Hepatocellular carcinoma (HCC): a global perspective /Sept 2010

EDUCATION IN GASTROENTEROLOGY

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World Gastroenterology Organisation Global Guideline. Hepatocellular carcinoma (HCC): a global perspective

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download Full Article (PDF file)

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Peter Ferenci (chair) (Austria), Michael Fried (Switzerland), Douglas Labrecque (USA), J. Bruix (Spain), M. Sherman (Canada), M. Omata (Japan), J. Heathcote (Canada), T. Piratsivuth (Thailand), Mike Kew (South Africa), Jesse A. Otegbayo (Nigeria), S.S. Zheng (China), S. Sarin (India), S. Hamid (Pakistan), Salma Barakat Modawi (Sudan), Wolfgang Fleig (Germany), Suliman Fedail (Sudan), Alan Thomson (Canada), Aamir Khan (Pakistan), Peter Malfertheiner (Germany), George Lau (Hong Kong), F.J. Carillo (Brazil), Justus Krabshuis (France), Anton Le Mair (The Netherlands)* QUIZ HQ 58Walled off cecal mass: an unusual case with an

unusual presentationR. Kibria, F. Ashraf, S.A. Ali, C.J. Barde

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Abdominal Pain /Right/Left Upper Quadrant

Abdominal pain

Common causes of abdominal pain :

Abdominal wall pain

Pain arising from the abdominal wall is usually constant and aching.

Movement, prolonged standing, and pressure accentuate the discomfort and muscle spasm.

This kind of pain may arise from a disease of the muscle (myositis, trauma and hematoma, muscle strain), nerve disease (diabetic neuropathy, postherpetic neuralgia), or it could be referred pain from an internal abdominal organ.

Abdominal wall pain often presents with a dermatomic pattern.

Characteristically, it starts off as sharp initially and can become dull over time. Coughing, sneezing, or lifting heavy weights may increase the pain, while applying heat or changing positions may relieve abdominal wall pain

Click On Image To Enlarge

Visceral pain

The best approach for visceral pain is according to location of pain and taking into account any associated symptoms to help guide the diagnosis.

Location is most easily categorized on the basis of embryologic origin. Pain located between the xiphoid process and the umbilicus originates in the foregut, which includes the distal esophagus, stomach, proximal duodenum, biliary tree, pancreas, and liver (although conditions of the liver usually do not cause chronic abdominal pain).

Pain in the periumbilical region arises from viscera of the midgut (eg, small intestine, appendix, ascending colon, proximal two thirds of the transverse colon).

Pain between the umbilicus and the symphysis pubis emanates from hindgut organs (eg, distal one third of the transverse colon, descending colon, rectosigmoid region).

1. The foregut

Click On Image To Enlarge

Pain in the epigastric area

The epigastrium is an area of the central abdomen lying just below the sternum.

Common causes are dyspepsia, peritonitis, pancreatitis, GI obstruction, gall bladder disease and peptic ulcer and ruptured aortic aneurysm. Other causes include inflammatory bowel syndrome, gastric cancer, referred pain (from a myocardial infarction, pleural disease or spinal disease) and psychosomatic diseases.

Pain in the right upper quadrant (hypochondrium)

Causes of right upper quadrant pain include liver diseases, gall bladder disease, lesions of the hepatic flexure of the colon (carcinoma, diverticulosis, ischaemic colitis, Chron’s disease, atypical appendicitis or even constipation), renal diseases (pyelonephritis, nephro-lithiasis, hydronephrosis, renal carcinoma or other disease of the kidney or ureter, including obstruction of the urinary tract) or a dissecting aneurysm. Other causes include referred pain from the heart or a respiratory disease of the lower lobe of the lungs (lobar pneumonia or infarction from pulmonary embolism).

Many metabolic diseases can give the same picture including, diabetic ketoacidosis, Addisionian crisis, adrenal tuberculosis and metastatic carcinoma. Infections such as herpes zoster or a subphrenic abscess can also lead to pain in the right upper quadrant.

Pain in the left upper quadrant (hypochondrium)

Left upper quadrant pain is commonly associated with colonic diseases or splenic diseases. The spleen may be enlarged or may be the seat of an infarction. Diseases of the colon may include anything from distension of the splenic flexure of the colon as in cases of irritable bowel syndrome to colonic cancer.

2. The midgut

Pain in the periumbulical region

Causes of periumbulical pain include intestinal obstruction, mesenteric occlusion or enteritis.

3. The hindgut

Right lower quadrant pain

Pain in the right lower quadrant may be diffuse, as in early appendicitis, or crampy and nonradiating, as in ectopic pregnancy. Colon obstruction secondary to colon cancer, diverticulitis, and ureterolithiasis are common causes of pain in this area. Yersinia enterocolitica and Campylobacter sp., may mimic appendicitis and cause right lower quadrant pain, anorexia, low grade fever, and vomiting preceding the onset of diarrhea leading to a syndrome of mesenteric adenitis (lymph node enlargement) and terminal ileitis. The classic presentation of Crohn’s disease is that of colicky right lower quadrant pain and diarrhea. Low-grade fever and weight loss are frequently present as well. High fever indicates a possible infectious complication (ie, abscess). Hematochezia occurs in a minority of patients, most often in those with colonic involvement.

In women right lower quadrant pain could be a manifestation of pelvic inflammatory disease, acute salpingitis, ectopic pregnancy, ovarian cysts, abscesses and tumors in addition to the causes listed above. Cancer of the cecum, ileal carcinoid, lymphosarcoma, systemic vasculitis, radiation enteritis, ileocecal TB, and ameboma should be excluded.

Left lower quadrant pain

Diverticulitis, inflammatory bowel disease, pelvic inflammatory disease, a kidney stone, endometriosis, ectopic pregnancy, and rupture of an ovarian cyst are common causes of abdominal pain in this area.

Pain in the hypogastrium and pelvis

Common causes of pain in this area include rectal disease (rectal cancer, proctitis); bladder disease (stones, cystitis, bladder cancer) and more importantly in females (salpingo-oopheritis, uterine cancer).

Pain in the costovertebral angle

This is usually attributed to renal causes (kidney stones, pyelonephritis and malignancy).

Clinical features of abdominal pain
Intensity and description of pain

Dull, gnawing sensation of mild to moderate severity can be caused by peptic ulcer disease.

Extremely intense pain of sudden onset may be the result of mesenteric ischemia or perforated peptic ulcer.

Renal colic refers to episodic pain with intervening pain-free intervals.

Biliary pain typically presents with constant, steady pain without intervening pain-free intervals.

Severe intensity and a “tearing” quality can be caused by a dissecting aneurysms causes pain.

Patients with postprandial pain, food avoidance, weight loss, and known atherosclerotic disease should be evaluated for mesenteric angina.

Time course
Sudden onset (over seconds to minutes) of abdominal pain suggests a catastrophic event such as a ruptured abdominal aneurysm, ruptured ectopic pregnancy, or perforated peptic ulcer.

Rapidly progressive (over 1-2 hours) pain is seen typically in pancreatitis, cholecystitis, diverticulitis, bowel obstruction, renal or biliary colic, and mesenteric ischemia.

Gradual (over several hours) pain that progresses more slowly is more typical of peptic ulcer disease, distal small bowel obstruction, appendicitis, pyelonephritis, pelvic inflammatory disease, and malignant neoplasm, although it may be seen with many of the diagnoses in the more rapidly progressive categories as well.

Pain occurring following the onset of vomiting often indicates a medical illness, whereas pain that precedes vomiting often indicates a surgical illness. Persistence of pain for over 6 hours after acute onset has a high likelihood of a surgical cause and requires admission for observation.

Aggravating or alleviating factors
Pain relieved by antacids suggests peptic ulcer disease or esophagitis.

Pain worsened by movement suggests peritonitis, whereas constant movement by the patient in an attempt to find a comfortable position is commonly seen in bowel obstruction and renal colic.

Patients with partial relief by leaning forward, and aggravation by lying supine suggests a retroperitoneal process (such as pancreatitis) commonly find

Pain relieved by defecation may suggest a colonic source.

Patients with postprandial pain, food avoidance, weight loss, and known atherosclerotic disease should be evaluated for chronic intestinal ischemia (mesenteric angina) or intermittent intestinal obstruction (from internal or abdominal wall hernias, adhesions, or Crohn’s disease).

