The clinical manifestations of liver disease are varied and particularly important are jaundice, cholestasis, hepatomegaly, portal hypertension, ascites, hepatic encephalopathy and liver failure. Physicians often consider the patient’s complaints and perform a physical examination when making a diagnosis of liver disease. Senescent or damaged red blood cells are removed from the bloodstream primarily by the spleen. During this process, hemoglobin, the main component of red blood cells that transports oxygen, is broken down and transported to the spleen as bilirubin, which is then secreted to form bile that is emptied into the small intestine via the common bile duct. The bilirubin secretion process is impeded, and excess bilirubin backs up into the bloodstream, leading to jaundice. Inflammation of the liver cells or other abnormalities can impede the secretion of bilirubin into the bile, resulting in elevated blood bilirubin levels. On the other hand, the extrahepatic bile ducts can cause hyperbilirubinemia due to obstruction by stones or tumors and, more rarely, massive destruction of red blood cells. For example, neonatal jaundice (see section 252). Gilbert’s syndrome is a familial nonhemolytic jaundice with mildly elevated bilirubin levels, usually not enough to cause jaundice, and this inherited condition is often detected on liver function tests without other manifestations or causing any problems. Symptoms: In jaundice, the skin and sclera appear yellow, and the urine color deepens because bilirubin is secreted by the kidneys. Other symptoms depend on the cause of jaundice, such as loss of appetite, nausea and vomiting, and fever in hepatitis. Obstruction of bile flow may produce cholestasis. Diagnosis and treatment] Doctors can use laboratory tests and imaging to determine the cause of jaundice. If the cause is the liver itself, such as viral hepatitis, the jaundice usually goes away as the liver improves; if the cause is a biliary obstruction, surgery or endoscopy (bendable endoscopy with surgical instruments) is often used to relieve the biliary obstruction as much as possible. Cholestasis Cholestasis is an obstruction or reduction in the flow of bile. Bile flow can be obstructed anywhere between the hepatocytes and the duodenum. Despite the complete obstruction of bile flow, the liver continues to produce bilirubin, which flows backward into the bloodstream, where it sloughs off into the skin and is excreted in the urine, causing jaundice. For diagnostic and therapeutic purposes, cholestasis is divided into two categories: endogenous and exogenous. Endogenous sources include hepatitis, alcoholic liver damage, primary biliary cirrhosis, drug damage, and hormonal changes during pregnancy (cholestasis during pregnancy); exogenous sources include bile duct stones, bile duct stenosis (structural), bile duct cancer, pancreatic cancer, and pancreatitis. Symptoms: Excessive bilirubin causes jaundice and deepening of urine color, especially due to the lack of bilirubin in the intestines, stools are often grayish-white terra cotta in color; due to the lack of bile in the intestines, which does not help the digestion of food fats, the stools can also contain a large amount of fat (steatorrhea), and also affects the absorption of calcium and vitamin D. If this condition persists, this type of nutrient is often associated with a lack of bile in the intestines. If this condition persists, deficiencies of such nutrients can cause loss of bone calcium, leading to bone pain and fractures. In addition, the absorption of substances necessary for blood clotting is reduced, causing a tendency to bleed easily. Retention of bile products within the blood circulation can cause pruritus (secondary to skin scratching and damage), and persistent jaundice can cause deepening of skin pigmentation and yellow fatty deposits in the skin. Depending on the cause of jaundice, the patient may present with different manifestations, such as abdominal pain, loss of appetite, vomiting or fever. To determine the cause of jaundice, the doctor will ask about medical conditions such as hepatitis, alcohol consumption, and recent medication history. Spider moles on the skin, an enlarged spleen, and ascites are signs of pre-existing lesions in the liver cells. If the jaundice is extrahepatic, the patient may have a history of chills, biliary colic, and an enlarged gallbladder (the doctor may be able to palpate or visualize the enlarged gallbladder). Typically, patients with cholestasis may have a significant elevation of alkaline phosphatase in the blood, and a blood bilirubin level test may indicate the severity of the cholestasis, but does not identify the cause. If the blood bilirubin level is abnormal, another ultrasound, CT scan, or both are usually done to help the doctor differentiate between intrahepatic or extrahepatic causes of jaundice. If the cause is intrahepatic, a liver biopsy (obtaining a small amount of liver tissue for microscopic examination) may be performed, which usually establishes the diagnosis; if the cause is an extrahepatic biliary obstruction, an endoscopy is often performed to clarify the nature of the obstruction. Treatment: Extrahepatic obstruction is usually treated with surgery or therapeutic endoscopy (a bendable, visual catheter with surgical instruments attached); intrahepatic obstruction is treated differently depending on the cause of the disease; if jaundice is caused by a certain medication, it is necessary to discontinue the medication; if it is hepatitis, jaundice tends to disappear as the course of hepatitis eases. Oral anticholinergics may be used to manage pruritus. The drug binds to certain bile products in the small intestine and blocks their reabsorption to reduce skin irritation. In cases of less severe liver damage, the administration of vitamin K improves blood clotting. Calcium and vitamin D supplements are often given when cholestasis persists, but are not very effective in preventing bone decalcification. Lipids