Liver biopsy can provide a tissue of the liver, which is then mounted on a slide and studied for changes due to disease. A small core of tissue is obtained that is representative even with focal lesions. Ultrasound- or CT-guided biopsies definitely improve the yield. A biopsy is valuable in detecting tuberculosis (TB) or other infiltrations and help to clarifying the underlying cause of the liver inflammation such as ischemic injury, rejection after liver transplantation, biliary tract disease, or viral hepatitis. Serial biopsies are commonly performed over years, may be necessary for monitoring disease progression. 
Gross examination and histopathology are often definitive. Cytology, frozen section, and culture are useful processes in selected cases. Metal content can be measured in the biopsy specimen: copper in suspected Wilson's disease and iron in hemochromatosis. 
Limitations of liver biopsy include a sampling error and occasional errors or uncertainty in cases of cholestasis. 
Indications for Liver Biopsy 

Unexplained liver enzyme abnormalities 

Alcoholic liver disease or nonalcoholic steatosis (diagnose and stage) 

Chronic hepatitis (diagnose and stage) 

Suspected rejection after liver transplantation that cannot be diagnosed by less invasive methods 

Hepatosplenomegaly of unknown cause 

Unexplained intrahepatic cholestasis 

Suspected malignancy (focal lesions) 

Unexplained systemic illness–eg, fever of unknown origin, inflammatory or granulomatous diseases (culture is performed with biopsy) 

Endoscopy 
An endoscope as used in the field of gastroenterology is a thin flexible tube which uses a lens or miniature camera to view various areas of the gastrointestinal tract. When the procedure is performed to examine certain organs such as the bile ducts or pancreas, the organs are not viewed directly, but rather indirectly through the injection of x-ray dye into the bile duct. 
The performance of an exam using an endoscope is referred by the general term endoscopy. Diagnosis through biopsies or other means and therapeutic procedures can be done with these instruments. 
Extracorporeal shock-wave lithotripsy (ESWL) 
This is a technique that uses high-pressure waves similar to sound waves that can be "focused" on a very small area, thereby fracturing small solid objects such as gallstones, kidney stones, etc. The small fragments can pass more easily and harmlessly into the intestine or can be dissolved with medications. 

The Hepatic Venous Pressure Gradient (HVPG) 
The HVPG represents the gradient between portal vein and intra-abdominal vena cava pressure. HVPG measurement is done after an overnight fast, under conscious sedation and monitoring for vital signs (This includes heart rate, arterial blood pressures, digital oxygen saturation, and ECG). 

Under local anesthesia, central vein (for pressure monitoring) is punctured using the Seldinger technique. There are four steps to the Seldinger technique 

Venepuncture is performed with a introducer needle or trocar (a sharp hollow needle) 

A soft tipped guide wire is passed through the needle and the needle removed 

A cannula or dilator is passed over the guide wire 

Cannula or dilator is removed and catheter is passed over wire using fluoroscopy to establish its position- The guidewire is then removed 

The Seldinger technique has been refined to help reduce complications such as infection, haemorrhage and accidental perforation during intervention into a vein. The advantage of this procedure is a possibility of a biopsy alongside measurement of the pressure in the portal vein. Use of doppler ultrasound helps to minimize complications such as leakage, hematoma, and rarely, reaction in the vein, rupture of venous trocar, or arteriovenous puncture causing a fistula. The key measurement of a HVPG procedure are the Free Hepatic Venous Pressure and the Wedge Hepatic Venous Pressure. The difference between the two measurements will provide the pressure gradient in the liver to ascertain severity of portal hypertension. 


Grading of pressure 

Persons with normal portal pressure measure between 1-5mmHg. 

Persons with portal pressure above 5mmHg are graded as subclinical portal hypertension. 

Persons with portal pressure equal and over 10mmHg are assessed to be clinically significant portal hypertension. 

Persons with a portal pressure over 12mmHg are at risk for a varaceal rupture. 

