahepatic cholestasis, to name but a few.

A number of liver function tests are available to test the proper function of the liver. These test for the presence of enzymes in blood that are normally most abundant in liver tissue, metabolites or products.

Liver transplantation
Main article: Liver transplantation
Human liver transplant was first performed by Thomas Starzl in USA and Roy Calne in England in 1963 and 1965 respectively.

Liver transplantation is the only option for those with irreversible liver failure. Most transplants are done for chronic liver diseases leading to cirrhosis, such as chronic hepatitis C, alcoholism, autoimmune hepatitis, and many others. Less commonly, liver transplantation is done for fulminant hepatic failure, in which liver failure occurs over days to weeks.

Liver allografts for transplant usually come from non-living donors who have died from fatal brain injury. Living donor liver transplantation is a technique in which a portion of a living person's liver is removed and used to replace the entire liver of the recipient. This was first performed in 1989 for pediatric liver transplantation. Only 20% of an adult's liver (Couinaud segments 2 and 3) is needed to serve as a liver allograft for an infant or small child.

More recently, adult-to-adult liver transplantation has been done using the donor's right hepatic lobe which amounts to 60% of the liver. Due to the ability of the liver to regenerate, both the donor and recipient end up with normal liver function if all goes well. This procedure is more controversial as it entails performing a much larger operation on the donor, and indeed there have been at least 2 donor deaths out of the first several hundred cases. A recent publication has addressed the problem of donor mortality, and at least 14 cases have been found.[6] The risk of postoperative complications (and death) is far greater in right sided hepatectomy than left sided operations.

Development
The liver develops as an endodermal outpocketing of the foregut called the hepatic diverticulum. Its initial blood supply is primarily from the vitelline veins that drain blood from the yolk sac. The superior part of the hepatic diverticulum gives rise to the hepatocytes and bile ducts, while the inferior part becomes the gallbladder and its associated cystic duct.

Fetal blood supply
In the growing fetus, a major source of blood to the liver is the umbilical vein which supplies nutrients to the growing fetus. The umbilical vein enters the abdomen at the umbilicus, and passes upward along the free margin of the falciform ligament of the liver to the inferior surface of the liver. There it joins with the left branch of the portal vein. The ductus venosus carries blood from the left portal vein to the left hepatic vein and then to the inferior vena cava, allowing placental blood to bypass the liver.

In the fetus, the liver develops throughout normal gestation, and does not perform the normal filtration of the infant liver. The liver does not perform digestive processes because the fetus does not consume meals directly, but receives nourishment from the mother via the placenta. The fetal liver releases some blood stem cells that migrate to the fetal thymus, so initially the lymphocytes, called T-cells, are created from fetal liver stem cells. Once the fetus is delivered, the formation of blood stem cells in infants shifts to the red bone marrow.

After birth, the umbilical vein and ductus venosus are completely obliterated two to five days postpartum; the former becomes the ligamentum teres and the latter becomes the ligamentum venosum. In the disease state of cirrhosis and portal hypertension, the umbilical vein can open up again.

Liver as food
Pork liver
Nutritional value per 100 g (3.5 oz)
Energy 130 kcal 560 kJ
Carbohydrates 2.5 g
Fat 3.7 g
Protein 21 g
Vitamin A equiv. 6500 μg 722%
Riboflavin (Vit. B2) 3 mg 200%
Niacin (Vit. B3) 15 mg 100%
Vitamin B6 0.7 mg 54%
Folate (Vit. B9) 212 μg 53%
Vitamin B12 26 μg 1083%
Iron 23 mg 184%
Sodium 87 mg 6%

Beef and chicken liver are comparable.
Percentages are relative to US
recommendations for adults.
Source: USDA Nutrient database
Mammal and bird livers are commonly eaten as food: products include liver pâté, Leberwurst, Braunschweiger, foie gras, chopped liver, leverpostej and liver sashimi.

Both animal and fish livers are rich in iron and Vitamin A and cod liver oil is commonly used as a supplement. Very high doses of Vitamin A can be toxic; Antarctic explorers Douglas Mawson and Xavier Mertz were both poisoned, the latter fatally, from eating husky liver. In the US, the USDA specifies 3000 μg per day as a tolerable upper limit, which amounts to about 50 g of raw pork liver or, as reported in a non scientific source, 3 g of polar-bear liver.[7] However, acute vitamin A poisoning is not likely to result from liver consumption, since it is present in a less toxic form than in many dietary supplements.[8]

Cultural allusions
In Greek mythology, Prometheus was punished by the gods for revealing fire to humans by being chained to a rock where a vulture (or an eagle, Ethon) would peck out his liver, which would regenerate overnight. Curiously, the liver is the only human internal organ that actually can regenerate itself to a significant extent, a characteristic which may have already been known to the Greeks, possibly due to survived injuries in battle.

The Talmud (tractate Berakhot 61b) refers to the liver as the seat of anger, with the gallbladder counteracting this.

In Arabic and Persian language, the liver is used in figurative speech to refer to courage and strong feelings, or "their best," e.g. "This Mecca has thrown to you the pieces of its liver!" [9]

The legend of Liver-Eating Johnson says that he would cut out and eat the liver of each man killed.

In the motion picture The Message, Hind bint Utbah is implied or portrayed eating the liver of Hamza ibn ‘Abd al-Muttalib during the Battle of Uhud.

Inuit will not eat the liver of polar bears (due to the fact a polar bears liver contains so much Vitamin A as to be virtually poisonous to humans) or seals [10]

In The Silence of the Lambs, Hannibal Lecter says famously, "I ate his liver with some fava beans and a nice Chianti."

Further reading
The following are standard medical textbooks:
Eugene R. Schiff, Michael F. Sorrell, Willis C. Maddrey, eds. Schiff's diseases of the liver, 9th ed. Philadelphia : Lippincott, Williams & Wilkins, 2003. ISBN 0-7817-3007-4
Sheila Sherlock, James Dooley. Diseases of the liver and biliary system, 11th ed. Oxford, UK ; Malden, MA : Blackwell Science. 2002. ISBN 0-632-05582-0
David Zakim, Thomas D. Boyer. eds. Hepatology: a textbook of liver disease, 4th ed. Philadelphia: Saunders. 2003. ISBN 0-7216-9051-3
These are for the lay reader or patient:
Sanjiv Chopra. The Liver Book: A Comprehensive Guide to Diagnosis, Treatment, and Recovery, Atria, 2002, ISBN 0-7434-0585-4
Melissa Palmer. Dr. Melissa Palmer's Guide to Hepatitis and Liver Disease: What You Need to Know, Avery Publishing Group; Revised edition May 24, 2004, ISBN 1-58333-188-3. her webpage.
Howard J. Worman. The Liver Disorders Sourcebook, McGraw-Hill, 1999, ISBN 0-7373-0090-6. his Columbia University web site, "Diseases of the liver"

See also
Look up liver in Wiktionary, the free dictionary.Liver function tests
Hepatocyte
Bile canaliculus
Bile

References
^ Physiology at MCG 6/6ch2/s6ch2_30
^ KMLE Medical Dictionary. KMLE Medical Dictionary Definition of liver. Retrieved 2007-02-16
^ The Greek word "ήπαρ" was derived from hēpaomai (ηπάομαι): to mend, to repair, hence hēpar actually means "repairable", indicating that this organ can regenerate itself spontaneously in the case of lesion.
^ http://dpi.radiology.uiowa.edu/nlm/app/livertoc/liver/liver.html
^ http://www.uni-bonn.de/~umm705/quiz0403.htm
^ Bramstedt K (2006). "Living liver donor mortality: where do we stand?". Am J Gastroenterol 101 (4): 755-9. PMID 16494593.
^ A. Aggrawal, Death by Vitamin A
^ Myhre et al., "Water-miscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations", Am. J. Clinical Nutrition, 78, 1152 (2003)
^ http://www.shawuniversitymosque.org/m/faq_qanda.php?id=94
^ http://www.studentbmj.com/issues/02/05/life/158.php

External links
Wikimedia Commons has media related to:
LiverChildren's Liver Association for Support Services, C.L.A.S.S. A large non-profit organization. An online Support Group full of resources, materials and stories; includes a Community Discussion Forum and Chat Room
The American Liver Foundation
American Association for the Study of Liver Diseases (AASLD) American Liver Society (ALS)
WikiLiver — a wiki dedicated to the liver
"It's Dangerous to Ignore Your Liver" — information provided by the American Liver Foundation
"The Liver and its Diseases" — information at h2g2
Liver Families — an online support group for families whose lives have been affected by pediatric liver disease and transplant issues
Children's Liver Disease Foundation — an organisation dedicated to fighting childhood liver disease and supporting affected families
Liver Specialists of Texas: a site designed for patients with liver disease, located in Houston, Texas USA
Autoimmune immune liver disease
British Liver Trust - includes patient info oriented to British situations

To view information on another disease click on Digestive Diseases Library

Cirrhosis

2007-06-29T12:28:00.000-07:00

Cirrhosis
From Wikipedia, the free encyclopedia

Classification & external resources
CT abdomen - liver cirrhosis
ICD-10 K70.3, K71.7, K74.
ICD-9 571
DiseasesDB 2729
eMedicine med/3183 radio/175
MeSH D008103

Cirrhosis of the liver is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrotic scar tissue as well as regenerative nodules, leading to progressive loss of liver function. Cirrhosis is most commonly caused by alcoholism and hepatitis C, but has many other possible causes.

Ascites (fluid retention in the abdominal cavity) is the most common complication of cirrhosis and is associated with a poor quality of life, increased risk of infection, and a poor long-term outcome. Other potentially life-threatening complications are hepatic encephalopathy (confusion and coma) and bleeding from esophageal varices. Cirrhosis is generally irreversible once it occurs, and treatment generally focuses on preventing progression and complications. In advanced stages of cirrhosis the only option is a liver transplant.

The word "cirrhosis" is a neologism that derives from Greek kirrhos, meaning "tawny" (the orange-yellow colour of the diseased liver). While the clinical entity was known before, it was René Laennec who gave it the name "cirrhosis" in his 1819 work in which he also describes the stethoscope.[1]

Symptoms and signs
The following signs and symptoms may occur in the presence of cirrhosis or as a result of the complications of cirrhosis. Many are nonspecific and may occur in other diseases and do not necessarily point to cirrhosis. Likewise, the absence of any does not rule out the possibility of cirrhosis.