Pain that occurs at approximately monthly intervals should raise the suspicion of endometriosis or Mittelschmerz.

Physical examination
Vital signs

Tachycardia & hypotension: Vital signs may show tachycardia and hypotension indicative of intraabdominal hemorrhage or septic shock.

Fever: The fever of appendicitis, diverticulitis, and cholecystitis is typically low grade, whereas high fevers are seen in cases of cholangitis, urinary tract infections, pelvic inflammatory disease, or perforation of a viscus with frank peritonitis.

Inspection

Abdominal distention: Abdominal distention may suggest bowel obstruction or the presence of ascites.

Scaphoid abdomen: A scaphoid, tense abdomen is seen in cases of peritonitis.

Auscultation

Auscultation of the abdomen should be performed before palpation or percussion so as not to interfere with the interpretation of bowel sounds.

Absence of bowel sounds: Absence of bowel sounds is a sign of diffuse peritonitis.

Hyperactive bowel sounds: Intermittent hyperactive bowel sounds occurring concurrently with worsening of pain suggest a bowel obstruction. High-pitched hyperactive bowel sounds may also be seen in gastroenteritis.

Succussion splash: The presence of a succussion splash suggests gastric outlet obstruction.

Percussion

Tenderness on percussion: Percussion of the abdomen allows assessment of the presence of peritonitis. Pain produced by light tapping indicates inflammation of the parietal peritoneum. This pain may also be elicited by asking the patient to cough or by gently agitating the gurney upon which the patient is lying.

Tympany: A distended abdomen with tympany upon percussion suggests a bowel obstruction.

Palpation

Tightening (rigidity) of the abdominal wall musculature occurs as a reflexive response to peritoneal inflammation (voluntary guarding refers to tightness or rigidity of the abdomen that relaxes when the patient takes a deep breath, whereas involuntary guarding refers to rigidity of the abdominal wall musculature that does not relax in response to deep inspiration). Involuntary guarding indicates peritoneal inflammation.

Tenderness over McBurney’s point should be considered very strong evidence of appendicitis.

Cholecystitis and salpingitis are often well localized as well, and salpingitis may be confused with appendicitis.

Patients with an unimpressive abdominal examination and complaints of severe, worsening pain should be suspected of having mesenteric infarction.

Murphy’s sign refers to pain produced by deep inspiration during palpation of the right subcostal area and suggests acute cholecystitis.

Pain produced by lightly punching the costovertebral angle (”punch tenderness”) is often present in pyelonephritis.

Carnett’s test refers to the response of pain when the patient tenses the abdominal wall muscles by raising their head off the examination table. Worsening of pain during this maneuver suggests an abdominal wall source whereas improvement in the pain suggests a visceral origin.

The iliopsoas sign refers to pain produced by passive extension of the leg and suggests a psoas abscess.

The obturator sign refers to pain produced by rotation of the thigh in a flexed position.

A rectal examination can reveal focal tenderness from an intraabdominal abscess or appendicitis.

A pelvic examination is mandatory in female patients to look for evidence of salpingitis or adnexal masses.

The inguinal and femoral canals, umbilicus, and surgical scars should be evaluated for the presence of incarcerating hernias.

Once a cause is suspected the appropriate diagnostic procedure for the provisional diagnosis is selected.

Diagnosis
If the picture is obscure then the following important points and causes should be taken into account:

Ruptured ectopic pregnancy in females

Dissecting aortic aneurysm: Absence of tenderness and rigidity in the presence of continuous, diffuse pain in a patient likely to have vascular disease is quite characteristic of occlusion of the superior mesenteric artery. Abdominal pain with radiation to the sacral region, flank, or genitalia should always signal the possible presence of a rupturing abdominal aortic aneurysm. This pain may persist over a period of several days before rupture and collapse occur.
Peritoneal pain: Rigidity, rebound tenderness, fever and leucocytosis

Metabolic causes
Familial mediterranean fever
Diabetic ketoacidosis
Irritable bowel syndrome: Is the commonest cause of abdominal pain and should always be kept in mind.
If the cause of abdominal pain is still unclear, investigations that can be requested include:

Lab work
X-rays (supine, erect, lateral view)
Ultrasound
CAT scan
Laparoscopy
Operation vs. watchful waiting
Chronic abdominal pain

Chronic pain usually has persisted for 3 to 6 months and is affecting the patient’s activities of daily living. Often, the diagnosis can be made through history taking.

Chronic epigastric pain can be caused by peptic ulcer, chronic pancreatitis, GERD, dyspepsia, gall bladder disease.

Chronic lower abdominal pain can be caused by irritable bowel syndrome, inflammatory bowel disease, cancer. Right lower quadrant fullness and pain or perianal disease may indicate Crohn’s disease.

Less common causes include causes in the abdominal wall, fibromyalgia, hernia, referred pain, metabolic disorders (porphyria, chronic renal failure, and Addison’s disease) and psychological disorders.

The evaluation of chronic abdominal pain in a patient younger than 50 years old typically begins with ruling out the presence of alarm symptoms (weight loss, gastrointestinal bleeding, anemia, fever, or frequent nocturnal symptoms).

If no alarm symptoms are present and the patient has altered bowel habits then evaluation for irritable bowel syndrome is considered. This my include a CBC, TSH and electrolyte levels, and examination with flexible sigmoidoscopy.

Those with alarm symptoms or age above 50 years old may require a referral to a gastroenterologist.

Source
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Related;

Functional Dyspepsia; Chronic and persistent upper abdominal pain that's often related to eating

Hepatitis C : Liver Pain

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Viral Load In Hepatitis C

What do viral loads mean?

By Tamra B. Orr


Most of us carry around a long list of important numbers in our heads, ready to be pulled out whenever they are needed. We remember our social security numbers, telephone numbers, addresses and zip codes, birth dates and others such as checking account numbers or lock combinations. For patients living with chronic hepatitis B or C, there is another number that joins the ranks: their viral load. It’s a number they usually learn soon after they are diagnosed with the condition, and over the years, although the number typically goes up and down, it remains an important one to remember.

Simply put, a viral load is the amount of virus found in each milliliter (mL) of a person’s blood. “It is reported as copies/mL, or more recently as IU/mL, or international units per milliliter,” explains Dr. Paul Thuluvath, director of the Institute of Digestive Health and Liver Disease at Mercy Medical Center in Baltimore. Converting IU/mL to copies /mL is complicated because several different assays can be used to measure viral load. According to Hepatitis C Support Project’s “HCSP Fact Sheet,” 1 IU can equal between 0.9 copies and 5 copies of the hepatitis C virus, depending on which test was used.

“Most labs give both values, and in the future it may be given only as IU/mL,” says Dr. Philip Rosenthal, medical director of the pediatric liver transplant program at University of California, San Francisco. “Viral load refers to the number of viral particles or amount actually present in the blood or other body fluids. Obviously, the more viral particles present in the blood or fluid, the more likely the virus can be spread to another person.”

The number does not stay constant, however. “It fluctuates and is not considered absolute,” says Dr. Silvia Degli-Esposti, hepatologist and gastroenterologist at the perinatal hepatitis program at the Women and Infants Hospital in Providence, R.I.

One of the first steps following the initial diagnosis of either hepatitis B or C is establishing a beginning viral load. It is typically done through specific blood tests known as quantitative HCV RNA or HBV DNA. This number helps determine what – if anything – is going to happen next.

Knowing the numbers

“Viral load is a measure of the severity of the viral infections,” says Dr. Rosenthal. “The higher the viral load, the more virus that is present and the more chance for the virus to cause harm or injury.”

For those with HBV, knowing the viral load is an essential element in deciding on treatment strategy. An HBV patient’s viral load “could be billions or many millions,” says Dr. Thuluvath. “When it is less than 10,000 IU/mL, the standard practice is not to treat it. We monitor the levels during treatment. Viral loads in HCV could be many thousands or millions.” Treatment for either virus is assessed by a decrease in viral loads; it’s a key to judging overall treatment response – hopefully all the way to where the virus is undetectable.

The viral loads in hepatitis B and C are different. Dr. Ned Snyder, chief of clinical gastroenterology and hepatology at the University of Texas Medical Branch in Galveston, explains, “In hepatitis B, there is a close correlation between the height of the viral load and prognosis. The higher the viral load, the more likely one is to develop cirrhosis or hepatocellular carcinoma (primary liver cancer). Also there are minimal levels of the virus below which treatment in most cases is not necessary.