What are some common liver disease symptoms? 
When diagnosing liver disease, the physician looks at the patient's symptoms and conducts a physical examination. In addition, the physician may request a liver biopsy, liver function tests, an ultrasound, or a CT scan (computerized tomography scan). 
Some common liver disease symptoms include the following, each of which are described briefly below: 

jaundice 

cholestasis 

liver enlargement 

portal hypertension 

ascites 

liver encephalopathy 

liver failure 


What is jaundice? 
Jaundice is a yellow discoloration of the skin and eye whites due to abnormally high levels of bilirubin (bile pigment) in the bloodstream. Urine is usually dark because of the bilirubin excreted through the kidneys. High levels of bilirubin may be attributed to inflammation or other abnormalities of the liver cells or blockage of the bile ducts. Sometimes jaundice is caused by the breakdown of a large number of red blood cells, which can occur in newborns. Jaundice is usually the first sign, and sometimes the only sign, of liver disease. 

What is cholestasis? 
Cholestasis is reduced or stopped bile flow. Bile flow may be blocked inside or outside the liver. Symptoms may include: 

jaundice 

dark urine 

pale stool 

bone loss 

easy bleeding 

itching 

small, spider-like blood vessels visible in the skin 

enlarged spleen 

fluid in the abdominal cavity 

chills 

pain from the biliary tract or pancrea 

enlarged gallbladder 

Some causes of cholestasis include: 

hepatitis 

primary biliary cirrhosis 

drug effects 

hormonal changes during pregnancy 

a stone in the bile duct 

bile duct narrowing 

bile duct cancer 

pancreatic cancer 

inflammation of the pancreas 

What is liver enlargement? 
Liver enlargement is usually an indicator of liver disease, although there are usually no symptoms associated with a slightly enlarged liver (hepatomegaly). Symptoms of a grossly enlarged liver include abdominal discomfort or "feeling full." 

What is portal hypertension? 
The portal vein carries about 1500 ml/min of blood from the small and large bowel, spleen, and stomach to the liver at a pressure of about 5 mmHg. Any obstruction or increased resistance to flow or due to pathological increases in portal blood flow could lead to portal hypertension with portal pressures over 12 mm Hg. Although the differential diagnosis is extensive, alcoholic and viral cirrhosis are the leading causes of portal hypertension in Western countries, whereas liver disease due to schistosomiasis is the main cause in other areas of the world (caused by a parasitic worm). Portal vein thrombosis is the commonest cause in children. In India and Japan non-cirrhotic portal fibrosis is a known cause of portal hypertension seen in lower-social groups and low hygiene. 

Portal hypertension is abnormal high blood pressure in the portal vein, which supplies the liver with blood from the intestine. Portal hypertension may be due to increased blood pressure in the portal blood vessels or resistance to blood flow through the liver. Portal hypertension can lead to the growth of collateral vessels that connect to the general circulation, bypassing the liver. When this occurs, substances that are normally removed by the liver pass into the general circulation. Symptoms of portal hypertension may include: 

a distended abdominal cavity (ascites) 

bleeding of the varicose veins at the lower end of the esophagus and in the stomach lining 


What is gastric bleeding? 
Increases in portal pressure disturb the portal systemic circulation. These factors are partly responsible for the important complications of chronic liver disease, including variceal bleeding, hepatic encephalopathy, ascites, hepatorenal syndrome, recurrent infection, and abnormalities in coagulation. Variceal or gastric bleeding is the most serious complication and is an important cause of death in patients with cirrhotic liver disease. 

Patients with varices have a 30% lifetime risk of gastric bleeding, and a third of those who bleed will die. Patients who have bled once from oesophageal varices have a 70% chance of bleeding again and about a third of further bleeding episodes are fatal. 

What is ascites? 
Ascites is fluid build-up in the abdominal cavity, caused by fluid leaks from the surface of the liver and intestine. Ascites due to liver disease usually accompanies other liver disease characteristics such as portal hypertension. Symptoms of ascites may include a distended abdominal cavity, which causes discomfort and shortness of breath. Causes of ascites may include: 

liver cirrhosis (especially cirrhosis caused by alcoholism) 

alcoholic hepatitis 

chronic hepatitis 

obstruction of the hepatic vein 

Ascites can also be caused by non-liver disorders. 