Spider angiomata or spider nevi. Vascular lesions consisting of central arteriole surrounded by many smaller vessels due to an increase in estradiol.
Palmar erythema. Exaggerations of normal speckled mottling of the palm, due to altered sex hormone metabolism.
Nail changes.

Muehrcke's nails - paired horizontal bands separated by normal color due to
hypoalbuminemia (low production of albumin).
Terry's nails - proximal two thirds of the nail plate appears white with distal one-third red, also due to
hypoalbuminemia
Clubbing --- Angle between the nail plate and proximal nail
fold > 180 degrees

Hypertrophic osteoarthropathy. Chronic proliferative periostitis of the long bones that can cause considerable pain.
Dupuytren's contracture. Thickening and shortening of palmar fascia that leads to flexion deformities of the fingers. Thought to be due to fibroblastic proliferation and disorderly collagen deposition. It is relatively common (33% of patients).
Gynecomastia. Benign proliferation of glandular tissue of male breasts presenting with a rubbery or firm mass extending concentrically from the nipples. This is due to increased estradiol and can occur up to 66% of patients.
Hypogonadism. Manifested as impotence, infertility, loss of sexual drive, and testicular atrophy due to primary gonadal injury or suppression of hypothalamic or pituitary function.
Liver size. Can be enlarged, normal, or shrunken.
Splenomegaly. Due to congestion of the red pulp as a result of portal hypertension.
Ascites. Accumulation of fluid in the peritoneal cavity giving rise to flank dullness (needs about 1500 mL to detect flank dullness).
Caput medusa. In portal hypertension, the umbilical vein may open. Blood from the portal venous system may be shunted through the periumbilical veins into the umbilical vein and ultimately to the abdominal wall veins, manifesting as caput medusa.
Cruveilhier-Baumgarten murmur. Venous hum heard in epigastric region due to collateral connections between portal system and the remnant of the umbilical vein in portal hypertension.
Fetor hepaticus. Sweet pungent smell in breath due to increased dimethyl sulfide due to severe portal-systemic shunting.
Jaundice. Yellow discoloring of the skin, eye, and mucus membranes due to increased bilirubin (at least 2-3 mg/dL or 30 mmol/L). Urine may also appear dark.
Asterixis. Bilateral asynchronous flapping of outstretched, dorsiflexed hands seen in patients with hepatic encephalopathy.
Other.

Weakness,
fatigue,
anorexia,
weight loss.

Complications
As the disease progresses, complications may develop. In some people, these may be the first signs of the disease.

Bruising and bleeding due to decreased production of coagulation factors.
Jaundice due to decreased processing of bilirubin.
Itching (pruritus) due to bile products deposited in the skin.
Hepatic encephalopathy - the liver does not clear ammonia and related nitrogenous substances from the blood, which are carried to the brain, affecting cerebral functioning:

neglect of personal appearance,
unresponsiveness,
forgetfulness,
trouble concentrating,
or changes in sleep habits.

Sensitivity to medication due to decreased metabolism of the active compounds.
Hepatocellular carcinoma is primary liver cancer, a frequent complication of cirrhosis. It has a high mortality rate.
Portal hypertension - blood normally carried from the intestines and spleen through the portal vein flows more slowly and the pressure increases; this leads to the following complications:
Ascites - fluid leaks through the vasculature into the abdominal cavity.
Esophageal varices - collateral portal blood flow through vessels in the stomach and esophagus. These blood vessels may become enlarged and are more likely to burst.
Problems in other organs.
Cirrhosis can cause immune system dysfunction, leading to infection. Signs and symptoms of infection may be aspecific are more difficult to recognize (e.g. worsening encephalopathy but no fever).
Fluid in the abdomen (ascites) may become infected with bacteria normally present in the intestines (spontaneous bacterial peritonitis).
Hepatorenal syndrome - insufficient blood supply to the kidneys, causing acute renal failure. This complication has a very high mortality (over 50%).
Hepatopulmonary syndrome - blood bypassing the normal lung circulation (shunting), leading to cyanosis and dyspnea (shortness of breath), characteristically worse on sitting up.[2]
Portopulmonary hypertension - increased blood pressure over the lungs as a consequence of portal hypertension.[2]

Causes
Cirrhosis has many possible causes; sometimes more than one cause is present in the same patient. In the Western World, chronic alcoholism and hepatitis C are the most common causes.

Alcoholic liver disease (ALD). Alcoholic cirrhosis develops in 15% of individuals who drink heavily for more than a decade. There is great variability in the amount of alcohol needed to cause cirrhosis (as little as 3-4 drinks a day in some men and 2-3 in some women). Alcohol seems to injure the liver by blocking the normal metabolism of protein, fats, and carbohydrates. Patients may also have concurrent alcoholic hepatitis with fever, hepatomegaly, jaundice, and anorexia. AST and ALT are both elevated but less than 300 IU/L with a AST:ALT ratio > 2.0, a value rarely seen in other liver diseases. Liver biopsy may show hepatocyte necrosis, Mallory bodies, neutrophilic infiltration with perivenular inflammation.
Chronic hepatitis C. Infection with this virus causes inflammation of and low grade damage to the liver that over several decades can lead to cirrhosis. Can be diagnosed with serologic assays that detect hepatitis C antibody or viral RNA. The enzyme immunoassay, EIA-2, is the most commonly used screening test in the US.
Chronic hepatitis B. The hepatitis B virus is probably the most common cause of cirrhosis worldwide, especially South-East Asia, but it is less common in the United States and the Western world. Hepatitis B causes liver inflammation and injury that over several decades can lead to cirrhosis. Hepatitis D is dependent on the presence of hepatitis B, but accelerates cirrhosis in co-infection. Chronic hepatitis B can be diagnosed with detection of HBsAG > 6 months after initial infection. HBeAG and HBV DNA are determined to assess whether patient will need antiviral therapy.
Non-alcoholic steatohepatitis (NASH). In NASH, fat builds up in the liver and eventually causes scar tissue. This type of hepatitis appears to be associated with diabetes, protein malnutrition, obesity, coronary artery disease, and treatment with corticosteroid medications. This disorder is similar to that of alcoholic liver disease but patient does not have an alcohol history. Biopsy is needed for diagnosis.
Primary biliary cirrhosis. May be asymptomatic or complain of fatigue, pruritus, and non-jaundice skin hyperpigmentation with hepatomegaly. There is prominent alkaline phosphatase elevation as well as elevations in cholesterol and bilirubin. Gold standard diagnosis is antimitochondrial antibodies with liver biopsy as confirmation if showing florid bile duct lesions. It is more common in women.
Primary sclerosing cholangitis. PSC is a progressive cholestatic disorder presenting with pruritus, steatorrhea, fat soluble vitamin deficiencies, and metabolic bone disease. There is a strong association with inflammatory bowel disease (IBD), especially ulcerative colitis. Diagnosis is best with contrast cholangiography showing diffuse, multifocal strictures and focal dilation of bile ducts, leading to a beaded appearance. Non-specific serum immunoglobulins may also be elevated.
Autoimmune hepatitis. This disease is caused by the immunologic damage to the liver causing inflammation and eventually scarring and cirrhosis. Findings include elevations in serum globulins, especially gamma globulins. Therapy with prednisone +/- azathioprine is beneficial. Cirrhosis due to autoimmune hepatitis still has 10-year survival of 90%+. There's no specific tool to diagnose autoimmune but it can be beneficial to initiate a trial of corticosteroids.
Hereditary hemochromatosis. Usually presents with family history of cirrhosis, skin hyperpigmentation, diabetes mellitus, pseudogout, and/or cardiomyopathy, all due to signs of iron overload. Labs will show fasting transferrin saturation of > 60% and ferritin > 300 ng/mL. Genetic testing may be used to identify HFE mutations. If these are present, biopsy may not need to be performed. Treatment is with phlebotomy to lower total body iron levels.
Wilson's disease. Autosomal recessive disorder characterized by low serum ceruloplasmin and increased hepatic copper content on liver biopsy. May also have Kayser-Fleischer rings in the cornea and altered mental status.
Alpha 1-antitrypsin deficiency (AAT). Autosomal recessive disorder. Patients may also have COPD, especially if they have a history of tobacco smoking. Serum AAT levels are low. Recombinant AAT is used to prevent lung disease due to AAT deficiency.
Cardiac cirrhosis. Due to chronic right sided heart failure which leads to liver congestion.
Galactosemia
Glycogen storage disease type IV
Cystic fibrosis
Drugs or toxins
Certain parasitic infections (such as schistosomiasis)

Diagnosis
The gold standard for diagnosis of cirrhosis is a liver biopsy, through a percutaneous, transjugular, laparoscopic, or fine-needle approach. Histologically cirrhosis can be classified as micronodular, macronodular, or mixed, but this classification has been abandoned since it is nonspecific to the etiology, it may change as the disease progresses, and serological markers are much more specific. However, a biopsy is not necessary if the clinical, laboratory, and radiologic data suggests cirrhosis. Furthermore, there is a small but significant risk to liver biopsy, and cirrhosis itself predisposes for complications due to liver biopsy.[citation needed]

Lab findings
The following findings are typical in cirrhosis:

Aminotransferases - AST and ALT are moderately elevated, with AST > ALT. However, normal aminotransferases do not preclude cirrhosis.
Alkaline phosphatase - usually slightly elevated.
GGT -- correlates with AP levels. Typically much higher in chronic liver disease from alcohol.
Bilirubin - may elevate as cirrhosis progresses.
Albumin - levels fall as the synthetic function of the liver declines with worsening cirrhosis since albumin is exclusively synthesized in the liver
Prothrombin time - increases since the liver synthesizes clotting factors.
Globulins - increased due to shunting of bacterial antigens away from the liver to lymphoid tissue.
Serum sodium - hyponatremia due to inability to excrete free water resulting from high levels of ADH and aldosterone.
Thrombocytopenia - due to both congestive splenomegaly as well as decreased thrombopoietin from the liver. However this rarely results in platete count <>
Leukopenia and neutropenia - due to splenomegaly with splenic margination.
Coagulation defects - the liver produces most of the coagulation factors and thus coagulopathy correlates with worsening liver disease.

