Aim: Master: Clinical Manifestation and Diagnosis of Hepatic cirrhosis Acquaint: Distinguish Diagnosis and Complication as well as Rule of TreatmentKnow: Causes and Risk Factors, Mechanism.

Times: 2 hours

Definition

Hepatic cirrhosis is a chronic, degenerative disease in which normal liver cells are damaged and are then replaced by scar tissue.

Description Hepatic Cirrhosis

changes the structure of the liver and the blood vessels that nourish it. The disease reduces the liver's ability to manufacture proteins and process hormones, nutrients, medications, and poisons.

Cirrhosis gets worse over time and

can become potentially life injury.

This disease can cause: 1. Excessive bleeding

(hemorrhage)2. Impotence 3. Liver cancer 4. Coma due to accumulated

ammonia and body wastes (liver

failure) 5. Death

Long-term alcoholism is the primary cause of cirrhosis in the United States. Men and women respond differently to alcohol. Although most men can safely consume two to five drinks a day, one to two drinks a day can cause liver damage in women. Individual tolerance to alcohol varies, but people who drink more and drink more often have a higher risk of developing cirrhosis. In some people, one drink a day can cause liver scarring.

Chronic liver infections, such as hepatitis B and particularly hepatitis C, are commonly linked to cirrhosis. People at high risk of contracting hepatitis B include those exposed to the virus through contact with blood and body fluids. This includes healthcare workers and intravenous (IV) drug users. In the past, people have contracted hepatitis C through blood transfusions. As of 2003, cirrhosis resulting from chronic hepatitis has emerged as a leading cause of death among HIV-positive patients; in Europe, about 30% of HIV-positive patients are coinfected with a hepatitis virus.

Liver injury, reactions to prescription medications, certain autoimmune disorders, exposure to toxic substances, and repeated episodes of heart failure with liver congestion can cause cirrhosis. A family history of diseases can genetically predispose a person to develop cirrhosis.

Cirrhosis is the seventh leading cause of disease related death in the United States. It is twice as common in men as in women. The disease occurs in more than half of all chronic alcoholics and kills about 25,000 peoples a year. It is the third most common cause of death in adults between the ages of 45 and 65.

Hepatitis is the first leading cause of disease related death in the China. So far, HBsAg+ peoples are about 1200 million (1, 200, 000, 000), and peoples who are infected HCV are about 38 million (38, 000, 000).

Types of cirrhosis Portal or nutritional cirrhosis is the form of

the disease most common in the United States. About 30–50% of all cases of cirrhosis are this type. Nine out of every 10 people who have nutritional cirrhosis have a history of alcoholism.

Biliary cirrhosis is caused by intrahepatic bile-duct diseases that impede bile flow. Bile is formed in the liver and is carried by ducts to the intestines. Bile then helps digest fats in the intestines. Biliary cirrhosis can scar or block these ducts. It represents 15–20% of all cirrhosis.

Various types of chronic hepatitis, especially hepatitis B and hepatitis C, can cause post-necrotic cirrhosis. This form of the disease affects up to 40% of all patients who have cirrhosis.

Chronic hepatitis B and CAlcoholic liver diseaseDrugs or toxinsCardiac cirrhosis (heart failure )Certain parasitic infections (such as schistosomiasis)Primary biliary cirrhosisAutoimmune hepatitisPrimary sclerosing cholangitisOther: such as Wilson's disease, Hereditary Hemochromatosis, Alpha 1-antitrypsin deficiency, Galactosemia, Cystic fibrosisIn China, the chronic hepatitis is common cause, but not the alcoholic liver disease.