What is Cirrhosis? 
Cirrhosis is characterized anatomically by widespread nodules in the liver combined with fibrosis. The fibrosis and nodule formation causes distortion of the normal liver architecture which interferes with blood flow through the liver. Cirrhosis can also lead to an inability of the liver to perform its biochemical functions. 

The journey of what goes wrong in Cirrhosis 

Cirrhosis results from damage to liver cells from toxins, inflammation, metabolic derangements and other causes. In cryptogenic liver disease, the cause is unknown. 


Damaged and dead liver cells are replaced by fibrous tissue leads to fibrosis (scarring). Liver cells begin to regenerate in an abnormal pattern primarily forming nodules that are surrounded by fibrous tissue 
. 

Grossly abnormal liver architecture leads to decreased blood flow to and through the liver. There is decreased blood flow to the liver and blood back up in the portal vein and portal circulation leads to some of the serious complications of cirrhosis. Blood can back up in the spleen causing it to enlarge and sequester blood cells. 


Most often, the platelet count falls because of splenic sequestration (withholding of the blood) leading to abnormal bleeding. If the pressure in the portal circulation increases because of cirrhosis and blood withheld, blood can flow backwards from the portal circulation to the systemic circulation where they are connected. This can lead to varicose veins in the stomach and esophagus (gastric and esophageal varices) and rectum (hemorrhoids). Gastric and esophageal varices can rupture, bleed massively and even cause death. 


Hypertension in the portal circulation, along with other hormonal, metabolic and kidney abnormalities in cirrhosis, can also lead to fluid accumulation the abdomen (ascites) and the peripheral tissue (peripheral edema). 


Decreased bilirubin secretion from hepatocytes in cirrhosis leads to the back up of bilirubin in the blood. This leads to jaundice, the yellow discoloration of the skin and eyes. As the water-soluble form of bilirubin also backs up in the blood, bilirubin can also spill into the urine giving it a bright yellow to dark brown color. 


Abnormal biochemical function of the liver in cirrhosis can lead to several complications. The serum albumin concentration falls which can lead to aggravation of ascites and edema. The metabolism of drugs can change requiring dose adjustments. 


In men, breast enlargement (gynecomastia) sometimes occurs because metabolism of estrogen in the liver is decreased. 


Decreased production of blood clotting factors can lead to bleeding complications. 


Derangements in the metabolism of triglycerides, cholesterol and sugar can occur. 


In earlier stages, cirrhosis frequently can cause insulin resistance and diabetes mellitus. 


In later stages or in severe liver failure, blood glucose may be low because it cannot be synthesized from fats or proteins. 


Cirrhosis, especially in advanced cases, can cause profound abnormalities in the brain. In cirrhosis, some blood leaving the gut bypasses the liver as blood flow through the liver is decreased. 


Metabolism of components absorbed in the gut can also be decreased as liver cell function deteriorates. 
Both of these derangements can lead to hepatic encephalopathy as toxic metabolites, normally removed from the blood by the liver, can reach the brain. 


In its early stages, subtle mental changes such as poor concentration or the inability to construct simple objects occurs. 
In severe cases, hepatic encephalopathy can lead to stupor, coma, brain swelling and death. 


Cirrhosis can lead to immune system dysfunction causing an increased risk of infection. Ascites fluid in the abdomen often becomes infected with bacteria normally present in the gut (spontaneous bacterial peritonitis). 


Cirrhosis can also lead to kidney dysfunction and failure. 


End-stage cirrhosis, can trigger kidney dysfunction called hepatorenal syndrome can occur. This is fatal unless a liver transplant takes place. 


Clinical Symptoms and Diagnosis of Cirrhosis 

Cirrhosis is usually an easy diagnosis to make when any or all of the above abnormalities and complications are present. This is especially true when the underlying liver disease can be identified. The underlying liver disease is identified in most patients, however, sometimes it will not be discovered despite recommending specific diagnostic tests. Such cases are called "cryptogenic" cirrhosis. 