Other laboratory studies performed in newly diagnosed cirrhosis may include:

Serology for hepatitis viruses, autoantibodies (ANA, anti-smooth muscle, anti-mitochondria, anti-LKM)
Ferritin and transferrin saturation (markers of iron overload), copper and ceruloplasmin (markers of copper overload)
Immunoglobulin levels (IgG, IgM, IgA) - these are non-specific but may assist in distinguishing various causes
Cholesterol and
glucose Alpha 1-antitrypsin

Imaging
Ultrasound is routinely used in the evaluation of cirrhosis, where it may show a small and nodular liver in advanced cirrhosis along with increased echogenicity with irregular appearing areas. Ultrasound may also screen for hepatocellular carcinoma, portal hypertension and Budd-Chiari syndrome.

Other tests performed in particular circumstances include abdominal CT and liver/bile duct MRI (MRCP).

Endoscopy
Gastroscopy (endoscopic examination of the esophagus, stomach and duodenum) is performed in patients with established cirrhosis to exclude the possibility of esophageal varices. If these are found, prophylactic local therapy may be applied (sclerotherapy or banding) and beta blocker treatment may be commenced.

If biliary pathology is suspected, ERCP may be performed. Generally MRCP (MRI of biliary tract and pancreas) is sufficient for diagnosis, but ERCP allows for particular interventions, such as placement of a biliary stent or extraction of gallstones.

Pathology
Macroscopically, the liver may be initially enlarged, but with progression of the disease, it becomes smaller. Its surface is irregular, the consistency is firm and the color is often yellow (if associates steatosis). Depending on the size of the nodules there are three macroscopic types: micronodular, macronodular and mixed cirrhosis. In micronodular form (Laennec's cirrhosis or portal cirrhosis) regenerating nodules are under 3 mm. In macronodular cirrhosis (post-necrotic cirrhosis), the nodules are larger than 3 mm. The mixed cirrhosis consists in a variety of nodules with different sizes.

Microscopically, cirrhosis is characterized by regeneration nodules, surrounded by fibrous septa. In these nodules, regenerating hepatocytes are disorderly disposed. Portal tracts, central veins and the radial pattern of hepatocytes are absent. Fibrous septa are important and may present inflammatory infiltrate (lymphocytes, macrophages) If it is a secondary biliary cirrhosis, biliary ducts are damaged, proliferated or distended - bile stasis. These dilated ducts contain inspissated bile which appear as bile casts or bile thrombi (brown-green, amorphous). Bile retention may be found also in the parenchyma, as the so called "bile lakes".[3]

Grading
The severity of cirrhosis is commonly classified with the Child-Pugh score. This score uses bilirubin, albumin, INR, presence and severity of ascites and encephalopathy to classify patients in class A, B or C; class A has a favourable prognosis, while class C is at high risk of death. It was devised in 1964 by Child and Turcotte and modified in 1973 by Pugh et al.[4]

More modern scores, used in the allocation of liver transplants but also in other contexts, are the Model for End-Stage Liver Disease (MELD) score and its pediatric counterpart, the Pediatric End-Stage Liver Disease (PELD) score.

Pathophysiology
The liver plays a vital role in synthesis of proteins (e.g. albumin, clotting factors and complement), detoxification and storage (e.g. vitamin A). In addition, it participates in the metabolism of lipids and carbohydrates.

Cirrhosis is often preceded by hepatitis and fatty liver (steatosis), independent of the cause. If the cause is removed at this stage, the changes are still fully reversible.

The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, blocking the portal flow of blood through the organ and disturbing normal function. Recent research shows the pivotal role of stellate cell, a cell type that normally stores vitamin A, in the development of cirrhosis. Damage to the hepatic parenchyma leads to activation of the stellate cell, which becomes contractile (called myofibroblast) and obstructs blood flow in the circulation. In addition, it secretes TGF-β1, which leads to a fibrotic response and proliferation of connective tissue. Furthermore, it disturbs the balance between matrix metalloproteinases and the naturally occurring inhibitors (TIMP 1 and 2), leading to matrix breakdown and replacement by connective tissue-secreted matrix.[5]

The fibrous tissue bands (septa) separate hepatocyte nodules, which eventually replace the entire liver architecture, leading to decreased blood flow throughout. The spleen becomes congested, which leads to hypersplenism and increased sequestration of platelets. Portal hypertension is responsible for most severe complications of cirrhosis.

Treatment

General care
Traditionally, liver damage from cirrhosis cannot be reversed, but treatment could stop or delay further progression and reduce complications. Close follow-up is often necessary. Alcohol and acetaminophen, as well as other potentially damaging substances, are discouraged. A healthy diet is encouraged, as cirrhosis may be an energy-consuming process. Salt restriction is often necessary, as cirrhosis leads to accumulation of salt (sodium retention). High-protein food increases the nitrogen balance, and would theoretically increase encephalopathy; in the past, this was therefore eliminated as much as possible from the diet. Recent studies show that this assumption was incorrect, and high-protein foods are even encouraged to maintain adequate nutrition.

Treatment exists of elimination of the causes and preventing complications:

Elimination of causes:

alcoholic cirrhosis caused by alcohol abuse is treated by abstaining from alcohol.
Treatment for hepatitis-related cirrhosis involves medications used to treat the different types of hepatitis, such as interferon for viral hepatitis and corticosteroids for autoimmune hepatitis.
Cirrhosis caused by Wilson's disease, in which copper builds up in organs, is treated with chelation therapy (e.g. penicillamine) to remove the copper.

Preventing complications.

Diuretics may be necessary to suppress ascites.
Antibiotics will be prescribed for infections, and
various medications can help with itching.
Laxatives, such as lactulose, decrease risk of constipation; their role in preventing encephalopathy is limited.
For portal hypertension, propranolol is a commonly used agent to lower blood pressure over the portal system.
In severe complications from portal hypertension, transjugular intrahepatic portosystemic shunting is occasionally indicated to relieve pressure on the portal vein. As this can worsen encephalopathy, it is reserved for those at low risk of encephalopathy, and is generally regarded only as a bridge to liver transplantation or as a palliative measure.

If complications cannot be controlled or when the liver ceases functioning, a liver transplant is necessary. Survival from liver transplantation has been improving over the 1990s and is now around 90%, depending largely on the severity of disease and other medical problems in the recipient.[citation needed] Transplantation necessitates the use of immune suppressants (ciclosporin or tacrolimus).

Decompensated cirrhosis
In patients with previously stable cirrhosis, decompensation may occur due to various causes, such as constipation, infection (of any source), increased alcohol intake, medication, bleeding from esophageal varices or dehydration. It may take the form of any of the complications of cirrhosis listed above.

Patients with decompensated cirrhosis generally require admission to hospital, with close monitoring of the fluid balance, mental status, and emphasis on adequate nutrition and medical treatment - often with diuretics, antibiotics, laxatives and/or enemas, thiamine and occasionally steroids, acetylcysteine and pentoxifylline. Administration of saline is generally avoided as it would add to the already high total body sodium content that typically occurs in cirrhosis.

Epidemiology
Cirrhosis and chronic liver disease were the 10th leading cause of death for men and the 12th for women in the United States in 2001, killing about 27,000 people each year.[6] Also, the cost of cirrhosis in terms of human suffering, hospital costs, and lost productivity is high.

Established cirrhosis has a 10-year mortality of 34-66%, largely dependent on the cause of the cirrhosis; alcoholic cirrhosis has a worse prognosis than primary biliary cirrhosis and cirrhosis due to hepatitis. The risk of death due to all causes is increased twelvefold; if one excludes the direct consequences of the liver disease, there is still a fivefold increased risk of death in all disease categories.[7]

Little is known on modulators of cirrhosis risk. Studies have recently suggested that coffee consumption may protect against cirrhosis, especially alcoholic cirrhosis.[8]

References
^ Roguin A. Rene Theophile Hyacinthe Laennec (1781-1826): the man behind the stethoscope. Clin Med Res 2006;4:230-5. PMID 17048358.
^ a b Rodriguez-Roisin R, Krowka MJ, Herve P, Fallon MB; ERS Task Force Pulmonary-Hepatic Vascular Disorders (PHD) Scientific Committee. Pulmonary-Hepatic vascular Disorders (PHD). Eur Respir J 2004;24:861-80. PMID 15516683.
^ Pathology atlas, "cirrhosis".
^ Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-9. PMID 4541913.
^ Iredale JP. Cirrhosis: new research provides a basis for rational and targeted treatments. BMJ 2003;327:143-7. Fulltext. PMID 12869458.
^ Anderson RN, Smith BL. Deaths: leading causes for 2001. Natl Vital Stat Rep 2003;52:1-85. PMID 14626726.
^ Sorensen HT, Thulstrup AM, Mellemkjar L, Jepsen P, Christensen E, Olsen JH, Vilstrup H. Long-term survival and cause-specific mortality in patients with cirrhosis of the liver: a nationwide cohort study in Denmark. J Clin Epidemiol 2003;56:88-93. PMID 12589875.
^ Klatsky AL, Morton C, Udaltsova N, Friedman GD. Coffee, cirrhosis, and transaminase enzymes. Arch Intern Med 2006;166:1190-5. PMID 16772246.