“On the other hand, the viral load in chronic hepatitis C has nothing to do with prognosis,” Dr. Snyder continues. “There is no correlation between the level of virus and the state of the disease. One may have 100,000 IUs and cirrhosis, and someone with 5 million IUs may have minimal disease. In hepatitis C, the viral load is primarily useful in guiding treatment. The goal of treatment is to make the viral load undetectable and have it remain undetectable after treatment is completed.”

The viral load in hepatitis C has a direct connection to treatment success. Research indicates that for a patient with a high hepatitis C viral load, pegylated interferon and ribavirin are only about 40 percent effective, while those with low viral loads have an effectiveness rate closer to 56 percent. The success of various treatments also depends on other factors including the amount of liver damage already present when the diagnosis is made and how long the person has had the virus, as well as the person’s weight, age and ethnicity.

While liver damage can be significantly influenced by lifestyle choices and diet, the viral load for hepatitis B and C patients is not. “Unfortunately, there is not much patients can do themselves to alter their viral load,” Dr. Snyder says. “Milk thistle and other herbs have not been shown to make a difference.” So although they do not change the viral load, Dr. Rosenthal reminds patients to avoid “medications, herbs or drugs such as alcohol that are known to be hepatotoxic” because they increase the damage being done to the liver.

Other tips

What other information should patients and their families know about viral load? Drs. Rosenthal, Snyder, Thuluvath and Degli-Esposti suggest the following:

For either virus, the higher the viral load, the more likely the virus can be transmitted to another person.

Viral loads should always decrease with appropriate treatment.
It is not useful to monitor hepatitis C viral loads when you are not receiving any treatment.
High viral loads do not necessarily indicate severe disease in hepatitis C.
The HCV RNA or viral load will vary significantly from month to month in patients not receiving interferon/ribavirin, but this does not mean anything.
Do not panic if you hear the viral load is in six or seven figures as this is the usual range with hepatitis C.

In hepatitis B, high viral loads may predispose patients to liver cancer even in the absence of cirrhosis.

In adults with chronic hepatitis B, there is some evidence to suggest that the longer the viral load is high, the more the risk of development of hepatocellular carcinoma.
The field of hepatitis B has changed markedly in recent years, and many generalist physicians are not aware of some of the new concepts and treatments in hepatitis B.

Viral loads can be complicated and confusing for many of us. Dr. Degli-Esposti says, “Explaining viral loads to patients is one of the hardest things I do. They rarely ever understand exactly what I am trying to convey to them.” Instead, our viral load is just one more number we tuck away on our individual internal lists and recall whenever it’s time for a new test. But understanding the significance of that number can help us make informed treatment decisions.

http://www.liverhealthtoday.org/viewarticle.cfm?aid=392

Esophageal varices/Bleeding in the digestive tract

Bleeding in the digestive tract

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Varices

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Normally, blood from your intestine, spleen and pancreas enters your liver through a large blood vessel called the portal vein. But if scar tissue blocks circulation through your liver, the blood backs up, leading to increased pressure within the portal vein (portal hypertension)

This forces blood into smaller veins in your esophagus, stomach and occasionally your rectum. The excess blood causes these fragile, thin-walled veins to balloon outward and sometimes to rupture and bleed. Once varices develop, they continue to grow larger.

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Portal Hypertension

This is an increase in the blood pressure in the portal vein, which carries the blood from the bowel and spleen to the liver. The pressure in the portal vein may rise because there is a blockage, such as a blood clot, or because the resistance in the liver is increased because of scarring, or cirrhosis. As a result, the pressure in the portal vein rises – this is known as portal hypertension.As the blood tries to find another way back to the heart, new blood vessels open up. Among these vessels are those that run along the wall under the lining of the upper part of the stomach and the lower end of the oesophagus (gullet). These veins protrude into the gullet and the stomach and can bleed. This bleeding may be a gentle ooze in which case anaemia is the commonest symptom. Sometimes there can be a major bleed and the person has a haemorrhage and either vomits blood or passes blood through the bowels. This blood may appear to be black, since it is often changed as it passes through the body.

Cirrhosis: A leading cause of esophageal varices Esophageal varices are usually a complication of cirrhosis. This serious liver disorder, which is irreversible scarring of liver tissue, often results from alcoholic liver disease or hepatitis B or C infection. Another liver disorder, primary biliary cirrhosis, which destroys the small ducts that carry bile, can also cause scarring of liver tissue and lead to esophageal varices.

Not everyone with cirrhosis has varices and not everyone with varices will bleed. In general, small varices rarely bleed and bigger ones may bleed. Small varices however, may well develop into large varices over time

About one-third of people with esophageal varices will develop bleeding. The signs and symptoms of esophageal bleeding range from mild to severe and include:

Vomiting blood
Black, tarry or bloody stools
Decreased urination from unusually low blood pressure
Excessive thirst
Lightheadedness
Shock, in severe cases
When to see a doctor
See your doctor if you develop signs and symptoms of liver disease, such as:

Weight loss
Small, red spider veins under your skin or easy bruising
Weakness
Fatigue
Yellowing of your skin and eyes and dark, cola-colored urine
The buildup of fluid in your abdominal cavity (ascites)
Itching of your hands and feet and eventually of your entire body
Swelling of your legs and feet from retained fluid (edema)
Mental confusion, such as forgetfulness or trouble concentrating (encephalopathy) .


When it's an emergency

If you've been diagnosed with esophageal varices and experience bloody vomit or stools, call 911 or your local emergency services right away. These may indicate that esophageal varices have ruptured — a life-threatening condition that requires immediate medical care.

Complications

Varices do not cause symptoms until they leak or rupture, leading to extensive bleeding. Signs of bleeding from varices can include vomiting blood, dark-colored or black stools, and lightheadedness. If bleeding is severe, the person may lose consciousness.


Bleeding varices require emergency medical treatment. If not treated quickly, a large amount of blood can be lost and there is a significant risk of dying. If one or more of these symptoms develop, the person needs to seek emergency care.


The most serious complication of esophageal varices is bleeding. Once you have had a bleeding episode, you're at greatly increased risk of another, especially immediately following the first episode. The risk of bleeding is related to the location, size, and appearance of the varix, presence of red wale markings, variceal pressure, prior history of variceal bleeding, as well as the severity of hepatic dysfunction (classified by Child-Pugh class.)

Recurrent bleeding is common in people with esophageal varices — up to 70 percent will bleed again within one year of the first episode of bleeding without treatment. The likelihood of death increases with each episode. You're at greater risk of repeat bleeding if you are older, have liver failure or kidney failure, or drink alcohol.

Other complications of bleeding esophageal varices include:

Hypovolemic shock. This occurs when your body loses some, often at least one-fifth, of its blood volume. Symptoms include low blood pressure, a rapid pulse, weakness, sweating, anxiety, mental confusion and possibly unconsciousness.

Encephalopathy. A damaged liver is less effective at removing toxins from your body — normally one of the liver's key tasks. The buildup of toxins can damage your brain, leading to changes in your mental state, behavior and personality (hepatic encephalopathy). Signs and symptoms include forgetfulness, confusion and mood changes, and in the most severe cases, delirium and coma.

Infection. Aspiration pneumonia, which occurs when you inadvertently inhale vomit or other substances into your lungs, can be a life-threatening complication of bleeding varices or of certain treatments to control them.

If you have cirrhosis or other serious liver disease, your doctor may screen you for esophageal varices, sometimes as often as every year or two.

These tests are usually used to look for varices:
Endoscopy. For this test, your doctor inserts a thin, flexible, lighted tube (endoscope) through your mouth and into your esophagus. If any dilated veins are found, they're graded according to their size and checked for red streaks, which usually indicate a significant risk of bleeding. An esophageal endoscopy takes about 20 to 30 minutes, and the risks are generally minor. The most common side effect is a sore throat from swallowing the endoscope.

Imaging tests. Both computerized tomography (CT) scans and magnetic resonance imaging (MRI) may be used to diagnose esophageal varices. Unlike an endoscopy, these noninvasive tests also allow your doctor to examine your liver and circulation in the portal vein. But imaging tests aren't as effective at finding varices as endoscopy is, and they're not as useful for determining which varices are likely to bleed. For that reason, they're most often used in addition to endoscopy or when endoscopy can't be performed.