Some patients with cirrhosis, especially early in the course of the disease, will have no overt clinical signs or symptoms. Some may have only subtle physical changes such as 


Red palms or red spots that blanch on their upper body (spider angiomata) 

Hypertrophy of the parotid glands 

Gynecomastia or fibrosis of tendons in the palms. 
Some patients may only have subtle abnormalities on blood tests, and in some cases, all blood tests may be normal. 

Radiological and nuclear medicine tests may give clues as to the presence of cirrhosis 

The diagnosis of cirrhosis can often be made by an ultrasound 

The diagnosis of the liver architecture can only be made by a biopsy. 


Treatment 
Cirrhosis of the liver is irreversible but treatment of the underlying liver disease may slow or stop the progression. Such treatment depends upon the underlying etiology. In cryptogenic cirrhosis, since the cause is unknown, supportive therapy directed at alleviating symptoms due to progression and its complications is the only answer. 


Bleeding esophageal varices can be treated with endoscopic sclerotherapy or rubber band ligation. 

Ascites and edema are often responsive to a low sodium diet and such a diet must be emphasized in patients with these symptoms. More advanced ascites and edema can respond to diuretic therapy. 

A low protein diet and agents such as lactulose may help hepatic encephalopathy. 
Infections such as spontaneous bacterial peritonitis must be rapidly treated with appropriate antibiotics. 

Drugs metabolized in the liver must be given with caution. 

Coagulation disorders will sometimes respond to vitamin K. 

Liver transplantation is highly effective for the treatment of end-stage cirrhosis. Transplantation is usually needed when complications such as encephalopathy, ascites or bleeding varices are uncontrollable or when biochemical function is severely depressed. 



What is liver encephalopathy? 
Liver encephalopathy is the deterioration of brain function due to toxic substances building up in the blood, which are normally removed by the liver. Liver encephalopathy is also called portal-systemic encephalopathy, hepatic encephalopathy, or hepatic coma. Symptoms may include: 

impaired consciousness 

changes in logical thinking, personality, and behavior 

mood changes 

impaired judgement 

drowsiness 

confusion 

sluggish speech and movement 

disorientation 

loss of consciousness 

coma 


What is liver failure? 
Liver failure is severe deterioration of liver function. Liver failure occurs when a large portion of the liver is damaged due to any type of liver disorder. Symptoms may include: 

jaundice 

tendency to bruise or bleed easily 

ascites 

impaired brain function 

general failing health 

fatigue 

weakness 

nausea 

loss of appetite 


Supportive Treatments in management of characteristics of Liver Disease 

Sclerotherapy 
In sclerotherapy a sclerosant solution (ethanolamine oleate or sodium tetradecyl sulphate) is injected into the bleeding varix or the overlying submucosa. Injection into the varix obliterates the lumen by thrombosis whereas injection into the submucosa produces inflammation followed by fibrosis. The first injection controls bleeding in 80% of cases. If bleeding recurs, the injection is repeated. Complications are related to toxicity of the sclerosant and include transient fever, dysphagia and chest pain, ulceration, stricture, and (rarely) perforation. 

Band ligation 
Band ligation is achieved by a banding device attached to the tip of the endoscope. The varix is aspirated into the banding chamber, and a trip wire dislodges a rubber band carried on the banding chamber, ligating the entrapped varix. One to three bands are applied to each varix, resulting in thrombosis. Band ligation eradicates oesophageal varices with fewer treatment sessions and complications than sclerotherapy. 




Balloon tube tamponade 
The balloon tube tamponade may be life saving in patients with active variceal bleeding if emergency sclerotherapy or banding is unavailable or not technically possible because visibility is obscured. In patients with active bleeding, an endotracheal tube is inserted to protect the airway before attempting to place the oesophageal balloon tube. 

A Minnesota balloon tube has four entry points 

1for gastric aspiration 

2 to inflate the gastric and oesophageal balloons 

1 above the oesophageal balloon for suction of secretions to prevent aspiration. 