For information on another Digestive Disease, click on Digestive Diseases Library

Digestive Diseases Library

NASH - Non-Alcoholic Fatty Liver Disease (NAFLD)

2007-06-29T12:00:00.000-07:00

Non-alcoholic fatty liver disease
From Wikipedia, the free encyclopedia

Classification & external resources ICD-10 K76.0
ICD-9 571.8
DiseasesDB 29786
eMedicine med/775

Non-alcoholic fatty liver disease (NAFLD) is fatty inflammation of the liver when this is not due to excessive alcohol use. It is related to insulin resistance and the metabolic syndrome, and may respond to treatments originally developed for other insulin resistant states (e.g. diabetes mellitus type 2), such as weight loss, metformin and thiazolidinediones.[1] Non-alcoholic steatohepatitis (NASH) is the most extreme form of NAFLD, which is regarded as a major cause of cryptogenic cirrhosis of the liver.[2]

Contents
1 Signs and symptoms
1.1 Symptoms and associations
1.2 Secondary causes
2 Diagnosis
3 Pathophysiology
4 Treatment
5 History
6 References
7 External links

Signs and symptoms

Symptoms and associations
Most patients with NAFLD have no or few symptoms. Infrequently patients may complain of fatigue, malaise and dull right upper quadrant abdominal discomfort. Mild jaundice can rarely be noticed. More commonly it is diagnosed as a result of abnormal liver function tests during routine blood tests. By definition, alcohol consumption of over 20 g/day excludes the condition.[1]

NAFLD is associated with insulin resistance and the metabolic syndrome (obesity, combined hyperlipidemia, diabetes mellitus (type II) and high blood pressure).[2][1]

Secondary causes
NAFLD can also be caused by the following medications (termed secondary NAFLD):[citation needed]

Amiodarone
Antiviral drugs (nucleoside analogues)
Aspirin / NSAIDS
Corticosteroids
Methotrexate
Nifedipine
Perhexiline
Tamoxifen
Tetracycline
Valproic acid

Diagnosis
Disturbed liver enzymes are common, and liver ultrasound may show steatosis; it may also be used to exclude gallstone problems (cholelithiasis). A biopsy (tissue examination) of the liver is the only widely accepted test which can distinguish NASH from other forms of liver disease, and can be used to assess the severity of the inflammation and resultant fibrosis.[1]

Other tests generally performed are other blood tests (erythrocyte sedimentation rate, glucose, albumin, renal function etc.) As the liver is important in coagulation, some coagulation studies will generally be done, especially the INR (international normalized ratio). To distinguish this disease from viral hepatitis, blood tests (serology) are generally done (hepatitis A, B, C, EBV, CMV and herpes viruses, as well as rubella) to ensure these are not playing a role. Additionally, autoimmune causes are ruled out with serology. TSH is warranted, as hypothyroidism is more prevalent in NASH patients.[3]

Pathophysiology
NAFLD is considered a spectrum of disease activity. This spectrum begins as fatty accumulation in the liver (hepatic steatosis). A fatty liver can remain without disturbing the function of the liver, but by varying mechanisms and possible insults to the liver, may progress to outright inflammation of the liver. When inflammation occurs in this setting, the condition is then called NASH. Over time, up to 20 percent of patients with NASH may develop cirrhosis.

The exact cause is still unknown. However both obesity and insulin resistance likely play a strong role in this disease process. The exact reasons and mechanisms by which this disease progresses from one entity to the next is a subject of much research and debate. One such debated mechanisim proposes a "second hit", or further injury, enough to cause change that leads from hepatic steatosis to hepatic inflammation. Oxidative stress, hormonal imbalances and mitochondrial abnormalities may be potential causes for this "second hit" phenomenon.[1]

Treatment
Trials are presently being conducted to optimise treatment of NASH. No standard treatment has yet emerged as the "gold standard". General recommendations include improving metabolic risk factors and reducing alcohol intake.[1]

A large number of treatments have been studied for NAFLD. While many may improve biochemical markers, such as alanine transaminase levels, most have not been shown to reverse the histological abnormalities or reduce clinical endpoints:[1]

Weight loss: gradual weight loss, and possibly bariatric surgery, may improve the process in obese patients.
Insulin sensitisers (metformin and rosiglitazone but more markedly pioglitazone) have shown efficacy in some studies.
Antioxidants and ursodeoxycholic acid, as well as lipid-lowering drugs, have little benefit.

History
NASH was described in 1980 in a series of patients of the Mayo Clinic[4]. Its relevance and high prevalence were recognized mainly in the 1990s.

References
^ a b c d e f g Adams LA, Angulo P. Treatment of non-alcoholic fatty liver disease. Postgrad Med J 2006;82:315-22. PMID 16679470.
^ a b Clark JM, Diehl AM. Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA 2003;289:3000-4. PMID 12799409.
^ Liangpunsakul S, Chalasani N. Is hypothyroidism a risk factor for non-alcoholic steatohepatitis? J Clin Gastroenterol 2003;37:340-3. PMID 14506393
^ Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434-438. PMID 7382552.

External links
Medscape article on NASH.
MEDICINENET article on Steatosis.
NIH page on Nonalcoholic Steatohepatitis

For Information on another Digestive Disease, click on Digestive Diseases Library!
..
Digestive Diseases Library

Budd-Chiari Syndrome

2007-06-28T17:30:00.000-07:00

Budd-Chiari Syndrome
From Wikipedia, the free encyclopedia

Classification & external resources ICD-10 I82.0
ICD-9 453.0

In medicine (gastroenterology and hepatology), Budd-Chiari syndrome is the clinical picture caused by occlusion of the hepatic vein or inferior vena cava. Its presents with the classical triad of abdominal pain, ascites and hepatomegaly. Examples of occlusion include thrombosis of hepatic veins and membranous webs in the inferior vena cava. The syndrome can be fulminant, acute, chronic, or asymptomatic. It occurs in 1 out of 100,000 individuals and is more common in females. Some 10-20% also have obstruction of the portal vein.

Contents
1 Signs and symptoms
2 Causes
3 Pathophysiology
4 Diagnosis
5 Prognosis
6 Treatment
7 External links
8 Notes

Signs and symptoms
The acute syndrome presents with rapidly progressive: severe upper abdominal pain, jaundice, hepatomegaly (enlarged liver), ascites, elevated liver enzymes, and eventual encephalopathy. The fulminant syndrome presents early with encephalopathy and ascites. Severe hepatic necrosis and lactic acidosis may be present as well. Caudate lobe hypertrophy is often present. The majority of patients have a slower-onset form of Budd-Chiari syndrome. This can be painless. A system of venous collaterals may form around the occlusion which may be seen on imaging as a "spider's web." Patients may progress to cirrhosis and show the signs of liver failure.

An asymptomatic form may be totally silent and discovered only incidentally. It is generally not concerning.

Causes

Primary (75%): thrombosis of the hepatic vein
Secondary (25%): compression of the hepatic vein by an outside structure (e.g. a tumor)
Often, the patient is known to have a tendency towards thrombosis, although Budd-Chiari syndrome can also be the first symptom of such a tendency. Examples of genetic tendencies include Protein C deficiency, Protein S deficiency, and the Factor V Leiden mutation. An important non-genetic risk factor is the use of oral contraceptives. Other risk factors include the antiphospholipid syndrome, aspergillosis, Behcet's disease, dacarbazine, pregnancy, and trauma.
Many patients have Budd-Chiari syndrome as a complication of polycythemia vera (myeloproliferative disease of red blood cells). [1] Patients suffering from paroxysmal nocturnal hemoglobinuria (PNH) appear to be especially at risk for Budd-Chiari syndrome, more than other forms of thrombophilia: up to 39% develop venous thromboses [2] and 12% may acquire Budd-Chiari. [3]
A related condition is veno-occlusive disease, which occurs in recipients of bone marrow transplants as a complication of their medication. Although its mechanism is similar, it is not considered a form of Budd-Chiari syndrome.

Pathophysiology
Any obstruction of the venous vasculature of the liver is referred to as Budd-Chiari syndrome, from the venules to the right atrium. This leads to increased portal vein and hepatic sinusoid pressures as the blood flow stagnates. The increased portal pressure causes: 1) increased filtration of vascular fluid with the formation of protein-rich ascites in the abdomen; and 2) collateral venous flow through alternative veins leading to gastric varices and hemorrhoids. Obstruction also causes hepatic necrosis and eventual centrilobular fibrosis due to ischemia. Renal failure may occur, perhaps due to the body sensing an "underfill" state and subsequent activation of the renin-angiotensin pathways and excess sodium retention.

Diagnosis

When Budd-Chiari syndrome is suspected, measurements are made of liver enzyme levels and other organ markers (creatinine, urea, electrolytes, LDH).
Budd-Chiari syndrome is most commonly diagnosed using ultrasound studies of the abdomen and retrograde angiography). Ultrasound may show obliteration of hepatic veins, thrombosis or stenosis, spiderweb vessels, large collateral vessels, or a hyperechoic cord replacing a normal vein.
Computed tomography (CT) or
magnetic resonance imaging (MRI) is sometimes employed although these methods are generally not as sensitive.
Liver biopsy is nonspecific but sometimes necessary to differentiate between Budd-Chiari syndrome and other causes of hepatomegaly and ascites, such as galactosemia or Reye's syndrome.

Prognosis
Several studies have attempted to predict the survival of patients with Budd-Chiari syndrome. In general, nearly 2/3 of patients with Budd-Chiari survive 10 years. [4] Important negative prognostic indicators include ascites, encephalopathy, elevated Child-Pugh scores, elevated prothrombin time, and altered serum levels of various substances (sodium, creatinine, albumin, and bilirubin). Survival is also highly dependent on the underlying cause of the Budd-Chiari syndrome. For example, patients with myeloproliferative disorders may progress to acute leukemia despite treatment for Budd-Chiari syndrome.

Treatment
A minority of patients can be treated medically with sodium restriction, diuretics to control ascites, anticoagulants such as heparin and warfarin, and general symptomatic management. The majority of patients require further intervention. Milder forms of Budd-Chiari may be treated with surgical shunts to divert blood flow around the obstruction or the liver itself. Shunts must be placed early after diagnosis for best results. [4] The transjugular intrahepatic portosystemic shunt (TIPS) is similar to a surgical shunt. It accomplishes the same goal but has a lower procedure-related mortality, which has lead to a growth in its popularity. Patients with stenosis or vena caval obstruction may benefit from angioplasty. [5] Limited studies on thrombolysis with direct infusion of urokinase and tissue plasminogen activator (tPA) into the obstructed vein have shown moderate success in treating Budd-Chiari syndrome; however, it is not routinely attempted.

Liver transplantation is an effective treatment for Budd-Chiari. It is generally reserved for patients with fulminant hepatic failure, failure of shunts, or progression of cirrhosis that reduces the life expectancy to 1 year. [6] Long-term survival after transplantation ranges from 69-87%. The most common complications of transplant include rejection, arterial or venous thromboses, and bleeding due to anticoagulation. Up to 10% of patients may have a recurrence of Budd-Chiari syndrome after the transplant.