Treatment and Drugs
The primary aim in treating esophageal varices is to prevent bleeding. To help achieve this goal, doctors usually prescribe high blood pressure drugs (beta blockers) to reduce pressure in the portal vein once your initial episode of bleeding has resolved.


Beta blockers, which are traditionally used to treat high blood pressure, are the most commonly recommended medication to prevent bleeding from varices. Beta blockers decrease pressure inside of the varices, which can reduce the risk of bleeding by 45 to 50 percent .


Side effects of beta blockers — The most common side effects of beta blockers are fatigue and dizziness. They can also cause insomnia, a decreased ability to exercise, a slow heart rate, impotence, and cold hands and feet. The beta blockers used for cirrhosis can worsen symptoms of asthma, other lung diseases, or blood vessel disease (such as peripheral vascular disease). As a result, they normally are not prescribed for people with these conditions. Side effects should be discussed with a healthcare provider before stopping the medication..


Other drugs may be used for people who don't respond to beta blockers or who have severe side effects. Sometimes the varices may be injected directly with a solution that causes them to shrink. Or they may be tied with elastic bands before they have a chance to bleed.

Treating bleeding

. Bleeding varices are life-threatening, and immediate treatment is essential. To stop bleeding, you're likely to have one of the following procedures:

Variceal ligation. This is the preferred treatment for bleeding esophageal varices. During the procedure, your doctor uses an endoscope to snare the varices with an elastic band, which essentially "strangles" the veins. Variceal ligation usually causes fewer serious complications than do other treatments. It's also less likely to lead to episodes of repeat bleeding.
Endoscopic injection therapy. In this procedure, the bleeding varices are injected with a solution that shrinks them. Bleeding is usually controlled after one or two treatments, but complications can occur, including perforation of the esophagus and scarring of the esophagus that can lead to trouble swallowing (dysphagia).

Medications. A drug called octreotide (Sandostatin, Sandostatin LAR) is often used in combination with endoscopic therapy to treat bleeding from esophageal varices. Octreotide works by reducing pressure in the varices. The drug is usually continued for five days after a bleeding episode.

Balloon tamponade. This procedure is sometimes used to stop severe bleeding while waiting for a more permanent procedure. A tube is inserted through your nose and into your stomach and then inflated. The pressure against your veins can temporarily stop bleeding.


Shunt. In this procedure, called transjugular intrahepatic portosystemic shunt (TIPS), a small tube called a shunt is placed between the portal vein and the hepatic vein, which carries blood from your liver back to your heart. The tube is kept open with a metal stent. By providing an artificial path for blood through the liver, the shunt often can control bleeding from esophageal varices. But TIPS can cause a number of serious complications, including liver failure and encephalopathy, which may develop when toxins that would normally be filtered by the liver are passed through the shunt directly into the bloodstream. TIPS is mainly used when all other treatments have failed or as a temporary measure in people awaiting a liver transplant.


Other Causes Of Bleeding;

Bleeding in the digestive tract

What causes bleeding in the digestive tract?
Stomach acid can cause inflammation that may lead to bleeding at the lower end of the esophagus. This condition, usually associated with the symptom of heartburn, is called esophagitis or inflammation of the esophagus. Sometimes a muscle between the esophagus and stomach fails to close properly and allows the return of food and stomach juices into the esophagus, which can lead to esophagitis. In another, unrelated condition, enlarged veins (varices) at the lower end of the esophagus may rupture and bleed massively. Cirrhosis of the liver is the most common cause of esophageal varices. Esophageal bleeding can be caused by a tear in the lining of the esophagus (Mallory-Weiss syndrome). Mallory-Weiss syndrome usually results from vomiting but may also be caused by increased pressure in the abdomen from coughing, hiatal hernia, or childbirth. Esophageal cancer can cause bleeding.

The stomach is a frequent site of bleeding. Infections with Helicobacter pylori (H. pylori), alcohol, aspirin, aspirin-containing medicines, and various other medicines (NSAIDs) (particularly those used for arthritis) can cause stomach ulcers or inflammation (gastritis). The stomach is often the site of ulcer disease. Acute or chronic ulcers may enlarge and erode through a blood vessel, causing bleeding. Also, patients suffering from burns, shock, head injuries, or cancer,or those who have undergone extensive surgery may develop stress ulcers. Bleeding can also occur from benign tumors or cancer of the stomach, although these disorders usually do not cause massive bleeding.

A common source of bleeding from the upper digestive tract is ulcers in the duodenum (the upper small intestine). Duodenal ulcers are most commonly caused by infection with H. pylori bacteria or drugs such as aspirin or NSAIDs.

In the lower digestive tract, the large intestine and rectum are frequent sites of bleeding. Hemorrhoids are the most common cause of visible blood in the digestive tract, especially blood that appears bright red. Hemorrhoids are enlarged veins in the anal area that can rupture and produce bright red blood, which can show up in the toilet or on toilet paper. If red blood is seen, however, it is essential to exclude other causes of bleeding since the anal area may also be the site of cuts (fissures), inflammation, or cancer.

Benign growths or polyps of the colon are very common and are thought to be forerunners of cancer. These growths can cause either bright red blood or occult bleeding. Colorectal cancer is the third most frequent of all cancers in the United States and often causes occult bleeding at some time, but not necessarily visible bleeding.

Inflammation from various causes can produce extensive bleeding from the colon. Different intestinal infections can cause inflammation and bloody diarrhea. Ulcerative colitis can produce inflammation and extensive surface bleeding from tiny ulcerations. Crohn's disease of the large intestine can also produce bleeding.

Diverticular disease caused by diverticula--outpouchings of the colon wall--can result in massive bleeding. Finally, as one gets older, abnormalities may develop in the blood vessels of the large intestine, which may result in recurrent bleeding.

Patients taking blood thinning medications (warfarin) may have bleeding from the GI tract, especially if they take drugs like aspirin.

What are the common causes of bleeding in the digestive tract?

Esophagus

inflammation (esophagitis)
enlarged veins (varices)
tear (Mallory-Weiss syndrome)
cancer
Stomach

ulcers
inflammation (gastritis)
cancer
Small intestine

duodenal ulcer
inflammation (irritable bowel disease)
Large intestine and rectum

hemorrhoids
infections
inflammation (ulcerative colitis)
colorectal polyps
colorectal cancer
diverticular disease


How is bleeding in the digestive tract recognized?
The signs of bleeding in the digestive tract depend upon the site and severity of bleeding. If blood is coming from the rectum or the lower colon, bright red blood will coat or mix with the stool. The stool may be mixed with darker blood if the bleeding is higher up in the colon or at the far end of the small intestine. When there is bleeding in the esophagus, stomach, or duodenum, the stool is usually black or tarry. Vomited material may be bright red or have a coffee-grounds appearance when one is bleeding from those sites. If bleeding is occult, the patient might not notice any changes in stool color.

If sudden massive bleeding occurs, a person may feel weak, dizzy, faint, short of breath, or have crampy abdominal pain or diarrhea. Shock may occur, with a rapid pulse, drop in blood pressure, and difficulty in producing urine. The patient may become very pale. If bleeding is slow and occurs over a long period of time, a gradual onset of fatigue, lethargy, shortness of breath, and pallor from the anemia will result. Anemia is a condition in which the blood's iron-rich substance, hemoglobin, is diminished.

How is bleeding in the digestive tract diagnosed?
The site of the bleeding must be located. A complete history and physical examination are essential. Symptoms such as changes in bowel habits, stool color (to black or red) and consistency, and the presence of pain or tenderness may tell the doctor which area of the GI tract is affected. Because the intake of iron, bismuth (Pepto Bismol), or foods such as beets can give the stool the same appearance as bleeding from the digestive tract, a doctor must test the stool for blood before offering a diagnosis. A blood count will indicate whether the patient is anemic and also will give an idea of the extent of the bleeding and how chronic it may be.

Endoscopy
Endoscopy is a common diagnostic technique that allows direct viewing of the bleeding site. Because the endoscope can detect lesions and confirm the presence or absence of bleeding, doctors often choose this method to diagnose patients with acute bleeding. In many cases, the doctor can use the endoscope to treat the cause of bleeding as well.