The tube is inserted through the mouth, and correct positioning in the stomach is checked by auscultation while injecting air through the gastric lumen. The gastric balloon is then inflated with 200 ml of air. Once fully inflated, the gastric balloon is pulled up against the oesophagogastric junction, compressing the submucosal varices. The tension is maintained by strapping a split tennis ball to the tube at the patient's mouth. 
An oesophageal balloon is rarely required. Complications could be 


gastric and oesophageal ulceration 

pneumonia 

oesophageal perforation. 


Continued bleeding during balloon tamponade indicates an incorrectly positioned tube or bleeding from another source. After resuscitation, and within 12 hours, the tube is removed and endoscopic treatment repeated. 





Transjugular intrahepatic portosystemic shunt (TIPS) 
Transjugular intrahepatic portosystemic shunt is the best procedure for patients whose bleeding is not controlled by endoscopy. It is effective only in portal hypertension of hepatic origin (caused by fibrosis of the liver for example). The procedure is performed via the internal jugular vein under local anaesthesia with sedation. The hepatic vein is cannulated and a tract created through the liver from the hepatic to the portal vein, with a needle under ultrasonographic and fluoroscopic guidance. The tract is dilated and an expandable metal stent inserted to create an intrahepatic portosystemic shunt. The success rate is excellent. Haemodynamic effects are similar to those found with surgical shunts, with a lower procedural morbidity and mortality. The process lasts one to three hours, but you should expect to stay in the hospital overnight after the procedure. 

Transjugular intrahepatic portosystemic shunting is an effective salvage procedure for stopping acute variceal haemorrhage, controlling bleeding from gastric varices, and congestive gastropathy after failure of medical and endoscopic treatment. 


What Tests Are Required Before the TIPS? 
Before receiving either of these procedures, the following tests may be performed to determine the extent and severity of your condition: 

Evaluation of your medical history 

A physical examination 

Blood tests 

Angiogram (an X-ray test that takes pictures of the blood flow within a particular artery) 

Ultrasound 

Endoscopy 

Before either the TIPS procedure, your doctor may ask you to have other preoperative tests, which may include an electrocardiogram (EKG) (a test that records the electrical activity of your heart), chest X-ray, or additional blood tests. If your doctor thinks you will need additional blood products they will be ordered at this time. 



How Successful Is the TIPS Procedure? 
The TIPS procedure controls bleeding immediately in more than 90% of patients. However, in about 20% of patients, the shunt may narrow, causing varices to re-bleed at a later time. 

What Complications Are Associated With TIPS? 
Shunt narrowing or occlusion (blockage) can occur within the first year after the procedure. Follow-up ultrasound examinations are performed frequently after the TIPS procedure to detect these complications. The signs of occlusion include increased ascites (accumulation of fluid in the abdomen) and re-bleeding. This condition can be treated by a radiologist who re-expands the shunt with a balloon or repeats the procedure to place a new stent. 
Encephalopathy, or abnormal functioning of the brain, can occur with severe liver disease. Hepatic encephalopathy can become worse when blood flow to the liver is reduced by TIPS, which may result in toxic substances reaching the brain without being metabolized first by the liver. This condition can be treated with medications, diet, or by occluding the shunt (making the shunt inaccessible). 

What is the Distal splenorenal shunt (DSRS) Procedure? 
The DSRS is a surgical procedure during which the vein from the spleen (called the splenic vein) is detached from the portal vein and attached to the left kidney (renal) vein. This surgery selectively reduces the pressure in the varices and controls the bleeding. It is usually performed only in patients with good liver function. General anesthesia is given before the surgery, which lasts about four hours. You should expect to stay in the hospital from seven to 10 days. 

How Successful Is the DSRS Surgery? 
DSRS controls bleeding in more than 90% of patients, with the highest risk of any re-bleeding occurring in the first month. The DSRS procedure provides good long-term control of bleeding. 

What Complications Are Associated With DSRS Surgery? 
Ascites, an accumulation of fluid in the abdomen, can occur. This can be treated with diuretics and restricted sodium intake. 

Follow-Up Care Following TIPS or DSRS Procedures 
DSRS controls bleeding in more than 90% of patients, with the highest risk of any re-bleeding occurring in the first month. The DSRS procedure provides good long-term control of bleeding. 