such as triglycerides need to be supplemented in patients with steatorrhea. Hepatomegaly An enlarged (swollen) liver means liver disease. Nonetheless, many patients with liver disease have livers that are in the normal size range or even have shrunken. Hepatomegaly is usually not clinically apparent, but if the liver is enlarged significantly, it can cause abdominal discomfort, such as a feeling of fullness. If the liver is enlarging rapidly, it may be painful to the touch, and the doctor usually palpates the liver through the abdominal wall during a physical examination and determines its size. When palpating the liver, the doctor should also pay attention to its texture. A liver enlarged due to hepatitis, fatty infiltration, hepatic congestion, or early bile duct obstruction is soft to the touch. The liver enlarged by cirrhosis is hard and irregular to touch. Hepatocellular carcinoma is characterized by a limited mass. Portal hypertension is an abnormally high blood pressure in the portal vein (the large vein that collects blood from the intestines and transports it to the liver). The portal vein collects blood flow throughout the small intestine, spleen, pancreas, and gallbladder. Upon entering the liver, the portal vein divides into tiny ducts, and the blood subsequently passes through the liver and then enters the body’s circulation through the hepatic vein. There are two factors that contribute to increased intravascular pressure in the portal vein; increased blood flow through the portal vein and increased resistance to blood flow through the liver. In Western countries, the most common cause of portal hypertension is increased resistance to blood flow due to cirrhosis. Portal hypertension leads to an increase in the number and thickening of venous vessels (called collateral vessels) to communicate between the portal system and the body circulation. These vessels bypass the liver to carry blood flow, and because of these bypasses, substances that are normally broken down and excreted through the liver are able to enter the circulation directly. The collateral vessels are established at different sites, the most important being the lower esophagus, where they thicken and twist into varicose veins (called esophageal varices). These thickened vessels become brittle and bleed easily, often causing severe hemorrhage. Other side branches may be established around the navel and the rectum. Symptoms and diagnosis] Portal hypertension is often characterized by an enlarged spleen and increased resistance to hepatic reflux leading to leakage of body fluids into the abdominal cavity, resulting in the formation of ascites. The lower esophagus and submucosal varices of the stomach bleed easily, often profusely. Varicose veins of the rectum may bleed, but this is extremely rare. The doctor usually identifies an enlarged spleen by palpation of the abdominal wall. Ascites is characterized by abdominal distension and a turbid tone on auscultation. Ultrasound scans and X-rays may reveal conditions related to portal hypertension. Ultrasound is used to detect blood flow in the portal vein vessels and the presence of ascites, and CT scans can also be used to examine thickened veins. The pressure in the portal vein system can be measured by puncture through the abdominal wall needle into the liver and spleen. [Treatment] To reduce the risk of bleeding from a varices vein in the lower esophagus, your doctor may use methods such as oral cardiac glycosides (a medication used to treat high blood pressure) to reduce the pressure within the portal vein. Bleeding from the lower esophageal varices is an emergency situation. Posterior pituitary hormone or Zondervan may be given intravenously to constrict the bleeding vein, and blood transfusions may be given to replace the blood loss. Endoscopy is usually needed to identify the site of bleeding, and endoscopic rubber bands or chemical injections are used to close the bleeding vein. If bleeding continues, a catheter with a balloon at the end can be inserted into the esophagus through the patient’s nose. Compression of the varicose vein by an inflated balloon usually stops the bleeding. If bleeding persists or recurs, surgery may be used to create a bypass (called a shunt) between the portal venous system and the systemic circulation. Because the pressure in the systemic venous system is very low, a shunt reduces the pressure in the portal vein. There are many types of portal vein shunt procedures, including those done with special instruments under radiologic X-ray guidance. Shunts are usually very successful in stopping bleeding, but they are dangerous and increase the risk of brain dysfunction (hepatic encephalopathy) due to liver failure. Ascites Ascites is the accumulation of fluid in the abdominal cavity. Ascites tends to be present in a long-term (chronic) form rather than in short-term (acute) episodes, and occurs most often in cirrhosis of the liver, especially alcoholic cirrhosis. Non-liver diseases such as cancer, heart failure, kidney failure and tuberculosis can also cause ascites. In patients with liver disease, fluid leaks from the surface of the liver and small intestine, often due to a combination of causes, including portal hypertension, decreased ability of blood vessels to retain water, and changes in hormones and chemicals that manage body fluids. Symptoms and Diagnosis] Small amounts of ascites usually cause no symptoms, but large amounts of ascites can cause abdominal distension and discomfort, shortness of breath, and turbid sounds in the abdomen when the doctor palpates. A large amount of ascites causes the abdomen to be tense or protruding. In some patients with ascites, the joints swell (edema) from excess water. If the cause of ascites cannot be determined or is not clear, an ultrasound may be done. Alternatively, a small sample of ascites may be taken by puncture through the abdominal wall (diagnostic puncture) and sent to the laboratory to help determine the cause. The