External links
Budd-Chiari Syndrome - eMedicine.com
Budd-Chiari Syndrome - Merck

Notes
^ Patel RK, Lea NC, Heneghan MA, Westwood NB, Milojkovic D, Thanigaikumar M, Yallop D, Arya R, Pagliuca A, Gaken J, Wendon J, Heaton ND, Mufti GJ. Prevalence of the activating JAK2 tyrosine kinase mutation V617F in the Budd-Chiari syndrome. Gastroenterology. 2006 Jun;130(7):2031-8.
^ Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995 Nov 9;333(19):1253-8.
^ Socie G, Mary JY, de Gramont A, Rio B, Leporrier M, Rose C, Heudier P, Rochant H, Cahn JY, Gluckman E. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet. 1996 Aug 31;348(9027):573-7.
^ a b Murad SD, Valla DC, de Groen PC, Zeitoun G, Hopmans JA, Haagsma EB, van Hoek B, Hansen BE, Rosendaal FR, Janssen HL Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome. Hepatology. 2004 Feb;39(2):500-8.
^ Fisher NC, McCafferty I, Dolapci M, Wali M, Buckels JA, Olliff SP, Elias E. Managing Budd-Chiari syndrome: a retrospective review of percutaneous hepatic vein angioplasty and surgical shunting. Gut. 1999 Apr;44(4):568-74.
^ Orloff MJ, Daily PO, Orloff SL, Girard B, Orloff MS. A 27-year experience with surgical treatment of Budd-Chiari syndrome. Ann Surg. 2000 Sep;232(3):340-52.

To view information on another disease click on Digestive Diseases Library

Primary Sclerosing Cholangitis (PSC)

2007-06-15T21:09:00.000-07:00

Primary Sclerosing Cholangitis (PSC)
..
The Liver
The liver is the largest organ in the body. It is found high in the right upper abdomen, behind the ribs. It is a very complex organ and has many functions. They include:

Storing energy in the form of sugar (glucose)
Storing vitamins, iron, and other minerals
Making proteins, including blood clotting factors, to keep the body healthy and help it grow
Processing worn out red blood cells
Making bile which is needed for food digestion
Metabolizing or breaking down many medications and alcohol
Killing germs that enter the body through the intestine

The liver cells excrete bile into tiny tubes within the liver called bile ducts. These tubes come together like the tiny veins on a leaf. They drain the bile into the common bile duct, a larger single tube leading into the intestine. There the bile aids digestion and gives stool its brown color. As you can see, the liver is a very important organ.

What is Primary Sclerosing Cholangitis (PSC)?
Primary sclerosing Cholangitis is a disease primarily of the bile ducts, both inside and outside the liver. The ducts of the gallbladder and pancreas may also be involved. The walls of the bile ducts become inflamed (Cholangitis). The inflammation causes scarring and hardening (fibrosis) that narrows the bile ducts. Because bile cannot drain properly through the ducts, it accumulates in the liver causing damage to liver cells. Eventually, so much bile is accumulated, it seeps into the bloodstream. Finally, with long term cell damage, the liver develops cirrhosis (hardening or fibrosis) and it can no longer function properly.

Cause
The exact cause of PSC is unknown. However, the most likely cause appears to be changes in the way the immune system works. When the immune system is working properly, it protects the body from infections caused by foreign invaders like bacteria and viruses. Sometimes, however, it recognizes certain body parts or organs as foreign. The body then goes to war against itself, damaging the body part it thinks is foreign.

PSC often starts between the ages of 30 and 50, and it occurs most often in men. It was once considered a rare disease, but recent studies show it is more common than previously thought. About 70% of the patients with PSC also have an inflammatory bowel disease, especially ulcerative colitis in which the colon becomes inflamed and ulcerated. Medical experts believe genetic factors may link PSC and ulcerative colitis.

Symptoms
PSC usually progresses very slowly. Early on there may be no symptoms. Usually the only findings are abnormal laboratory test results. For example, a liver enzyme called alkaline phosphatase may be above normal ranges in the blood. When symptoms do develop, they may be intermittent or persistent. Gradually, they may worsen. The symptoms are caused by two things: the bile is not being drained properly through the bile ducts, and the liver is not doing its job. Bile ducts can become infected, causing chills, fever and upper abdominal tenderness. Itching may occur when bile seeps into the bloodstream. As the disease progresses, chronic fatigue, loss of appetite, weight loss and jaundice (yellowing of skin and eyes) may occur. Finally, in the advanced stages of cirrhosis, extensive swelling can occur in the abdomen and feet. Liver failure may take many years to develop.

Diagnosis
The physician may suspect PSC from the patient's medical history, especially a history of inflammatory bowel disease, and from abnormal blood tests. The diagnosis is usually made by cholangiography, an x-ray called ERCP that involves injecting dye into the bile ducts. The test is performed under sedation. A lighted, flexible endoscope is inserted through the mouth, stomach and then into the small intestine. A thin tube is place through the scope into the bile ducts, and the dye is injected to highlight the bile ducts on the x-ray. If there is narrowing of the bile ducts, the diagnosis of PSC is confirmed.

As the disease progresses, a liver biopsy is usually needed to determine how much damage has occurred. Under local anesthesia, a slender needle is inserted through the right lower chest to extract a small piece of liver for microscopic analysis.

Treatment
At the present time there is no cure for PSC, but effective treatment is available. There are a number of ways to treat symptoms and the various stages of the disease. Itching, from too much bile in the bloodstream, can be controlled with drugs such as Questran. Bile is usually reabsorbed into the bloodstream from the large intestine, and goes back to the liver to be reused. Questran binds up bile in the intestine, allowing it to be eliminated with the stool instead. This helps to reduce the build-up of bile in the body. Actigall is a drug that favorably changes the make-up of bile in the liver. This, in turn, seems to reduce the amount of liver damage that occurs. Results of early medical studies seem to indicate that this drug may increase survival. Sometimes the bile ducts become infected and must be treated with antibiotics. If ulcerative colitis is also present, it is treated with the appropriate medicines. Swelling of the abdomen and feet, due to fluid retention from cirrhosis, can be treated with a salt-restricted diet and diuretics (fluid pills). Presently, there are exciting studies being done to test the effectiveness of other drugs on the body's immune system, since this seems to be the underlying problem.

In some cases, endoscopic or surgical procedures may be used to open major blockages in bile ducts. Through an endoscope, the physician places a tiny tube with a balloon on the end into the narrowed bile duct. The balloon is inflated to expand the duct so bile can flow through it once again. Sometimes stents (plastic tubing) can be placed in the narrowed ducts to keep them open. Often PSC progresses to a point where liver transplantation must be considered.

Liver Transplantation
Liver transplantation is now an accepted form of treatment for chronic, severe liver disease. Advances in surgical techniques and the use of new drugs to suppress rejection have improved the success rate of transplantation. The outcome for PSC patients is excellent. Because of the disease's slow progress, it is possible to plan elective transplant surgery. Survival rates at transplant centers are well over 90 percent, with a good quality of life after recovery.

Summary
Primary sclerosing cholangitis is a slow, progressive disease. Once diagnosed, treatment is directed at managing symptoms and opening narrowed bile ducts. A great deal of research is underway aimed at preventing damage to the bile ducts, improving symptoms and prolonging life. By working closely with the physician, there is good reason to expect a favorable long-term outlook.
..

To View another Digestive Disease, Click on Digestive Diseases Library!
..
Digestive Diseases Library

Hepatocellular carcinoma

2007-06-14T11:00:00.000-07:00

Hepatocellular carcinoma
From Wikipedia, the free encyclopedia

Classification & external resources ICD-10 C22.0
ICD-9 155
ICD-O: 8170/3
MedlinePlus 000280
eMedicine med/787

Hepatocellular carcinoma (HCC, also called hepatoma) is a primary malignancy (cancer) of the liver. Most cases of HCC are secondary to either a viral hepatitide infection (hepatitis B or C) or cirrhosis (alcoholism being the most common cause of hepatic cirrhosis).[1] In countries where hepatitis is not endemic, most malignant cancers in the liver are not primary HCC but metastasis (spread) of cancer from elsewhere in the body, e.g. the colon. Treatment options of HCC and prognosis are dependent on many factors but especially on tumor size and staging.

Outside of the West, the commonly accepted prognosis is a median survival of 3 months from diagnosis[citation needed]. This is partially due to late presentation with large tumours, but also the lack of medical expertise and facilities. This is a rare tumor in the United States.

Contents [hide]
1 Epidemiology
1.1 Non-Western Countries
1.2 North America and Western Europe
2 Pathogenesis
3 Diagnosis, screening and monitoring
4 Pathology
5 Staging and prognosis
6 Treatment
7 Awareness
8 Future directions
9 References
10 External links

Epidemiology
HCC is the 5th most common tumor worldwide.[citation needed] The epidemiology of HCC exhibits two main patterns, one in North America and Western Europe and another in non-Western countries, such as sub-Saharan Africa, central and Southeast Asia, and the Amazon basin. Males are affected more than females usually and its common in the 3rd to 5th decade of life[1] Hepatocellular carcinoma causes 662,000 deaths worldwide per year.[2]

Non-Western Countries
In some parts of the world—such as sub-Saharan Africa and Southeast Asia—HCC is the most common cancer, generally affecting men more than women, and with an age of onset between late teens and 30s. This variability is in part due to the different patterns of hepatitis B transmission in different populations - infection at or around birth predispose to earlier cancers than if people are infected later. The time between hepatitis B infection and development into HCC can be years even decades, but from diagnosis of HCC to death the average survival period is only 5.9 months, according to one Chinese study during the 1970-80s, or 3 months (median survival time) in Sub-Saharan Africa according to Manson's textbook of tropical diseases. HCC is one of the deadliest cancers in China. Food infected with Aspergillus flavus (especially peanuts and corns stored during prolonged wet seasons) which produces aflatoxin, poses another risk factor for HCC.

North America and Western Europe
Most malignant tumors of the liver discovered in Western patients are metastases (spread) from tumors elsewhere.[1] In the West, HCC is generally seen as rare cancer, normally of those with pre-existing liver disease. It is often detected by ultrasound screening, and so can be discovered by health-care facilities much earlier than in developing regions such as Sub-Saharan Africa.

Acute and chronic hepatic porphyrias (acute intermittent porphyria, porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria) and tyrosinemia type I are risk factors for hepatocellular carcinoma. The diagnosis of an acute hepatic porphyria (AIP, HCP, VP) should be sought in patients with hepatocellular carcinoma without typical risk factors of hepatitis B or C, alcoholic liver cirrhosis or hemochromatosis. Both active and latent genetic carriers of acute hepatic porphyrias are at risk for this cancer, although latent genetic carriers have developed the cancer at a later age than those with classic symptoms. Patients with acute hepatic porphyrias should be monitored for hepatocellular carcinoma.