Ten days after hospital discharge, meet with your surgeon or hepatologist (liver specialist) to evaluate your progress. Lab work will be done at this time. 

Six weeks after the TIPS procedure (and again three months after the procedure), have an ultrasound so your doctor can check that the shunt is functioning properly. You will have an angiogram (an x-ray of blood vessels) only if the ultrasound indicates that there is a problem. You will also have lab work done at these times. 

Six weeks after the DSRS procedure (and again three months after the procedure), meet with the surgeon to evaluate your progress. Lab work will be done at this time. 

Six months after either the TIPS or DSRS procedure, have an ultrasound to make sure the shunt is working properly. Also, visit the surgeon or hepatologist. 

Twelve months after either procedure, have another ultrasound of the shunt. Also, you may have an angiogram so that your doctor can check the pressure within your veins across the shunt. 

If the shunt is working well, every six months after the first year of follow-up appointments, have an ultrasound, lab work, and visit with your doctor. 

More frequent follow-up visits may be necessary, depending on your condition. 

Attend all follow-up appointments as scheduled to ensure that the shunt is functioning properly. Be sure to follow the dietary recommendations that your healthcare providers give you. 


Long term management 
After the acute variceal haemorrhage has been controlled, treatment should be initiated to prevent rebleeding, which occurs in most patients. 

Repeated endoscopic treatment 
Repeated endoscopic treatment eradicates oesophageal varices in most patients, and provided that follow up is adequate serious recurrent variceal bleeding is uncommon. Because the underlying portal hypertension persists, patients remain at risk of developing recurrent varices and therefore require lifelong regular surveillance endoscopy. 

Long term drug treatment 
The use of beta blockers after variceal bleeding has been shown to reduce portal blood pressures and lower the risk of further variceal bleeding. Patients would be recommended beta blockers unless they have contraindications. Best results are obtained when portal blood pressure is reduced by more than 20% of baseline or to below 12 mm Hg. 



Surgical management of varices 

Surgical procedures 
Patients with good liver function in whom endoscopic management fails or who live far from centres where endoscopic sclerotherapy services are available are candidates for surgical shunt procedures. A successful portosystemic shunt prevents recurrent variceal bleeding but is a major operation that may cause further impairment of liver function. 

Partial portacaval shunts with 8 mm interposition grafts are equally effective to other shunts in preventing rebleeding and have a low rate of encephalopathy. Oesophageal transection and gastric devascularisation are now rarely performed but have a role in patients with portaland splenic vein thrombosis who are unsuitable for shunt procedures 

and continue to have serious variceal bleeding despite endoscopic and drug treatment. Liver transplantation is the treatment of choice in advanced liver disease. Hepatic decompensation is the ultimate decompressive shunt for portal hypertension and also restores liver function. Transplantation treats other complications of portal hypertension and has one year and five year survival rates of 80% and 60% respectively. 

Prophylactic management 
Most patients with portal hypertension never bleed, and it is difficult to predict who will. Attempts at identifying patients at high risk of variceal haemorrhage by measuring the size or appearance of varices have been largely unsuccessful. Beta blockers have been shown to reduce the risk of bleeding, and all patients with varices should take them unless contraindicated. 

Hypertensive portal gastropathy 
Gastric varices and portal hypertensive gastropathy 
Gastric varices are the source of bleeding in 5.10% of patients with variceal haemorrhage. Higher rates are reported in patients with left sided portal hypertension due to thrombosis of the splenic vein. Endoscopic control of gastric varices is difficult unless they are located on the proximal lesser curve in continuation with oesophageal varices. Endoscopic administration of cyanoacrylate monomer (superglue) is useful for gastric varices. The transjugular intrahepatic portosystemic shunt is increasingly used to control bleeding in this group. Bleeding from portal hypertensive gastropathy accounts for 2.3% of bleeding episodes in cirrhosis. When bleeding occurs its diffuse nature precludes the use of endoscopic treatment. Optimal management is with a combination of terlipressin and beta blockers.