Liver cirrhosis

Liver cirrhosis is a chronic liver disease accompanied by irreversible replacement of parenchymal liver tissue by fibrous connective tissue.

Etiology
Alcohol
Hepatitis B can cause liver inflammation and damage that can lead to cirrhosis.
Hepatitis C occurs by sexual intercourse or exposure to infected blood or blood products
Hepatitis D can also cause cirrhosis. It’s often seen in people who already have hepatitis B.
Autoimmune hepatitis causes inflammation that can lead to cirrhosis.

Damage to the bile ducts, which function to drain bile: One example of such a condition is primary biliary cholangitis.
Disorders that affect the body’s ability to handle iron and copper: Two examples are hemochromatosis and Wilson’s disease.
Medications, including prescription and over-the-counter drugs like acetaminophen, some antibiotics, and some antidepressants, can lead to cirrhosis.

Classification
1

According to etiology:
Postinfectious cirrhosis- viruses, parasites, syphilis, bacterial infection of biliary tract
Toxic and toxic allergic cirrhosis- alcohol, drugs, hepatotoxic poisons
Metabolic and nutritional cirrhosis- deficiency of proteins, vitamins, lipotropic factors, Wilson’s disease ( impaired copper metabolism)
Primary biliary cirrhosis- due to destructive cholangitis or cholangiolitis
Secondary biliary cirrhosis- due to obstruction of the biliary tract or infectious ( bacterial ) cholangitis
Circulatory- as a result of chronic venous congestion
Cryptogenic

According to macroscopic appearance:
Micronodular cirrhosis
Macronodular cirrhosis
According to microscopic appearance:
Monolobular cirrhosis
Multilobular cirrhosis
According to morphogenesis:
Portal
Post necrotic
mixed

According to course:
Active
Inactive

Pathogenesis
2

Irrespective of the aetiology, cirrhosis in general is initiated by hepatocellular necrosis
Replacement of BM collagen type iv and vi by fibrillary collagen type I and iii
This lead to capillarization with quantitative and qualitative ECM change

ECM regulates cellular activity and availability of growth factors
Decorin and biglycan binds TGF-B
Fibronectin and laminin binds TNF-alpha
Collagen binds PDGF, HGF, IL-2
Binding of the survival factors to ECM prevents apoptosis in damage liver and proteolysis
ECM can modulate the activation of & proliferation of HSC, angiogenesis GF & MMP

HSC activation represents a critical event in the fibrosis
This cell become the primary source of ECM in liver upon injury
This is modulated by immune signaling that is influence by genetic and environmental factors

Sources of ECM
HSC
Bone marrow derive cells
Epithelial mesenchymal transition
Portal fibroblast

CYTOKINES AND SIGNALING PATHWAYS
Inflammatory cytokines play a key role in fibrosis, given that persistent inflammation precedes fibrosis.
Following liver injury, several cell types can secrete inflammatory cytokines;
Cell types include; KCs, hepatocytes, HSCs, natural killer (NK)cells, lymphocytes, and dendritic cells.
Ligand + receptor = transduction of extracellular signals into the cell =modulation of changes in gene expression.
Common form of ligand-receptor interaction=dimerization/trimerization of receptor molecules
Receptors with intrinsic tyrosine kinase
Receptors lacking intrinsic tyrosine kinase activity .
Seven transmembrane G-protein-coupled receptors (GPCRs). Steroid hormone receptors.

Systemic Syndromes

Clinical Features
3

More serious symptoms include:
confusion and difficulty thinking clearly
abdominal swelling (ascites)
swelling of the legs (edema)
impotence
gynecomastia (when males start to develop breast tissue)
decreased appetite
nose bleeds
jaundice (yellow discoloration)
small spider-shaped veins underneath the skin
weight loss
anorexia
itchy skin
weakness
The symptoms of cirrhosis occur because the liver is unable to purify the blood, break down toxins, produce clotting proteins, and help with absorption of fats and fat-soluble vitamins. Often, there are no symptoms until the disorder has progressed. Some of the symptoms include:

Liver dysfunction
The following features are a direct consequence of liver cells not functioning.
Spider angiomata or spider nevi are vascular lesions consisting of a central arteriole surrounded by many smaller vessels (hence the name "spider") and occur due to an increase in estradiol. One study found that spider angiomata occur in about 1/3 of cases.
Palmar erythema is a reddening of palms at the thenar and hypothenar eminences seen in about 23% of cirrhosis cases as a result of increased estrogen.
Gynecomastia, or benign increase in breast size in men, is caused by increased estradiol and can occur in up to 2/3 of cases. This is different from increase in breast fat in overweight people. A swollen scrotum may also be evident.
Hypogonadism, a decrease in male sex hormones may manifest as impotence, infertility, loss of sexual drive, and testicular atrophy, and can result from primary gonadal injury or suppression of hypothalamic/pituitary function. Hypogonadism is associated with cirrhosis due to alcoholism or iron overload.
Liver size can be enlarged, normal, or shrunken in people with cirrhosis.
Ascites, accumulation of fluid in the peritoneal cavity in the abdomen, gives rise to bulging flanks.
Jaundice, is yellow discoloration of the skin and mucous membranes notably of the white of the eyes due to increased levels of bilirubin which may also cause the urine to be dark colored.