Risk factors of Hepatic cirrhosis

Worldwide Prevalence of Worldwide Prevalence of HBV HBV

and Incidence of HCCand Incidence of HCC

World prevalence of HBV carriersWorld prevalence of HBV carriers

HBsAg carriers-prevalenceHBsAg carriers-prevalence

<2%<2%2–7%2–7%>8%>8%Poorly documentedPoorly documented

Annual incidence of primary Annual incidence of primary HCCHCC

Cases/100,000 populationCases/100,000 population

1–31–33–103–1010–15010–150Poorly documentedPoorly documented

WHO 2003

Hepatitis B Related Death in Hepatitis B Related Death in ChinaChina

Cause of Cause of deathdeath

No. of No. of DeathsDeaths

MortalityMortality Percentage Percentage of total of total deathdeath

Rank orderRank order

Per 100,000 person/yrPer 100,000 person/yr

Chronic Chronic liver liver

diseases*diseases*

TotalTotal 306306 21.321.3 1.51.5 88

MenMen 193193 26.726.7 1.71.7 88

WomenWomen 113113 16.016.0 1.31.3 1010

* >85% related to HBV infection He et al. NEJM 2006

1. Hepatitis B is a viral infection that attacks the liver and can cause both acute and chronic disease.

2. The virus is transmitted through contact with the blood or other body fluids of an infected person - not through casual contact.

3. About 2 billion peoples worldwide have been infected with the virus and about 350 million live with chronic infection. An estimated 600 000 persons die each year due to the acute or chronic consequences of hepatitis B.

4. About 25% of adults who become chronically infected during childhood later die from liver cancer or cirrhosis (scarring of the liver) caused by the chronic infection.

5. The hepatitis B virus is 50 to 100 times more infectious than HIV.

6. Hepatitis B virus is an important occupational hazard for health workers.

7. Hepatitis B is preventable with a safe and effective vaccine. Data is from WHO

Hepatocytes necrosis

Hepatocytes regeneration

Fibrotic scar tissueRegenerative nodules form

Virus Alcohol Other

Cirrhosis of Liver

Spleen

Cirrhosis of Liver

Nodular

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

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

Fatty Liver

H&E

Fatty Liver

lipid vacuoles

Healthy

Normal liver

Cirrhosis after hepatitis

Cirrhosis after fatty liver

Regenerative nodules

Fibrotic scar tissue

Hepatic lobule

Centre vein

Fatty granule

Hepatic cord

CBDL TAA

CCl4 TAA

Pathology

Type of hepatic cirrhosis:1. Macronodular cirrhosis, ф>3.0 mm2. Micronodular cirrhosis, ф<3.0 mm3. Mix: Macro- +Micro-nodular cirrhosis

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

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

Macronodular cirrhosis Micronodular cirrhosis

>3.0mm <3.0mm

Mix is including maro- and micronodular cirrhosis

Pathology

Clinical Manifestation Compensation Stage: The signs and symptoms of cirrhosis are nonspecific and frequently related to the complications.

anemiableeding gums constipation decreased interest in sex diarrhea dull abdominal pain dry skin and itching fatigue fever fluid in the lungs hallucinations

indigestionlethargy lightheadedness loss of appetite muscle weakness musty breath nauseaneuritis vomiting weakness weight loss

Decompensation

1. Common symptom: • Fatigue • Lethargy• Weakness• weight loss• Fever• Dark yellow or brown

urine

2. Digest system symptoms

• Diarrhea• Constipation• Dull abdominal pain• Indigestion• Nausea

3. Anemia and bleeding

• Anemia• bleeding gums

4. Hypoendocrinism• Decreased interest

in sex• women may have

menstrual irregularities

• Gynaecomastia • Spider nevi• Palmar erythema

Disfunction of liver:

Portal hypertension:

1. Esophageal and gastric varices 2. Ascites 3. Legs edema4. Spleen enlarges 5. Abdomen varices6. The liver enlarges during the early

stages of illness 7. The liver dwindles during the later

stages of illness

Decompensation

Jaundice is a condition in which a person's skin and the whites of the eyes are discolored yellow due to an increased level of bile pigments in the blood resulting from liver disease. Jaundice is sometimes called icterus, from a Greek word for the condition.