The endoscope is a flexible instrument that can be inserted through the mouth or rectum. The instrument allows the doctor to see into the esophagus, stomach, duodenum (esophago-duodenoscopy), colon (colonoscopy), and rectum (sigmoidoscopy); to collect small samples of tissue (biopsies); to take photographs; and to stop the bleeding.

Small bowel endoscopy, or enteroscopy, is a procedure using a long endoscope. This endoscope may be used to localize unidentified sources of bleeding in the small intestine.

Other Procedures
Several other methods are available to locate the source of bleeding. Barium x rays, in general, are less accurate than endoscopy in locating bleeding sites. Some drawbacks of barium x rays are that they may interfere with other diagnostic techniques if used for detecting acute bleeding, they expose the patient to x rays, and they do not offer the capabilities of biopsy or treatment.

Angiography is a technique that uses dye to highlight blood vessels. This procedure is most useful in situations when the patient is acutely bleeding such that dye leaks out of the blood vessel and identifies the site of bleeding. In selected situations, angiography allows injection of medicine into arteries that may stop the bleeding.

Radionuclide scanning is a noninvasive screening technique used for locating sites of acute bleeding, especially in the lower GI tract. This technique involves injection of small amounts of radioactive material. Then, a special camera produces pictures of organs, allowing the doctor to detect a bleeding site.

In addition, barium x rays, angiography, and radionuclide scans can be used to locate sources of chronic occult bleeding. These techniques are especially useful when the small intestine is suspected as the site of bleeding since the small intestine may not be seen easily with endoscopy.

How is bleeding in the digestive tract treated?
Endoscopy is the primary diagnostic and therapeutic procedure for most causes of GI bleeding.

Active bleeding from the upper GI tract can often be controlled by injecting chemicals directly into a bleeding site with a needle introduced through the endoscope. A physician can also cauterize, or heat treat, a bleeding site and surrounding tissue with a heater probe or electrocoagulation device passed through the endoscope. Laser therapy is useful in certain specialized situations.

Once bleeding is controlled, medicines are often prescribed to prevent recurrence of bleeding. Medicines are useful primarily for H. pylori, esophagitis, ulcer, infections, and irritable bowel disease. Medical treatment of ulcers, including the elimination of H. pylori, to ensure healing and maintenance therapy to prevent ulcer recurrence can also lessen the chance of recurrent bleeding.

Removal of polyps with an endoscope can control bleeding from colon polyps. Removal of hemorrhoids by banding or various heat or electrical devices is effective in patients who suffer hemorrhoidal bleeding on a recurrent basis. Endoscopic injection or cautery can be used to treat bleeding sites throughout the lower intestinal tract.

Endoscopic techniques do not always control bleeding. Sometimes angiography may be used. However, surgery is often needed to control active, severe, or recurrent bleeding when endoscopy is not successful.

How do you recognize blood in the stool and vomit?

bright red blood coating the stool
dark blood mixed with the stool
black or tarry stool
bright red blood in vomit
coffee-grounds appearance of vomit
What are the symptoms of acute bleeding?

any of bleeding symptoms above
weakness
shortness of breath
dizziness
crampy abdominal pain
faintness
diarrhea
What are the symptoms of chronic bleeding?

any of bleeding symptoms above
weakness
fatigue
shortness of breath
lethargy
faintness
Publications produced by the clearinghouse are carefully reviewed

http://www.mamashealth.com/stomach/bleeding.asp

Sources/Excerpts http://www.cnn.com/HEALTH/library/esophageal-varices/DS00820.html
http://www.uptodate.com/patients/content/topic.do?topicKey=~l.22S8wqWBcwQG
http://www.uptodate.com/patients/content/topic.do?topicKey=~l.22S8wqWBcwQG
http://www.mombu.com/medicine/heart/t-portal-hypertension-and-bleeding-of-oesophageal-varices-sclerosing-cholangitis-endoscopy-cholangitis-stomach-heart-2382216.html

Botanicals,Herbs and Supplements

www.artknowledgenews.com/2009-11-14-22-52-11-...

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Herbal Supplements Face New Scrutiny

Elderberry extract and acai to boost the immune system. Black cohosh to lessen the discomforts of menopause. Soy capsules to prevent bone loss and prostate cancer.

Many botanical supplements—made from the seeds, bark, leaves, flowers and stems of a wide range of plants—have been widely used as folk remedies for centuries. Americans have been consuming growing quantities of the supplements in hopes of warding off disease and easing symptoms of various conditions. But there is scant scientific evidence to support their health benefits.

Now, the federal government is stepping up research into the safety and effectiveness of a wide range of over-the-counter supplements, including plant oils, garlic, soy, elderberry, licorice, black cohosh, St. John's wort and the Asian herb dong quai. The aim is to better understand how compounds in the plants affect health and to help consumers make more informed choices about supplements, which can interact with prescription drugs, cause side effects or lead to new health risks. Sales of botanical supplements in the U.S. topped $5 billion last year, up 17% from five years earlier, according to the non-profit American Botanical Council.

"Sometimes people assume because a product is natural, it is also safer. But these compounds can have both benefits and potential side effects and we need to understand both of those," says Floyd Chilton III, director of the Center for Botanical Lipids and Inflammatory Disease Prevention at Wake Forest University Baptist Medical Center in Winston-Salem, N.C. Dr. Chilton's center received a $7.5 million federal grant to study botanicals, including whether plant oils such as echium and borage can help play a role in preventing cardiovascular disease, asthma and diabetes.

"People are using supplements for purposes for which they were not intended," such as treating health conditions they have self-diagnosed, or using multiple supplements in combination with prescription medications, says Marguerite Klein, director of the Botanical Centers Research program at the National Institutes of Health. One concern, she says is the heavy use by women of black cohosh to treat menopause symptoms, such as hot flashes. Limited research seems to support the black cohosh's benefit. But it isn't known how the botanical works. Black cohosh has been linked in some patients to liver damage, and breast-cancer patients are often advised to avoid using it because its effects on breast tissue are unknown.

Helping to spur the research initiative are the Office of Dietary Supplements and the National Center for Complementary and Alternative Medicine, both part of the National Institutes of Health. The agencies last month awarded grants totaling about $37 million to five dietary supplement research centers, expanding a program that has already awarded more than $250 million in research grants for herbs and botanicals since 2002. The NIH is also funding research into botanical products through the National Cancer Institute, which is interested in how components in botanicals might influence cancer risk and tumor growth.


Adding garlic to your diet has several health benefits including assistance in warding off cancer and boosting the immune system.

Studies funded by the federal grants have so far shown that chamomile capsules may help reduce anxiety compared to a placebo and that an extract from the milk thistle plant can interfere with the life cycle of the hepatitis C virus. They also have refuted some purported benefits of botanicals, showing, for instance, that ginkgo biloba does not prevent heart attack, stroke, or cancer, or stem memory loss and that St. John's wort was no better than a placebo in treating symptoms of attention deficit hyperactivity disorder in children and teens.

Unlike drugs, which must be tested in clinical trials and approved by the Food and Drug Administration before they can be marketed, botanicals and other supplements don't require regulatory approval. The FDA in June began requiring all supplement makers to follow strict quality manufacturing standards, but the agency only periodically inspects plants.

An investigation published in May by the General Accounting Office found deceptive marketing practices at a number of online retailers, including claims that supplements could prevent or cure conditions such as diabetes, cancer, or cardiovascular disease. The investigation also found trace amounts of potentially hazardous contaminants, such as lead or bacteria, in 37 of 40 herbal dietary supplement products it tested.

Tod Cooperman, president of ConsumerLab.com, which tests supplement brands for quality, says the group finds problems with about 25% of all supplements, and especially with herbal products, many with ingredients from overseas. A recent review of supplements made from ginseng—commonly taken to boost energy and vitality—found that 45% failed quality tests because they didn't contain the advertised amount of ginseng or were contaminated with lead. Test results and other information are available to members, who pay $30 annually.

Consumers also can find information about potential uses, benefits and risks of dietary supplements at federal websites ods.gov and nccam.gov. Another government site, Medlineplus.gov, grades scientific evidence on a variety of supplements.

William Cefalu, director of the Pennington Biomedical Research Center at Louisiana State University in Baton Rouge, says researchers are only beginning to understand how thousands of different compounds in a single plant may interact, and how the concentration of a particular plant chemical affects its potency. For example, peppermint tea is considered safe to drink, but peppermint oil, often taken for irritable bowel syndrome or indigestion, is much more concentrated and can be toxic if used in high doses.