basic treatment for ascites is bed rest and a low-salt diet, combined with diuretics, which cause the kidneys to remove more water from the urine. If ascites makes breathing and eating difficult, ascites may be drained via a puncture in the abdominal wall (therapeutic laparotomy). Draining ascites can easily recur unless the patient is also on diuretics. Usually, large amounts of albumin (the main plasma protein) are lost from the plasma into the ascites and can therefore be replaced by intravenous albumin. Occasionally, an infection of the ascites can develop secondary to the ascites for no apparent reason, especially in patients with alcoholic cirrhosis; this infection is called idiopathic bacterial peritonitis and requires antibiotic treatment. Hepatic encephalopathy Hepatic encephalopathy (also known as portal systemic encephalopathy and hepatic coma) is a disease in which toxic substances normally produced in the blood and excreted by the liver act on the brain to cause brain dysfunction. Substances absorbed into the blood from the small intestine are eliminated when they flow through the liver. In hepatic encephalopathy, toxins are not eliminated when liver function is impaired, and there may be some direct connection between the portal system and the circulation as a result of liver disease, allowing certain toxins to bypass the liver and enter the circulation. Surgical procedures to reduce portal hypertension (portacaval shunts) have the same result, and whatever the cause, the result is the same: toxins can reach the brain and affect its function. It is not clear which substances are toxic to the brain. In any case, increased levels of protein degradation products in the blood, such as increased concentrations of ammonia, seem to be the main cause. In patients with chronic liver disease, encephalopathy is usually triggered by events that increase hepatic impairment, such as acute infections or alcoholism, but can also occur as a result of eating too much protein, which increases the level of degraded protein products in the blood. Gastrointestinal bleeding, such as bleeding from esophageal varices, can also lead to an increase in protein degradation products that act directly on the brain. Certain medications, particularly certain tranquilizers, pain relievers, and diuretics, can also induce encephalopathy. Encephalopathy can be relieved by eliminating these triggers. [Symptoms and Diagnosis] Symptoms of hepatic encephalopathy are the result of reduced brain function, especially impaired consciousness. Early manifestations include small changes in logical thinking, personality and behavior, with alterations in the patient’s mental state and decreased judgment. As the disease progresses, patients usually show drowsiness and disorientation, slow movement and speech, and disorientation is common; agitation and excitement may also be shown, but are uncommon, and epileptic-like seizures are uncommon, and ultimately the patient loses consciousness and enters a coma. The presence of cerebral dysfunction in patients with liver disease is a strong diagnostic basis. The patient exhales sweet-smelling gas, develops hand tremors when stretching the arms, and has a pronounced fluttering wing-like movement. An electroencephalogram can help in the diagnosis of early hepatic encephalopathy and may show abnormal brain waves even in very mild cases. Blood tests usually show high blood ammonia. [Treatment] The doctor will try to find and remove the causative agent. For example, infections or medications being taken, reduction of absorption of toxic substances from the intestinal tract, the need for protein restriction in the diet, and the provision of calories from carbohydrates mainly by mouth or intravenously. Synthetic sugars (lactose, fructose) taken orally have three benefits: firstly, they change the intestinal pH and therefore the type of intestinal flora; secondly, they reduce the absorption of ammonia; and secondly, they have a light laxative effect (cleansing enemas can also be used). Instead of a laxative, neomycin can sometimes be used, which reduces the number of gut bacteria that normally help digest protein. With treatment, hepatic encephalopathy is often reversible, and in fact, complete recovery is possible, especially if the encephalopathy is stimulated by some reversible cause. However, severe hepatic coma caused by acute hepatitis has a mortality rate of up to 80%, even with aggressive intensive treatment. Liver Failure Liver failure is a severe deterioration of liver function. Liver failure can be caused by any type of liver disease, including viral hepatitis, cirrhosis, and alcohol or drug (e.g., analgesics) induced liver damage. Liver failure must be preceded by extensive liver tissue damage. Symptoms and Diagnosis] Patients with liver failure usually have jaundice, bruising or bleeding tendencies, ascites, cerebral dysfunction (hepatic encephalopathy), and deterioration of general health. Other common symptoms include fatigue, weakness, nausea, and loss of appetite. The clinical picture establishes the diagnosis of liver failure, and blood tests may show severe liver impairment. Prognosis and Management Management is determined by the etiology and the particular clinical presentation. Patients usually require a strictly controlled diet. Protein intake should be carefully controlled; too much protein causes hepatic encephalopathy and too little causes weight loss. Sodium intake should also be restricted to control ascites. Alcohol is completely avoided, as it can exacerbate liver damage. Liver disease continues to progress, treatment for liver failure is ineffective, and eventually the patient dies. Even with treatment, the disease is irreversible, and patients with advanced disease may die of renal failure (hepatorenal syndrome). Liver transplantation, if performed in a timely manner, can restore the patient to a normal state of health, but is only appropriate for a small number of patients with liver failure.