Pathogenesis
Main article: Carcinogenesis
Hepatocellular carcinoma like any other cancer, develops when there is a mutation to the cellular machinery that causes the cell to replicate at a higher rate and/or results in the cell avoiding apoptosis. In particular, chronic infections of Hepatitis B and/or C can aid the development of hepatocellular carcinoma by repeatedly causing the body's own immune system to attack the liver cells, some of which are infected by the virus, others merely bystanders. This constant cycle of damage, followed by repair can lead to mistakes during repair which in turn lead to carcinogenesis. Alternatively, repeated consumption of large amounts ethanol can have a similar effect. The toxin aflatoxin from certain Aspergillus species of fungus is a carcinogen and aids carcinogenesis of hepatocellular cancer by building up in the liver. The combined high prevalence of rates of aflaxtoxin and hepatitis B in countries like China and western Africa has lead to relatively high rates of heptatocellular carcinoma in these regions. Other viral hepatitides such as hepatitis A have no potential to become a chronic infection and thus are not related to hepatocellular carcinoma.

Diagnosis, screening and monitoring
Hepatocellular carcinoma (HCC) most commonly appears in a patient with chronic viral hepatitis (hepatitis B or hepatitis C, 20%) or with cirrhosis (about 80%). These patients commonly undergo surveillance with ultrasound due to the cost-effectiveness.

In patients with a higher suspicion of HCC (such as rising alpha-fetoprotein and des-gamma carboxyprothrombin levels), the best method of diagnosis involves a CT scan of the abdomen using intravenous contrast agent and three-phase scanning (before contrast administration, immediately after contrast administration, and again after a delay) to increase the ability of the radiologist to detect small or subtle tumors. It is important to optimize the parameters of the CT examination, because the underlying liver disease that most HCC patients have can make the findings more difficult to appreciate.

On CT, HCC can have three distinct patterns of growth:

A single large tumor
Multiple tumors
Poorly defined tumor with an infiltrative growth pattern

The key characteristics on CT are hypervascularity in the arterial phase scans, washout or de-enhancement in the portal and delayed phase studies, a pseudocapsule and a mosaic pattern. Both calcifications and intralesional fat may be appreciated.

In patients who have a contrast agent allergy or poor renal function, an MRI scan of the abdomen is a more costly but effective substitute.

Once imaged, diagnosis is confirmed by percutaneous biopsy and histopathologic analysis.

Pathology

Macroscopically, liver cancer appears as a nodular or infiltrative tumor. The nodular type may be solitary (large mass) or multiple (when developed as a complication of cirrhosis). Tumor nodules are round to oval, grey or green (if the tumor produces bile), well circumscribed but not encapsulated. The diffuse type is poorly circumscribed and infiltrates the portal veins, or the hepatic veins (rarely).
Microscopically, there are four architectural and cytological types (patterns) of hepatocellular carcinoma:

fibrolamellar,
pseudoglandular (adenoid),
pleomorphic (giant cell) and
clear cell.

In well differentiated forms, tumor cells resemble hepatocytes, form trabeculae, cords and nests, and may contain bile pigment in cytoplasm. In poorly differentiated forms, malignant epithelial cells are discohesive, pleomorphic, anaplastic, giant. The tumor has a scant stroma and central necrosis because of the poor vascularization.1

Staging and prognosis
Important features that guide treatment include: -

size
spread (stage)
involvement of liver vessels
presence of a tumor capsule
presence of extrahepatic metastases
presence of daughter nodules
vascularity of the tumor

MRI is the best imaging method to detect the presence of a tumor capsule.

Treatment

Liver transplantation to replace the liver with a cadaver liver or a live donor lobe. Historically low survival rates (20%-36%) recent improvement (61.1%; 1996-2001), likely related to adoption of Milan criteria at US transplantation centers. If the tumor disease has metastasized, the immuno-suppressant post-transplant drugs decrease the chance of survival. NIH
Surgical resection to remove a tumor to treat small or slow-growing tumors if they are diagnosed early. This treatment offers the best prognosis for long-term survival but unfortunately is possible in only 10-15% of cases. Resection in cirrhotic patients carries high morbidity and mortality. Medicinenet
Percutaneous ethanol injection (PEI) well tolerated, high RR in small (< color="#ffffcc">..
Transcatheter arterial chemoembolization (TACE) is usually perform in the treatment of large tumors (larger than 3 cm and less than 4 cm in diameter) most frequently performed by intraarterially injecting an infusion of antineoplastic agents mixed with iodized oil (such as Lipiodol). As of 2005, multiple trials show objective tumor responses and slowed tumor progression but questionable survival benefit compared to supportive care; greatest benefit seen in patients with preserved liver function, absence of vascular invasion, and smallest tumors.
Radiofrequency ablation (RFA) uses high frequency radio-waves to ablate the tumour.
Intra-arterial iodine-131–lipiodol administration Efficacy demonstrated in unresectable patients, those with portal vein thrombus. This treatment is also used as adjuvant therapy in resected patients (Lau at et, 1999). It is believed to raise the 3-year survival rate from 46 to 86%. This adjuvant therapy is in phase III clinical trials in Singapore and is available as a standard medical treatment to qualified patients in Hong Kong.
Combined PEI and TACE can be used for tumors larger than 4 cm in diameter, although some Italian groups have had success with larger tumours using TACE alone.
High intensity focused ultrasound (HIFU) (not to be confused with normal diagnostic ultrasound) is a new technique which uses much more powerful ultrasound to treat the tumour. Still at a very experimental stage. Most of the work has been done in China. Some early work is being done in Oxford and London in the UK.
Hormonal therapy Antiestrogen therapy with tamoxifen studied in several trials, mixed results across studies, but generally considered ineffective Octreotide (somatostatin analogue) showed 13-month MS v 4-month MS in untreated patients in a small randomized study; results not reproduced.
Chemotherapy adjuvant: No randomized trials showing benefit of neoadjuvant or adjuvant systemic therapy in HCC; single trial showed decrease in new tumors in patients receiving oral synthetic retinoid for 12 months after resection/ablation; results not reproduced. Clinical trials have varying results.[3]
Palliative: Regimens that included doxorubicin, cisplatin, fluorouracil, interferon, epirubicin, or taxol, as single agents or in combination, have not shown any survival benefit (RR, 0%-25%); a few isolated major responses allowed patients to undergo partial hepatectomy; no published results from any randomized trial of systemic chemotherapy.
Cryosurgery: Cryosurgery is a new technique that can destroy tumors in a variety of sites (brain, breast, kidney, prostate, liver). Cryosurgery is the destruction of abnormal tissue using sub-zero temperatures. The tumor is not removed and the destroyed cancer is left to be reabsorbed by the body. Initial results in properly selected patients with unresectable liver tumors are equivalent to those of resection. Cryosurgery involves the placement of a stainless steel probe into the center of the tumor. Liquid nitrogen is circulated through the end of this device. The tumor and a half inch margin of normal liver are frozen to -190°C for 15 minutes, which is lethal to all tissues. The area is thawed for 10 minutes and then re-frozen to -190°C for another 15 minutes. After the tumor has thawed, the probe is removed, bleeding is controlled, and the procedure is complete. The patient will spend the first post-operative night in the intensive care unit and typically is discharged in 3 - 5 days. Proper selection of patients and attention to detail in performing the cryosurgical procedure are mandatory in order to achieve good results and outcomes. Frequently, cryosurgery is used in conjunction with liver resection as some of the tumors are removed while others are treated with cryosurgery. Patients may also have insertion of a hepatic intra-arterial artery catheter for post-operative chemotherapy. As with liver resection, your surgeon should have experience with cryosurgical techniques in order to provide the best treatment possible.
Interventional radiology

Abbreviations:

HCC, hepatocellular carcinoma;
TACE, transarterial embolization/chemoembolization;
PFS, progression-free survival;
PS, performance status;
HBV, hepatitis B virus;
PEI, percutaneous ethanol injection;
RR, response rate;
MS, median survival

To view information on another Digestive Disease, Click on Digestive Diseases Library!

Digestive Diseases Library

Liver Diseases

2006-11-08T03:12:00.000-08:00

Liver Fatty Metamorphosis

This liver is slightly enlarged and has a pale yellow appearance, seen both on the capsule and cut surface. This uniform change is consistent with fatty metamorphosis (fatty change). (LIVER004)

This is the histologic appearance of hepatic fatty change. The lipid accumulates in the hepatocytes as vacuoles. These vacuoles have a clear appearance with H&E staining. The most common cause of fatty change in developed nations is alcoholism. In developing nations, kwashiorkor in children is another cause. Diabetes mellitus, obesity, and severe gastrointestinal malabsorption are additional causes.(LIVER006)

Here are seen the lipid vacuoles within hepatocytes. The lipid accumulates when lipoprotein transport is disrupted and/or when fatty acids accumulate. Alcohol, the most common cause, is a hepatotoxin that interferes with mitochondrial and microsomal function in hepatocytes, leading to an accumulation of lipid. (LIVER007)

Cirrhosis

Ongoing liver damage with liver cell necrosis followed by fibrosis and hepatocyte regeneration results in cirrhosis. This produces a nodular, firm liver. The nodules seen here are larger than 3 mm and, hence, this is an example of "macronodular" cirrhosis. (LIVER008)

Here is another example of macronodular cirrhosis. Viral hepatitis (B or C) is the most common cause for macronodular cirrhosis. Wilson's disease and alpha-1-antitrypsin deficiency also can produce a macronodular cirrhosis. (LIVER009)

This is an example of a micronodular cirrhosis. The regenerative nodules are quite small, averaging less than 3 mm in size. The most common cause for this is chronic alcoholism. The process of cirrhosis develops over many years. (LIVER011)

Here is another example of micronodular cirrhosis. Note that the liver also has a yellowish hue, indicating that fatty change (also caused by alcoholism) is present. (LIVER012)

A close-up view of a micronodular cirrhosis in a liver with fatty change demonstrates the small, yellow nodules. Micronodular cirrhosis may also be seen with Wilson's disease, primary biliary cirrhosis, and hemochromatosis. (LIVER013)

Microscopically with cirrhosis, the regenerative nodules of hepatocytes are surrounded by fibrous connective tissue that bridges between portal tracts. Within this collagenous tissue are scattered lymphocytes as well as a proliferation of bile ducts. (LIVER014)

Micronodular cirrhosis is seen along with moderate fatty change. Note the regenerative nodule surrounded by fibrous connective tissue extending between portal regions. (LIVER063)