Because the potency of wild plants can vary, some researchers are cultivating their own. At the Center for Botanical Interaction Studies at the University of Missouri in Columbia, 600 types of soybean seeds are being cultivated to study different concentrations of the same compounds in the plants and how they might work to prevent prostate cancer. The center is also growing 60 types of elderberries to study the plant's possible role in boosting the immune system against infection and fighting cancer and inflammation in the body. Center director Dennis Lubahn says there may be variations in individual plants that will make a difference in how well they fight disease. "We've come a long way from the traditional medicine woman sampling leaves in the forest," he says.

Source: http://online.wsj.com/

FDA Rule On: Investigational drugs/biologics

FDA NEWS RELEASE
For Immediate Release: Sept. 28, 2010
Media Inquiries: Karen Riley, 301-796-4674, karen.riley@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

FDA issues final rule on safety information during clinical trials

The U.S. Food and Drug Administration today issued a final rule that clarifies what safety information must be reported during clinical trials of investigational drugs and biologics.

“This final rule will expedite FDA’s review of critical safety information and help the agency monitor the safety of investigational drugs and biologics,” said Rachel Behrman, M.D, associate director for medical policy in the FDA’s Center for Drug Evaluation and Research. “These changes will better protect people who are enrolled in clinical trials.”

The new rule requires that certain safety information that previously had not been required to be reported to FDA be reported within 15 days of becoming aware of an occurrence.

These reports include:

findings from clinical or epidemiological studies that suggest a significant risk to study participants serious suspected adverse reactions that occur at a rate higher than expected
serious adverse events from bioavailability studies which determine what percentage and at what rate drug is absorbed by the bloodstream and bioequivalence studies which determine whether a generic drug has the same bioavailability as the brand name drug
The rule also provides examples of evidence that would suggest that an investigational product may be the cause of a safety problem.

Under current regulations, drug sponsors often report all serious adverse events, even if there is little reason to believe the product caused the event. Such reporting complicates and delays the FDA’s ability to detect a safety signal. The examples address when a single event should be reported or when there is need to wait for more than one occurrence.

In addition, the rule revises definitions and reporting standards so that they are more consistent with two international organizations, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use and the World Health Organization’s Council for International Organizations of Medical Sciences. The changes are designed to help ensure harmonized reporting of globally conducted clinical trials.

Along with this final rule, the FDA also issued a draft guidance for industry and investigators that provides information and advice about the new requirements and other information.

For more information

Final Rule: Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalance Studies in Humans

#
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm227386.htm



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Hepatitis C News:New details of studies of rival hepatitis C drugs

eternallycool.net/2007/10/

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l

Vertex Edges Merck In First Round of Hepatitis C Fight
By ROBERT LANGRETH

New details of studies of rival hepatitis C drugs from Merck and Vertex Pharmaceuticals were released today in advance of a crucial upcoming meeting of liver specialists at the end of the month in Boston. The drugs, so-called hepatitis C protease inhibitors, represent the first class of agents that directly target the hepatitis C virus. Both have substantially boosted the cure rate in big trials, raising excitement among hepatitis c specialists.

While the drugs haven’t been compared directly, it appears that Vertex’s telaprevir drug is is a nudge better. Unless differences in tolerability and side effects emerge, if both drugs are approved, doctors may look at the data and go with the Vertex drug first because its cure rates appear to be a few percentage points higher.

Here’s what Howard Liang of Leerink Swann wrote in a note today:

“Apples-to-apples” comparison of boceprevir vs. telaprevir in treatment-experienced patients is possible for the first time and appears to favor telaprevir. In prior relapsers, SVR was 69%-75% for boceprevir vs. 83-88% for telaprevir. In what we would call partial responders MRK has a different definition, SVR was 40-52% for boceprevir vs. 54-59% for telaprevir. Cross-trial comparisons are always difficult but we believe the totality and consistency of both treatment-experienced and treatment-naïve data give an impression that telaprevir may be more potent.

If there are significant side effects to the Vertex compound that haven’t emerged yet, it could totally negate Vertex’s apparent advantage. But if Vertex’s drug is perceived by doctors as slightly more effective, who does Merck sell its drug to?

Merck R&D head Peter Kim may have some answers to this question. He is going to the liver meeting where he will face lots of questions from Wall Street types about where Merck’s drug will fit in. He needs to rebut the doubts about his company’s drug.

http://blogs.forbes.com/robertlangreth/2010/10/01/vertex-edges-merck-in-first-round-of-hepatitis-c-fight/?boxes=businesschannelsections

Noninvasive tests for liver disease, fibrosis, and cirrhosis: Is liver biopsy obsolete?

Liver biopsy remains an important tool in the evaluation and management of liver disease

EMILY CAREY, DO
+ Author Affiliations
Digestive Disease Institute, Cleveland Clinic
ADDRESS: Emily Carey, DO, Digestive Disease Institute, A30, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail careye2@ccf.org.

WILLIAM D. CAREY, MD
+ Author Affiliations
Transplant Center and Digestive Disease Institute, Cleveland Clinic; Director, Center for Continuing Education; Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University


Abstract

Liver biopsy has been used to diagnose chronic liver disease and to assess the degree of hepatic inflammation and fibrosis. However, it is an invasive test with many possible complications and the potential for sampling error. Noninvasive tests are increasingly precise in identifying the cause of many cases of liver disease and even the amount of liver injury (fibrosis). This review discusses the role of noninvasive tests to diagnose liver disease and to assess hepatic fibrosis and cirrhosis.

KEY POINTS
Liver biopsy remains an important tool in the evaluation and management of liver disease.

The role of liver biopsy for diagnosis of chronic liver disease has diminished, owing to accurate blood tests and imaging studies.

Noninvasive tests for assessing the degree of hepatic fibrosis are showing more promise and may further reduce the need for liver biopsy. Elastography, in particular, shows promise in measuring hepatic fibrosis.

Liver biopsy is still needed if laboratory testing and imaging studies are inconclusive.


Primary care physicians and specialists alike often encounter patients with chronic liver disease. Fortunately, these days we need to resort to liver biopsy less often than in the past.

The purpose of this review is to provide a critical assessment of the growing number of noninvasive tests available for diagnosing liver disease and assessing hepatic fibrosis, and to discuss the implications of these advances related to the indications for needle liver biopsy.


WHEN IS LIVER BIOPSY USEFUL?

In diagnosis
Needle liver biopsy for diagnosis remains important in cases of:

Diagnostic uncertainty (eg, in patients with atypical features)

Coexisting disorders (eg, human immunodeficiency virus [HIV] and hepatitis C virus infection, or alcoholic liver disease and hepatitis C)

An overlapping syndrome (eg, primary biliary cirrhosis with autoimmune hepatitis).

Fatty liver. Needle liver biopsy can distinguish between benign steatosis and progressive steatohepatitis in a patient with a fatty liver found on imaging, subject to the limitations of sampling error.

Because fatty liver disease is common and proven treatments are few, no consensus has emerged about which patients with suspected fatty liver disease should undergo needle biopsy. Many specialists eschew needle biopsy and treat the underlying risk factors of metabolic syndrome, reserving biopsy for patients with findings that raise the concern of cirrhosis.

Hereditary disorders, eg, hemochromatosis, alpha-1 antitrypsin deficiency, and Wilson disease.

In management
Periodic needle biopsy is also valuable in the management of a few diseases.

In autoimmune hepatitis, monitoring the plasma cell score on liver biopsy may help predict relapse when a physician is considering reducing or discontinuing immunosuppressive therapy.1

After liver transplantation, a liver biopsy is highly valuable to assess for rejection and the presence and intensity of disease recurrence.


PROBLEMS WITH LIVER BIOPSY

Liver biopsy is invasive and can cause significant complications. Nearly 30% of patients report having substantial pain after liver biopsy, and some experience serious complications such as pneumothorax, bleeding, or puncture of the biliary tree. In rare cases, patients die of bleeding.2

Furthermore, hepatic pathology, particularly fibrosis, is not always uniformly distributed. Surgical wedge biopsy provides adequate tissue volume to overcome this problem. Needle biopsy, on the other hand, provides a much smaller volume of tissue (1/50,000 of the total mass of the liver).3

As examples of the resulting sampling errors that can occur, consider the two most common chronic liver diseases: hepatitis C and fatty liver disease.