Many of these outward-bound chemicals are excreted into the bile. One particular substance, bilirubin, is yellow. Bilirubin is a product of the breakdown of hemoglobin, which is the protein inside red blood cells. If bilirubin cannot leave the body, it accumulates and discolors other tissues. The normal total level of bilirubin in blood serum is between 0.2 mg/dL and 1.2 mg/dL. When it rises to 3 mg/dL or higher, the person's skin and the whites of the eyes become noticeably yellow.

Jaundice, a yellow discoloration of all tissues and organs, including

the eye and the skin.

After liver is damaged, the hepatocytes are not able to treat estrogen, resulting in Spider nevi and Palmar erythema.

Spider nevi

Palmar erythema

As the liver becomes fibrotic, there is obstruction of the blood flow through the liver. This results in portal hypertension, an increase in blood pressure within the portal vein and its tributaries. The obstructed hepatic blood flow also causes congestion of the spleen, leading to a markedly enlarged spleen (splenomegaly). Also, most people with cirrhosis eventually develop fluid in their abdomen (ascites) and are at an increased risk of developing a spontaneous intraabdominal infection.

Ascites

Ascites Legs edema

Cirrhosis of Liver

Spleen enlarges

Cirrhosis of Liver

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

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

Abdomen varices Esophageal varices

Esophageal varices

Red spot

Esophageal varices

Gastric varices

Image of portal hypertensive gastropathy seen on endoscopy of the stomach. The normally smooth mucosa of the stomach has developed a mosaic like appearance, that resembles snake-skin

gastric antral vascular ectasia

Complications

1. Esophageal and gastric variceal bleeding2.　 Hepatic encephalopathy3.　 Infection4.　 Hepatocellular carcinoma5.　 Hepatorenal syndrome6.　 Hepatopulmonary syndrome7.　 Portal vein thrombus

Esophageal variceal bleeding

Hepatocellular carcinoma

Hepatocellular carcinoma

Portal vein stenosis

Portal vein thrombus

Lab findings Aminotransferases - AST and ALT are moderately elevated, with AST > ALT. However, normal aminotransferases do not preclude cirrhosis. Alkaline phosphatase – (AKP)usually slightly elevated. GGT -- correlates with AP levels. Typically much higher in chronic liver disease from alcohol. Bilirubin - may elevate as cirrhosis progresses. Albumin - levels fall as the synthetic function of the liver declines with worsening cirrhosis since albumin is exclusively synthesized in the liver Prothrombin time - increases since the liver synthesizes clotting factors. Globulins - increased due to shunting of bacterial antigens away from the liver to lymphoid tissue. Serum sodium - hyponatremia due to inability to excrete free water resulting from high levels of ADH and aldosterone. Thrombocytopenia - due to both congestive splenomegaly as well as decreased thrombopoietin from the liver. However this rarely results in platelet count < 50,000/mL. Leukopenia and neutropenia - due to splenomegaly with splenic margination. Coagulation defects - the liver produces most of the coagulation factors and thus coagulopathy correlates with worsening liver disease.

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

Imaging Ultrasound , CT and MRIare routinely used in the evaluation of cirrhosis, where it may show a small and nodular liver in advanced cirrhosis along with increased echogenicity with irregular appearing areas. Ultrasound may also screen for hepatocellular carcinoma, portal hypertension and Budd-Chiari syndrome (by assessing flow in the hepatic vein).

MRIMRI

Ascites

Hepatic cirrhosis

Enlarged spleen

DSA DSA

Portal vein

Laparoscope can observe hepatic regenerative nodular, and get liver

biopsy sample.

Cirrhosis of Liver

Spleen enlarges

EndoscopyGastroscopy (endoscopic

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

Esophageal varices

Portal hypertensive gastropathy

Liver biopsy: The gold standard for diagnosis of cirrhosis is a liver biopsy, through a percutaneous, transjugular, laparoscopic, or fine-needle approach. However, a biopsy is not necessary if the clinical, laboratory, and radiologic data suggests cirrhosis. Furthermore, there is a small but significant risk to liver biopsy, and cirrhosis itself predisposes for complications due to liver biopsy.