At high magnification can be seen globular red hyaline material within hepatocytes. This is Mallory's hyaline, also known as "alcoholic" hyaline because it is most often seen in conjunction with chronic alcoholism. The globules are aggregates of intermediate filaments in the cytoplasm resulting from hepatocyte injury. (LIVER015)

Mallory's hyaline is seen here, but there are also neutrophils, necrosis of hepatocytes, collagen deposition, and fatty change. These findings are typical for acute alcoholic hepatitis. Such inflammation can occur in a person with a history of alcoholism who goes on a drinking "binge" and consumes large quantities of alcohol over a short time. (LIVER145)

Portal hypertension results from the abnormal blood flow pattern in liver created by cirrhosis. The increased pressure is transmitted to collateral venous channels. Sometimes these venous collaterals are dilated. Seen here is "caput medusae" which consists of dilated veins seen on the abdomen of a patient with cirrhosis of the liver. (LIVER061)

A much more serious problem produced by portal hypertension results when submucosal veins in the esophagus become dilated. These are known as esophageal varices. Varices are seen here in the lower esophagus as linear blue dilated veins. There is hemorrhage around one of them. Such varices are easily eroded, leading to massive gastrointestinal hemorrhage. (GI127)

One of the most common findings with portal hypertension is splenomegaly, as seen here. The spleen is enlarged from the normal 300 grams or less to between 500 and 1000 gm. Another finding here is the irregular pale tan plaques of collagen over the purple capsule known as "sugar icing" or "hyaline perisplenitis" which follows the splenomegaly and/or multiple episodes of peritonitis that are a common accompaniment to cirrhosis of the liver. (HEME054)

The hepatocytes and Kupffer cells here are full of granular brown deposits of hemosiderin from accumulation of excess iron in the liver. The term "hemosiderosis" is used to denote a relatively benign accumulation of iron. The term "hemochromatosis" is used when organ dysfunction occurs. The iron accumulation may lead to a micronodular cirrhosis (so called "pigment" cirrhosis). (LIVER017)

A Prussian blue iron stain demonstrates the blue granules of hemosiderin in hepatocytes and Kupffer cells. Hemochromatosis can be primary (the cause is probably an autosomal recessive genetic disease) or secondary (excess iron intake or absorption, liver disease, or numerous transfusions). Hemochromatosis leads to bronze pigmentation of skin, diabetes mellitus (from pancreatic involvement), and cardiac arrhythmias (from myocardial involvement). (LIVER018)

The dark brown color of the liver, as well as the pancreas (bottom center) and lymph nodes (bottom right) on sectioning is due to extensive iron deposition in a middle-aged man with hereditary hemochromatosis (HHC). HHC results from a mutation involving the hemochromatosis gene (HFE) that leads to increased iron absorption from the gut. The prevalence is between 1:200 and 1:500 persons in the U.S. About 1 in 10 persons of northern European ancestry carries the abnormal recessive HFE gene, and most of these are the C282Y mutation. (LIVER074)

The Prussian blue iron stain reveals extensive hepatic hemosiderin deposition microscopically in this case of hereditary hemochromatosis (HH). Note that there is also cirrhosis. Excessive iron deposition in persons with HH can affect many organs, but heart (congestive failure), pancreas (diabetes mellitus), liver (cirrhosis and hepatic failure), and joints (arthritis) are the most severely affected. (LIVER076)

The pale golden brown finely granular pigment seen here in nearly all hepatocytes is lipchrome (lipofuscin). One such deposit within a hepatocyte is marked by the arrow. This is a "wear and tear" pigment from the accumulation of autophagolysosomes over time. This pigment is of no real pathologic importance. (LIVER019)

The yellowish-green accumulations of pigment seen here are bile. Most often this is due to extrahepatic biliary tract obstruction. However, bile may also accumulate in liver (called cholestasis) when there is hepatocyte injury. (LIVER020)

Here is an example of intrahepatic obstruction with a small stone in an intrahepatic bile duct. This could produce a localized cholestasis, but the serum bilirubin would not be increased, because there is plenty of non-obstructed liver to clear the bilirubin from the blood. However, the serum alkaline phosphatase is increased with biliary tract obstruction at any level. (LIVER022)

At the upper right is a well-circumscribed neoplasm that is arising in liver. This is an hepatic adenoma. (LIVER023)

The cut surface of the liver reveals the hepatic adenoma. Note how well circumscribed it is. The remaining liver is a pale yellow brown because of fatty change from chronic alcoholism. (LIVER058)

Normal liver tissue with a portal tract is seen on the left. The hepatic adenoma is on the right and is composed of cells that closely resemble normal hepatocytes, but the neoplastic liver tissue is disorganized hepatocyte cords and does not contain a normal lobular architecture. (LIVER025)

Here is an hepatocellular carcinoma. Such liver cancers arise in the setting of cirrhosis. Worldwide, viral hepatitis is the most common cause, but in the U.S., chronic alcoholism is the most common cause. The neoplasm is large and bulky and has a greenish cast because it contains bile. To the right of the main mass are smaller satellite nodules. (LIVER026)

The satellite nodules of this hepatocellular carcinoma represent either intrahepatic spread of the tumor or multicentric origin of the tumor. (LIVER027)

Here is another hepatocellular carcinoma with a greenish yellow hue. One clue to the presence of such a neoplasm is an elevated serum alpha-fetoprotein. Such masses may also focally obstruct the biliary tract and lead to an elevated alkaline phosphatase. (LIVER028)

The malignant cells of this hepatocellular carcinoma (seen mostly on the right) are well differentiated and interdigitate with normal, larger hepatocytes (seen mostly at the left). (LIVER029)

Note that this hepatocellular carcinoma is composed of liver cords that are much wider than the normal liver plate that is two cells thick. There is no discernable normal lobular architecture, though vascular structures are present. (LIVER030)

The carcinoma at the left has a glandular appearance that is most consistent with a cholangiocarcinoma. A liver cancer may have both hepatocellular as well as cholangiolar differentiation. Cholangiocarcinomas do not make bile, but the cells do make mucin, and they can be almost impossible to distinguish from metastatic adenocarcinoma on biopsy or fine needle aspirate. (LIVER032)

Note the numerous mass lesions that are of variable size. Some of the larger ones demonstrate central necrosis. The masses are metastases to the liver. The obstruction from such masses generally elevates alkaline phosphatase, but not all bile ducts are obstructed, so hyperbilirubinemia is typically not present. Also, the transaminases are usually not greatly elevated. (LIVER059)

Here are liver metastases from an adenocarcinoma primary in the colon, one of the most common primary sites for metastatic adenocarcinoma to the liver. (LIVER034)

Microscopically, metastatic infiltrating ductal carcinoma from breast is seen on the right, with normal liver parenchyma on the left. (LIVER035)

Grossly, there are areas of necrosis and collapse of liver lobules seen here as ill-defined areas that are pale yellow. Such necrosis occurs with hepatitis. (LIVER036)

The necrosis and lobular collapse is seen here as areas of hemorrhage and irregular furrows and granularity on the cut surface of the liver. (LIVER037)

Viral hepatitis leads to liver cell destruction. A mononuclear inflammatory cell infiltrate extends from portal areas and disrupts the limiting plate of hepatocytes which are undergoing necrosis, the so-called "piecemeal" necrosis of chronic active hepatitis. In this case, the hepatitis B surface antigen (HbsAg) and hepatitis B core antibody (HbcAb) were positive. (LIVER038)

Individual hepatocytes are affected by viral hepatitis. Viral hepatitis A rarely leads to signficant necrosis, but hepatitis B can result in a fulminant hepatitis with extensive necrosis. A large pink cell undergoing "ballooning degeneration" is seen below the right arrow. At a later stage, a dying hepatocyte is seen shrinking down to form an eosinophilic "councilman body" below the arrow on the left.(LIVER039)

This is a case of viral hepatitis C, which in half of cases leads to chronic liver disease. The extent of chronic hepatitis can be graded by the degree of activity (necrosis and inflammation) and staged by the degree of fibrosis. In this case, necrosis and inflammation are prominent, and there is some steatosis as well. Regardless of the grade or stage, the etiology of the hepatitis must be sought, for the treatment may depend upon knowing the cause, and chronic liver diseases of different etiologies may appear microscopically and grossly similar. (LIVER082)

This is a case of viral hepatitis C which is at a high stage with extensive fibrosis and progression to macronodular cirrhosis, as evidenced by the large regenerative nodule at the center right. The screening laboratory test for this form of viral hepatitis is the hepatitis C antibody test. Hepatitis C accounts for most (but not all) cases formerly called "non-A, non-B hepatitis". In addition to this serologic test PCR and genotyping can be performed.

Nucleic acid sequencing identifies of six common HCV types (1a,b-5) which have different clinical courses and responsiveness to alpha interferon therapy. Infection with HCV type 1b or 4 leads to more severe liver disease, faster progression to chronic hepatitis, and less responsiveness to interferon therapy. Type 1a, 2, 3, and 5 infections have a more favorable prognosis. Type 2 and 3 infections may be treated with shorter therapeutic regimens. (LIVER079)

This trichrome stain demonstrates the collapse of the liver parenchyma with viral hepatitis. The blue-staining areas are the connective tissue of many portal tracts that have collapsed together. (LIVER040)

Here is an example of a "nutmeg" liver seen with chronic passive congestion of the liver. Note the dark red congested regions that represent accumulation of RBC's in centrilobular regions. (LIVER041)

Microscopically, the nutmeg pattern results from congestion around the central veins, as seen here. This is usually due to a "right sided" heart failure. (LIVER042)

If the passive congestion is pronounced, then there can be centrilobular necrosis, because the oxygenation in zone 3 of the hepatic lobule is not great. The light brown pigment seen here in the necrotic hepatocytes around the central vein is lipochrome. (LIVER043)

If chronic hepatic passive congestion continues for a long time, a condition called "cardiac cirrhosis" may develop in which there is fibrosis bridging between central zonal regions, as shown below, so that the portal tracts appear to be in the center of the reorganized lobule. This process is best termed "cardiac sclerosis" because, unlike a true cirrhosis, there is minimal nodular regeneration. (LIVER147)

At the right are seen several infarcts of the liver. Infarcts are uncommon because the liver has two blood supplies-portal venous system and hepatic arterial system. The infarcts seen here are yellow, with geographic borders and surrounding hyperemia. About half of liver infarcts occur with arteritis, and the remaining half are due to a variety of causes. (LIVER044)