Regev et al 4 performed laparoscopically guided biopsy of the right and left hepatic lobes in a series of 124 patients with chronic hepatitis C. Biopsy samples from the right and left lobes differed in the intensity of inflammation in 24.2% of cases, and in the intensity of fibrosis in 33.1%. Differences of more than one grade of inflammation or stage of fibrosis were uncommon. However, in 14.5%, cirrhosis was diagnosed in one lobe but not the other.

In a study in patients with nonalcoholic fatty liver disease, Ratziu et al5 found that none of the features characteristic of nonalcoholic steatohepatitis were highly concordant in paired liver biopsies. Clearly, needle liver biopsy is far from an ideal test.
Increasingly, liver diseases can be diagnosed precisely with laboratory tests, imaging studies, or both. Thus, needle liver biopsy is playing a lesser role in diagnosis.


ADVANCES IN NONINVASIVE DIAGNOSIS OF LIVER DISEASE

Over the past 30 years, substantial strides have been made in our ability to make certain diagnoses through noninvasive means.
Blood tests can be used to diagnose viral hepatitis A, B, and C and many cases of hemochromatosis and primary biliary cirrhosis. For a detailed discussion of how blood tests are used in diagnosing liver diseases, see www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/guide-to-common-liver-tests/.

Imaging studies. Primary sclerosing cholangitis can be diagnosed with an imaging study, ie, magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). The value of needle biopsy in these patients is limited to assessing the degree of fibrosis to help with management of the disease and, less often, to discovering other liver pathologies.6

Most benign space-occupying liver lesions, both cystic and solid, can be fully characterized by imaging, especially in patients who have no underlying chronic liver disease, and no biopsy is needed. Whether biopsy should be performed to investigate liver lesions depends on the clinical scenario; the topic is beyond the scope of this paper but has been reviewed in detail by Rockey et al.2


CAN NONINVASIVE TESTS DETECT HEPATIC FIBROSIS?


Fibrosis, an accumulation of extracellular matrix, can develop in chronic liver disease. FIGURE 1 shows the typical stages and distribution. 7 Cirrhosis (stage 4 fibrosis) results in nodular transformation of the liver and impedance of portal blood flow, setting the stage for portal hypertension and its sequelae. Knowing whether cirrhosis is present is important in subsequent management.


In advanced cases, cirrhosis is associated with typical clinical manifestations and laboratory and radiographic findings. In such cases, needle biopsy will add little. However, in most cases, particularly early in the course, clinical, laboratory, and radiologic correlates of cirrhosis are absent. In one study of patients with hepatitis C, 27% had cirrhosis, but in only a small number would cirrhosis have been apparent from clinical signs and laboratory and imaging studies.6

Since a major contemporary role for liver biopsy is in assessing the degree of fibrosis, it is reasonable to ask if newer noninvasive means are available to estimate hepatic fibrosis. The remainder of this review focuses on assessing our increasing ability to stage the degree of fibrosis (including the presence or absence of cirrhosis) by noninvasive means.


Clinical features point to cirrhosis, but not earlier fibrosis

Clinical manifestations help point to the diagnosis of cirrhosis but not to earlier stages of fibrosis.
For example, if a patient is known to have liver disease, the findings of ascites, splenomegaly, or asterixis mean that cirrhosis is highly probable. Similarly, hypersplenism (splenomegaly with a decrease in circulating blood cells but a normal to hyperactive bone marrow) in a patient with liver test abnormalities almost always represents portal hypertension due to cirrhosis, although other, nonhepatic causes are possible, such as congestive heart failure and constrictive pericarditis.

These features generally emerge late in the course of cirrhosis. The absence of such stigmata certainly does not preclude the presence of cirrhosis. Thus, these clinical signs have a high positive predictive value but a low negative predictive value, making them insufficient by themselves to diagnose or stage liver disease.

Laboratory tests are of limited value in assessing the degree of fibrosis

Standard liver tests are of limited value in assessing the degree of fibrosis.

Usual laboratory tests.

At one end of the spectrum, anemia, thrombocytopenia, and leukopenia in the presence of liver disease correlate with cirrhosis. At the other end, a serum ferritin concentration of less than 1,000 mg/mL in a patient with hemochromatosis and no confounding features such as hepatitis C, HIV infection, or heavy alcohol use strongly predicts that the patient does not have significant hepatic fibrosis.8

Bilirubin elevation is a late finding in cirrhosis, but in cholestatic diseases bilirubin may be elevated before cirrhosis occurs.

Albumin is made exclusively in the liver, and its concentration falls as liver function worsens with progressive cirrhosis.

The prothrombin time increases as the liver loses its ability to synthesize clotting factors in cirrhosis. Coagulopathy correlates with the degree of liver disease.

Hyponatremia due to impaired ability to excrete free water is seen in patients with cirrhosis and ascites.

In summary, the usual laboratory tests related to liver disease are imprecise and, when abnormal, often indicate not just the presence of cirrhosis, but impending or actual decompensation.

Newer serologic markers, alone or in combination, have been proposed as aids in determining the degree of fibrosis or cirrhosis in the liver. Direct markers of fibrosis measure the turnover or metabolism of extracellular matrix. Indirect markers of fibrosis reflect alterations in hepatic function (see below).

Parkes et al9 reviewed 10 different panels of serum markers of hepatic fibrosis in chronic hepatitis C. Only 35% of patients had fibrosis adequately ruled in or ruled out by these panels, and the stage of fibrosis could not be adequately determined.

These serologic markers have not been validated in other chronic liver diseases or in liver disease due to multiple causes. Thus, although they show promise for use by the general internist, they need to be validated in patients with disease and in normal reference populations before they are ready for “prime time.”

Direct serologic markers of fibrosis

Direct serologic markers of fibrosis include those associated with matrix deposition—eg, procollagen type III amino-terminal peptide (P3NP), type I and IV collagens, laminin, hyaluronic acid, and chondrex.

P3NP is the most widely studied marker of hepatic fibrosis. It is elevated in both acute and chronic liver diseases; serum levels reflect the histologic stage of hepatic fibrosis in various chronic liver diseases, including alcoholic, viral, and primary biliary cirrhosis.10–12 Successful treatment of autoimmune hepatitis has been shown to lead to reductions of P3NP levels.13

Other direct markers of fibrosis are those associated with matrix degradation, ie, matrix metalloproteinases 2 and 3 (MMP-2, MMP-3) and tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1, TIMP-2). Levels of MMP-2 proenzymes and active enzymes are increased in liver disease, but studies are inconsistent in correlating serum levels of MMP-2 to the degree of hepatic fibrosis.14,15 These tests are not commercially available, and the components are not readily available in most clinical laboratories.

Indirect serologic markers of fibrosis

Some indirect markers are readily available:

The AST:ALT ratio. The normal ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) is approximately 0.8. A ratio greater than 1.0 provides evidence of cirrhosis. However, findings have been inconsistent.

The AST:platelet ratio index (APRI), a commonly used index, is calculated by the following formula:

In studies of hepatitis C and hepatitis C-HIV, the APRI has shown a sensitivity of 37% to 80% and a specificity of 45% to 98%, depending on the cutoff value and whether a diagnosis of severe fibrosis or cirrhosis was being tested.16–19 These sensitivities and specificities are disappointing and do not provide information equal to that provided by needle liver biopsy in most patients with chronic liver disease.

The combination of prothrombin, gamma glutamyl, and apolipoprotein AI levels (PGA index) has been validated in patients with many types of chronic liver disease, and its accuracy for detecting cirrhosis is highest (66%–72%) in patients with alcoholic liver disease.20,21

FibroIndex uses the platelet count, AST level, and gamma globulin level to detect significant fibrosis in chronic hepatitis C, but its accuracy has yet to be validated.22

The FIB-4 index is based on four independent predictors of fibrosis, ie, age, the platelet count, AST level, and ALT level. It has shown good accuracy for detecting advanced fibrosis in two studies in patients with hepatitis C.23,24

Fibrometer (based on the platelet count; the prothrombin index; the levels of AST, alfa-2 macroglobulin, hyaluronate, and blood urea nitrogen; and age) predicted fibrosis well in chronic viral hepatitis.25,26

Fibrotest and Fibrosure are proprietary commercial tests available in many laboratories. They employ a mathematical formula to predict fibrosis (characterized as mild, significant, or indeterminate) using the levels of alpha-2 macroglobulin, alpha-2 globulin, gamma globulin, apolipoprotein A1, gamma glutamyl transferase, and total bilirubin. For detecting significant fibrosis, these tests are reported to have a sensitivity of about 75% and a specificity of 85%.27–29

ActiTest incorporates the ALT level into the Fibrotest to reflect liver fibrosis and necro-inflammatory activity.