A patient's medical history can reveal illnesses or lifestyles likely to lead to cirrhosis. Liver changes can be seen during a physical examination. A doctor who suspects cirrhosis may order blood and urine tests to measure liver function. Because only a small number of healthy cells are needed to carry out essential liver functions, test results may be normal even when cirrhosis is present.

Diagnosis

In about 10 out of every 100 patients, the cause of cirrhosis cannot be determined. Many people who have cirrhosis do not have any symptoms (often called compensated cirrhosis). Their disease is detected during a routine physical or when tests for an unrelated medical problem are performed. This type of cirrhosis can also be detected when complications occur (decompensated cirrhosis).

Computed tomography scans (CT), ultrasound, and other imaging techniques can be used during diagnosis. They can help determine the size of the liver, indicate healthy and scarred areas of the organ, and detect gallstones. Cirrhosis is sometimes diagnosed during surgery or by examining the liver with a laparoscope. This viewing device is inserted into the patient's body through a tiny incision in the abdomen.

Liver biopsy is usually needed to confirm a diagnosis of cirrhosis. In this procedure, a tissue sample is removed from the liver and examined under a microscope in order to learn more about the organ's condition and to properly diagnose it.

A newer and less invasive test involves the measurement of hyaluronic acid (HA) in the patient's blood serum. As of 2003, however, the serum HA test is most useful in monitoring the progress of liver disease; it is unlikely to completely replace liver biopsy in the diagnosis of cirrhosis.

PreventionEliminating alcohol abuse could prevent 75–80% of all cases of cirrhosis.Other preventive measures include:Maintaining a healthy diet that includes whole foods and grains, vegetable, and fruits Obtaining counseling or other treatment for alcoholism Taking precautions (practicing safe sex, avoiding dirty needles) to prevent hepatitis Getting immunizations against hepatitis if a person is in a high-risk group receiving appropriate medical treatment quickly when diagnosed with hepatitis B or hepatitis C Having blood drawn at regular intervals to rid the body of excess iron from hemochromatosis Using medicines (chelating agents) to rid the body of excess copper from Wilson's disease Wearing protective clothing and following product directions when using toxic chemicals at work, at home, or in the garden

General treatment1. Etiological treatment No drink alcoholic Treatment of HBV and HCV and so on2. Protecting liver treatment3. Treatment of ascites4. Treatment of jaundice

1. Common treatment: Rest, nutritional and supportable therapy.

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

3. Preventing further liver damage: Drug application of ameliorate liver function.

4. Treatment of complications: Please see other part.

5. Surgery treatment: Please see surgery6. Transplantation: If complications cannot be

controlled or when the liver ceases functioning, liver transplantation is necessary.

The therapy of cirrhosis is aimed primarily at preventing or reducing the complications. Bleeding esophageal varices (collateral venous channels) are a frequent serious complication of cirrhosis. Various techniques are used to control the bleeding. In some individuals with severe portal hypertension, vascular shunts are made to reduce the pressure in the portal vein by bypassing the liver. Most frequently the portal vein is surgically connected to the inferior vena cava so that some of the blood in the portal vein does not pass through the liver.

Treatment

Endoscope band ligation (EBL) can prevent Endoscope band ligation (EBL) can prevent and treat and treat Esophageal and gastric varices or

with bleeding

Ref: De Franchis R. Digestive and liver disease 2004;36(S1):S93Ref: De Franchis R. Digestive and liver disease 2004;36(S1):S93

Endoscopic sclerotherapy (EST) is an established method for

controlling and preventing bleeding from oesophageal varices

Endoscopic sclerotherapy (EST)

AT Injection

Portal hypertension

Portal vein

Vena cava

Distal Splenorenal ShuntDistal Splenorenal Shunt

Harvard　University

Harvard　University

Harvard　University

Harvard　Medical　School

The Third Affiliated HospitalSun Yat-Sen University

Position Open

Postdoctoral FellowPh.D. Program Master’s Program