There is extensive hepatocyte necrosis seen here in a case of acetaminophen overdose. The hepatocytes at the right are dead, and those at the left are dying. This pattern can be seen with a variety of hepatotoxins. Acute liver failure leads to hepatic encephalopathy. (LIVER045)

Numerous cysts appear in this liver from a patient with dominant polycystic kidney disease (DPKD). Such cases occur in adults and manifest with renal failure beginning in middle age. Sometimes the liver (as seen here) can be affected as well by polycystic change. Less commonly the pancreas is involved. These patients with DPKD can also have berry aneurysms in the cerebral arteries. (LIVER047)

This is a case of primary biliary cirrhosis, a rare autoimmune disease (mostly of middle-aged women) that is characterized by destruction of bile ductules within the triads of the liver. Antimitochondrial antibody can be detected in serum. Seen here in a portal tract is an intense chronic inflammatory infiltrate with loss of bile ductules. Micronodular cirrhosis ensues. (LIVER048)

This immunofluorescence pattern is positive for anti-mitochondrial antibody (AMA) which has an association with primary biliary cirrhosis. The tissue substrate for this test is renal parenchyma, and the tubule cells have lots of mitochondria, which stain bright green. (IMM013)

This 3 month old child died with extrahepatic biliary atresia, a disease in which there is inflammation with stricture of hepatic or common bile ducts. This leads to marked cholestasis with intrahepatic bile duct proliferation, fibrosis, and cirrhosis. This liver was rock hard. The dark green color comes from formalin acting on bile pigments in the liver from marked cholestasis, turning bilrubin to biliverdin. (LIVER049)

Microscopically, extrahepatic biliary atresia leads to this appearance in the liver, with numerous brown-green bile plugs, bile duct proliferation (seen at lower center), and extensive fibrosis. If a large enough bile duct can be found to anastomose and provide bile drainage, then surgery can be curative. (LIVER050)

Seen here is the major differential diagnosis of biliary atresia: this is neonatal giant cell hepatitis. There is lobular disarray with focal hepatocyte necrosis, giant cell transformation, lymphocytic infiltration, Kupffer cell hyperplasia, and cholestasis (not seen here). Neonatal hepatitis may be idiopathic or of viral origin. Many neonates recover in a couple of months. (LIVER051)

The periportal red hyaline globules seen here with periodic acid-Schiff (PAS) stain are characteristic for alpha-1-antitrypsin (AAT) deficiency. More persons with AAT deficiency are likely to develop chronic obstructive pulmonary disease with panlobular emphysema. The globules are collections of alpha-1-antitrypsin not being excreted from hepatocytes. This may eventually lead to chronic hepatitis and cirrhosis. Liver disease is more likely to occur in children with AAT deficiency, while lung disease occurs in adults.

The gene for AAT is on chromosome 14. There are over 100 known mutations. The normal allele is designated PiM, and the two most common abnormal alleles are designated PiS and PiZ. Heterozygotes PiMS and PiMZ may on occasion develop pulmonary and/or liver disease, but less often severe. The homozygotes PiSS and PiZZ, and the heterozygote PiSZ, are more likely to develop significant COPD and/or liver disease. The persons most likely to develop severe AAT deficiency and its complications have PiZZ. About 1 in 10 persons of European ancestry has one of the 5 abnormal phenotypes (the normal is PiMM. (LIVER052)

This trichrome stain of the liver demonstrates extensive portal tract fibrosis with sclerosing cholangitis. The hepatocytes are normal. (LIVER053)

Microscopically, this bile duct in a case of sclerosing cholangitis is surrounded by marked collagenous connective tissue deposition. (LIVER054)

To view information on another disease click on Digestive Diseases Library

Liver Function Tests

2006-10-20T11:45:00.000-07:00

Liver Function Tests
From Wikipedia, the free encyclopedia

Liver function tests (LFTs or LFs), which include liver enzymes, are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. Most liver diseases cause only mild symptoms initially, but it is vital that these diseases be detected early. Hepatic (liver) involvement in some diseases can be of crucial importance. This testing is performed by a medical technologist on a patient's serum or plasma sample obtained by phlebotomy. Some tests are associated with functionality (eg. albumin); some with cellular integrity (eg. transaminase) and some with conditions linked to the biliary tract (gamma-glutamyl transferase and alkaline phosphatase).

Standard liver panel
________________________________________________________
Measurement......Significance..........................Reference range
________________________________________________________
Alanine trans-.....Alanine transaminase.............5 to 40 IU/L
aminase (ALT)....(ALT), also called
.........................Serum Glutamic Pyru-
.........................vate Transaminase(SGPT)
.........................or Alanine aminotrans-
.........................ferase (ALAT) is an
.........................enzyme present in Hepato-
.........................cytes(liver cells). When
.........................a cell is damaged, it
.........................leaks this enzyme into
.........................the blood, where it is
.........................measured. ALT rises
.........................dramatically in acute
.........................liver damage, such as
.........................Viral hepatitis or Para-
.........................cetamol toxicity(acetamin-
.........................ophen) overdose. Elevations
.........................are often measured in multi-
.........................ples of the upper limit of
.........................normal (ULN).

Measurement......Significance..........................Reference range
________________________________________________________
Aspartate tran-...also called Serum...................10 to 40 IU/L
saminase (AST)..Glutamic Oxaloatate
.........................Transaminase(SGOT) or aspar-
.........................tate aminotransferase.(ASAT)
.........................is similar to ALT in that it
.........................is another enzyme associated
.........................with liver parenchymal cells.
.........................It is raised in acute liver
.........................damage, but is also present in
.........................red cells, and cardiac and skel-
.........................etal muscle and is therefore not
.........................specific to the liver. The ratio
.........................of AST to ALT is sometimes useful
.........................in differentiating between causes
.........................of liver damage.

Measurement......Significance..........................Reference range
________________________________________________________
Alkaline phos-....is an enzyme in the cells........30 to 120 IU/L
phatase(ALP).....lining the biliary ducts
.........................of the liver. ALP levels in plasma
.........................will rise with large bile duct
.........................obstruction, intrahepatic chole-
.........................stasis or infiltrative diseases of
.........................the liver. ALP is also present in
.........................bone and placental tissue, so it is
.........................higher in growing children (as their
.........................bones are being remodelled) and
.........................elderly patients with Paget's disease

Measurement......Significance..........................Reference range
________________________________________________________
Total bilirubin......Bilirubin is a breakdown...........2 - 14 μmol/L
(TBIL).................product of heme(a part of haemo-
.........................globin in red blood cells). The
.........................liver is responsible for clearing
.........................the blood of bilirubin. It does this
.........................by the following mechanism: bilirubin
.........................is taken up into hepatocytes, conju-
.........................gated (modified to make it water-
.........................soluble), and secreted into the bile,
.........................which is excreted into the intestine.
.........................Increased total bilirubin causes
.........................jaundice, and can signal a number of
.........................problems:

Prehepatic: Increased bilirubin production. This can be due to a number of
causes, including hemolytic anemias and internal hemorrhage.
Hepatic:
Problems with the liver, which are reflected as deficiencies in bilirubin
metabolism (e.g. reduced hepatocyte uptake, impaired conjugation of bilirubin,
and reduced hepatocyte secretion of bilirubin). Some examples would be cirrhosis
and viral hepatitis.
Posthepatic: Obstruction of the bile ducts,
reflected as deficiencies in bilirubin excretion. (Obstruction can be located
either within the liver or Bile duct outside the liver.)

Measurement......Significance..........................Reference range
________________________________________________________
Direct bilirubin....The diagnosis is narrowed.......0 - 4 μmol/L
.........................down further by looking at
.........................the levels of direct bilirubin.
.........................If direct (i.e. conjugated)
.........................bilirubin is normal, then the
.........................problem is an excess of unconju-
.........................gated bilirubin, and the loca-
.........................tion of the problem is upstream
.........................of bilirubin excretion. Hemolysis,
.........................viral hepatitis, or cirrhosis can
.........................be suspected. If direct bilirubin
.........................is elevated, then the liver is
.........................conjugating bilirubin normally, but
.........................is not able to excrete it. Bile
.........................duct obstruction by gallstones or
.........................cancer should be suspected.

Measurement......Significance..............................Reference range
________________________________________________________

Gamma glutamyl.Although reasonably specific to....0 to 51 IU/L
transpeptidase...the liver and a more sensitive
(GGT)................marker for cholestatic damage
.........................than ALP, Gamma glutamyl transpep-
.........................tidase(GGT) may be elevated with
.........................even minor, sub-clinical levels of
.........................liver dysfunction. It can also be
.........................helpful in identifying the cause
.........................of an isolated elevation in ALP.
.........................GGT is raised in alcohol toxicity
.........................acute and chronic). In some labora-
.........................tories, GGT is not part of the
.........................standard LFTs and must be specifi-
.........................cally requested.
________________________________________________________

Other tests commonly requested alongside LFTs:

5' nucleotidase (5'NTD)
5' nucleotidase is another test specific for cholestasis or damage to the intra or extrahepatic biliary system, and in some laboratories, is used as a substitute for GGT for ascertaining whether an elevated ALP is of biliary or extra-biliary origin.
Coagulation tests (e.g. INR)
The liver is responsible for the production of coagulation factors. The international normalized ratio (INR) measures the speed of a particular pathway of coagulation, comparing it to normal. If the INR is increased, it means it is taking longer than usual for blood to clot. The INR will only be increased if the liver is so damaged that synthesis of vitamin K-dependent coagulation factors has been impaired: it is not a sensitive measure of liver function.
It is very important to normalize the INR before operating on people with liver problems (usually by transfusion with blood plasma containing the deficient factors) as they could bleed excessively.
Serum glucose (BG, Glu)
The liver's ability to produce glucose (gluconeogenesis) is usually the last function to be lost in the setting of fulminant liver failure.
Lactate dehydrogenase (LDH)
Lactate dehydrogenase is an enzyme found in many body tissues, including the liver. Elevated levels of LDH may indicate liver damage.

References
^ a b c d

External links

Retrieved from

"http://en.wikipedia.org/wiki/Liver_function_tests"

Categories: Blood tests Chemical pathology Gastroenterology Hepatology

To view information on another disease click on Digestive Diseases Library