A meta-analysis showed that Fibrotest and ActiTest could be reliable alternatives to liver biopsy in patients with chronic hepatitis C.30 The area under the receiver operator characteristic curve for the diagnosis of significant fibrosis ranged from 0.73 to 0.87; for the diagnosis of significant histologic activity it ranged from 0.75 to 0.86. Fibrotest had a negative predictive value for excluding significant fibrosis of 91% with a cutoff of 0.31. ActiTest’s negative predictive value for excluding significant necrosis was 85% with a cutoff of 0.36. None of these serum tests have become part of standard of practice for diagnosing fibrosis or cirrhosis.

The Sequential Algorithm for Fibrosis Evaluation (SAFE) combines the APRI and Fibrotest-Fibrosure tests in a sequential fashion to test for fibrosis and cirrhosis. In a large multicenter study31 validating this algorithm to detect significant fibrosis (stage F2 or greater by the F0–F4 METAVIR scoring system32), its accuracy was 90.1%, the area under the receiver operating characteristic curve was 0.89 (95% CI 0.87–0.90), and it reduced the number of liver biopsies needed by 46.5%. When the algorithm was used to detect cirrhosis, its accuracy was 92.5%, the area under the curve was 0.92 (95% CI 0.89–0.94), and it reduced the number of liver biopsies needed by 81.5%.


Another algorithm was developed to simultaneously detect significant fibrosis and cirrhosis. It had a 97.4% accuracy, but 64% of patients still required a liver biopsy.31

SAFE algorithms have the potential to reduce the number of needle biopsies needed to assess the degree of hepatic fibrosis.


CONVENTIONAL IMAGING STUDIES ARE NOT SENSITIVE FOR FIBROSIS

Standard imaging studies often show findings of cirrhosis but are not particularly sensitive, with a low negative predictive value.
Ultrasonography can show a small, nodular liver in advanced cirrhosis, but surface nodularity or increased echogenicity can be seen in hepatic steatosis as well as in cirrhosis. In one study,33 ultrasonography identified diffuse parenchymal disease but could not reliably distinguish fat from fibrosis or diagnose cirrhosis.

Often, in cirrhosis, the right lobe of the liver is atrophied and the caudate or left lobes are hypertrophied. Efforts to use the ratio of the widths of the lobes to diagnose cirrhosis have shown varying performance characterstics.34,35

One study of the splenic artery pulsatility index has shown this to be an accurate predictor of cirrhosis.36

Computed tomography provides information similar to that of ultrasonography, and it can identify complications of cirrhosis, including portal hypertension and ascites. On the other hand, it costs more and it exposes the patient to radiation and contrast media.


ELASTOGRAPHY, A PROMISING TEST

Hepatic elastography, a method for estimating liver stiffness, is an exciting recent development in the noninvasive measurement of hepatic fibrosis. Currently, elastography can be accomplished by ultrasound or magnetic resonance.

Ultrasound elastography

The FibroScan device (EchoSens, Paris, France) uses a mild-amplitude, low-frequency (50-Hz) vibration transmitted through the liver.37 It induces an elastic shear wave that is detected by pulse-echo ultrasonography as the wave propagates through the organ.
The velocity of the wave correlates with tissue stiffness: the wave travels faster through denser, fibrotic tissue.38,39
Ultrasound elastography (also called transient elastography) can sample a much larger area than liver biopsy can, providing a better understanding of the entire hepatic parenchyma. 40 Moreover, it can be repeated often without risk. This device is in widespread use in many parts of the world, but it is not yet approved in the United States.

A meta-analysis of 50 studies assessed the overall performance of ultrasound elastography for diagnosing liver fibrosis.41 The areas under the receiver operating characteristic curve were as follows:

?? For significant fibrosis: 0.84 (95% CI 0.82–0.86)
?? For severe fibrosis: 0.89 (95% CI 0.88–0.91)
?? For cirrhosis: 0.94 (95% CI 0.93–0.95).

The type of underlying liver disease influenced the diagnosis of significant fibrosis, which was diagnosed most consistently in patients with hepatitis C. The authors concluded that ultrasound elastography had excellent diagnostic accuracy for diagnosing cirrhosis irrespective of the underlying liver disease, while the diagnosis of significant fibrosis had higher variation, which was dependent on the underlying liver disease.

A meta-analysis of nine studies42 showed ultrasound elastography to have a sensitivity of 87% (95% CI 84%–90%) and a specificity of 91% (95% CI 89%–92%) for the diagnosis of cirrhosis. In seven of the nine studies, it diagnosed stage II to IV fibrosis with 70% sensitivity (95% CI 67%–73%) and 84% specificity (95% CI 80%–88%).

Limitations.
Ultrasound elastography is less effective in obese patients, as the adipose tissue attenuates the elastic wave, and it has not been reliable in patients with acute viral hepatitis.43 Male sex, body mass index greater than 30, and metabolic syndrome seem to increase liver stiffness, thus limiting the use of this test.44

Until more data are available, the ultimate value of ultrasound elastography in reducing the number of liver biopsies needed remains unknown. However, this test shows potential as a reliable and noninvasive way to assess the degree of fibrosis in patients with liver disease.

Magnetic resonance elastography

Magnetic resonance elastography appears more promising than ultrasound elastography (FIGURE 2).32,37 The technique used is similar to that used in ultrasound elastography in that it uses a vibration device to induce a shear wave in the liver. However, in this case, the wave is detected by a modified magnetic resonance imaging machine, and a color-coded image is generated that depicts the wave velocity, and hence stiffness, throughout the organ.

Studies have shown a magnetic resonance scoring system that distinguishes Child-Pugh grade A cirrhosis from other grades to be 93% sensitive and 82% specific.45

In a recent direct comparison,46 the separation of values for varying stages of fibrosis was poor with the APRI index, fair with ultrasound elastography, and very good with magnetic resonance elastography (FIGURE 3). Indeed, in magnetic resonance elastography, a value greater than 4.46 kPa indicates cirrhosis (and a value less than 4.13 indicates no cirrhosis) with a high degree of likelihood, and a value less than 2.84 appears to exclude the likelihood of significant fibrosis. These findings need to be confirmed, and assurance is needed that the test performs accurately across all liver disease states.

Cost may limit the use of magnetic resonance elastography, and some patients may be unable to tolerate the procedure because of claustrophobia. It seems clear, though, that this test currently has the most promise in reducing the need for liver biopsy for grading the severity of hepatic fibrosis.

WHERE ARE WE NOW?


The importance of liver biopsy in arriving at a diagnosis of diffuse parenchymal liver disease is being diminished by accurate blood testing strategies for chronic viral hepatitis, autoimmune hepatitis, and primary biliary cirrhosis. Further, imaging tests are superior to liver biopsy in the diagnosis of primary sclerosing cholangitis.

However, many cases remain in which diagnostic confusion exists even after suitable laboratory testing and imaging studies. Diagnosing infiltrative disease (eg, amyloidosis, sarcoidosis), separating benign fatty liver disease from steatohepatitis, and evaluating liver parenchyma after liver transplantation are best accomplished by liver biopsy.

While needle biopsy is still the mainstay in diagnosing hepatic fibrosis, its days of dominance seem limited as technology improves. When physical examination or standard laboratory tests reveal clear-cut signs of portal hypertension, liver biopsy will seldom add useful information. Similarly, when imaging studies provide compelling evidence of cirrhosis and portal hypertension, needle biopsy is not warranted.

The SAFE algorithms warrant further evaluation in all chronic liver diseases, as they may help decrease the number of liver biopsies required. And we believe elastography will play an ever-increasing role in the assessment of hepatic fibrosis and will significantly reduce the need for biopsy in patients with liver disease.

The Cleveland Clinic Foundation