Spider angiomata
Palmnar Erythema

Epitaxis
Jaundice

Portal hypertension
Liver cirrhosis increases resistance to blood flow and leads to higher pressure in the portal venous system, resulting in portal hypertension. Effects of portal hypertension include:
An enlarged spleen is found in 35% to 50% of cases.
Esophageal varices result from collateral portal blood flow through vessels in the stomach and esophagus (a process called portacaval anastomosis). When these blood vessels become enlarged, they are called varices and are more likely to rupture. Variceal rupture often leads to severe bleeding, which can prove fatal.
Caput medusae are dilated paraumbilical collateral veins due to portal hypertension. Blood from the portal venous system may be shunted through the paraumbilical veins and ultimately to the abdominal wall veins, manifesting as a pattern that may resemble the head of Medusa.
Cruveilhier-Baumgarten bruit is a venous hum heard in the epigastric region (on examination by stethoscope) due to collateral connections forming between the portal system and the paraumbilical veins as a result of portal hypertension.

Advanced disease
As the disease progresses, complications may develop. In some people, these may be the first signs of the disease.
Bruising and bleeding resulting from decreased production of clotting factors.
Hepatic encephalopathy (HE) – occurs when ammonia and related substances build up in the blood and affect brain function when they are not cleared from the blood by the liver. This may result in neglect of personal appearance, unresponsiveness, forgetfulness, trouble concentrating, changes in sleep habits or psychosis. One classic physical exam findings is asterixis, bilateral asynchronous flapping of outstretched, dorsiflexed hands. Fetor hepaticus is a musty breath odor resulting from increased dimethyl sulfide and is a feature of HE.
Sensitivity to medication caused by decreased metabolism of the active compounds.
Acute kidney injury (particularly hepatorenal syndrome).
Cachexia associated with muscle wasting and weakness.

Bruising
Cachexic patient with jaundice

Lab findings
The following findings are typical in cirrhosis:
Thrombocytopenia – typically multifactorial. Due to alcoholic marrow suppression, sepsis, lack of folate, platelet sequestering in the spleen as well as decreased thrombopoietin. However, this rarely results in a platelet count < 50 000/mL.
Aminotransferases – AST and ALT are moderately elevated, with AST > ALT. However, normal aminotransferase levels do not preclude cirrhosis.
Alkaline phosphatase – slightly elevated but less than 2–3 times the upper limit of normal.
Gamma-glutamyl transferase – correlates with AP levels. Typically much higher in chronic liver disease from alcohol.
Bilirubin – levels normal when compensated but 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.
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.
Glucagon – increased in cirrhosis
Vasoactive intestinal peptide – increased as blood is shunted in the intestinal system because of portal hypertension
Vasodilators – increased (such as nitric oxide and carbon monoxide) reducing afterload with compensatory increase in cardiac output, mixed venous oxygen saturation
Renin – increased (as well as sodium retention in kidneys) secondary to fall in systemic vascular resistance

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 as in hemochromatosis, copper and ceruloplasmin: markers of copper overload as in Wilson's disease
Immunoglobulin levels (IgG, IgM, IgA) – these immunoglobins are non-specific but may help in distinguishing various causes
Cholesterol and glucose
Alpha 1-antitrypsin
Markers of inflammation and immune cell activation are typically elevated in cirrhotic patients especially in the decompensated disease stage:
C-reactive protein (CRP)
Procalcitonin (PCT)
Presepsin
soluble CD14
soluble CD163
soluble CD206 (mannose receptor)
soluble TREM-1

Liver ultrasound to assess the severity of cirrhosis.
Liver biopsy to identify liver cell changes & alterations in the lobular structure.
Prolonged prothrombin time (11-12sec)
Rarely are diseases of the bile ducts, such as primary sclerosing cholangitis, causes of cirrhosis. Imaging of the bile ducts, such as ERCP or MRCP (MRI of biliary tract and pancreas) may aid in the diagnosis.
upper endoscopy (to see if esophageal varices are present)
CT scan of the abdomen

Liver Cirrhosis with ascitis

Trichrome stain, showing cirrhosis as a nodular texture surrounded by fibrosis (wherein collagen is stained blue)

Treatment & Prevention
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Treatment for cirrhosis varies based on what caused it and how far the disorder has progressed. Some treatments your doctor might prescribe include:
beta blockers or nitrates (for portal hypertension)
quitting drinking (if the cirrhosis is caused by alcohol)
banding procedures (used to control bleeding from esophageal varices)
intravenous antibiotics (to treat peritonitis that can occur with ascites)
hemodialysis (to purify the blood of those in kidney failure)
lactulose and a low protein diet (to treat encephalopathy)
Liver transplantation is an option of last resort, when other treatments fail.
All patients must stop drinking alcohol. Medications, even over-the-counter ones, should not be taken without consulting your doctor.

Practicing sex with a barrier method can reduce the risk of getting hepatitis B or C. The U.S. Centers for Disease Control and Prevention Trusted Source recommend that all infants and at-risk adults (such as healthcare providers and rescue personnel) be vaccinated against hepatitis B.
Limiting alcohol intake or avoiding alcohol, eating a balanced diet, and getting adequate exercise can prevent or slow cirrhosis.
Vaccination of susceptible patients should be considered for hepatitis A and hepatitis B. Treating the cause of cirrhosis prevents further damage; for example, giving oral antivirals such as entecavir and tenofovir where cirrhosis is due to hepatitis B prevents progression of cirrhosis. Similarly, control of weight and diabetes prevents deterioration in cirrhosis due to non-alcoholic fatty liver disease.
Prevention