DR. JOAQUIN MASOUD C. SHAFIEE

This report has been compiled from various sources on the internet.

I would like to thank the authors of the reports which I might taken the slides from .

This presentation is made to aid the students in 2nd year dentistry course and I hope it will benefit them.

CIRRHOSIS

CIRRHOSIS

Cirrhosis is a pathologically defined entity that is associated with a spectrum of characteristic clininical manifestation

1-Irreversible chronic injury of the hepatic parenchyma

2-Extensive fibrosis

3-formation of regenerative nodules

Normal liver

Cirrhosis of the liver is the third leading cause of death in people between the ages of 25 and 65 years, exceeded only by cardiovascular disease and cancer.

The cost of cirrhosis in terms of human suffering, financial burden, and loss of productive life is devastating.

PATIENTS WITH CIRRHOSIS MAY PRESENT IN A VARIETY OF WAYS.

Variceal bleeding

New onset of ascites

Hepatomegaly and/or

splenomegaly

PATIENTS WITH CIRRHOSIS MAY PRESENT IN A VARIETY OF WAYS.

Incidental Discovery Of Abnormal Laboratory Tests

Serum Aminotransferases,

Hypoalbuminemia,

Prolonged Prothrombin Time,

Hrombocytopenia)

PATIENTS WITH CIRRHOSIS MAY PRESENT IN A VARIETY OF WAYS.

Detection of the peripheral stigmata ofchronic liver disease such as

Jaundice, Dupuytren's contracture, Manifestations related to hyperestrogenemia such as oSpider angiomata,

oPalmar erythema,

oGynecomastia, and testicular atrophy which may also be related to low testosterone concentrations

PATIENTS WITH CIRRHOSIS MAY PRESENT IN A

VARIETY OF WAYS.

hepatic encephalopathy or one or more complications or systemic manifestations of hepatocellular carcinoma

Some patients never come to clinical attention. In older reviews, cirrhosis was diagnosed at autopsy in up to 30 to 40 percent of patients

CIRRHOSIS REPRESENTS THE TERMINAL STAGE OF A NUMBER OF CHRONIC LIVER DISEASES INCLUDING THOSE CAUSED BY

excessive ethanol consumption

Viral hepatitis

Drugs and toxins,

Vascular

Autoimmune

Metabolic disorders

Cryptogenic.

In some cases, no cause can be determined and the cirrhosis is

Early cirrhosis may be asymptomatic and undetectable except by biopsy.

However, by the time cirrhosis becomes clinically apparent, hepatic functional reserve is markedly impaired.

If liver injury cannot be arrested, the prognosis without intervention is poor

The onset of complications

(eg, ascites, encephalopathy, variceal hemorrhage) indicates a more advanced stage of disease and a poorer prognosis, with median survival of about 5 years or less.

CIRRHOSIS & PORTAL HYPERTENSION

CIRRHOSIS Term was 1st coined by Laennec in 1826

Many definitions but common theme is injury, repair, regeneration and scarring

NOT a localized process; involves entire liver

Primary histologic features:1. Marked fibrosis2. Destruction of vascular & biliary elements3. Regeneration4. Nodule formation

CIRRHOSIS: PATHOPHYSIOLOGY

Primary event is injury to hepatocellular elements

Initiates inflammatory response with cytokine release->toxic substances

Destruction of hepatocytes, bile duct cells, vascular endothelial cells

Repair thru cellular proliferation and regeneration

Formation of fibrous scar

CIRRHOSIS: PATHOPHYSIOLOGY

Primary cell responsible for fibrosis is stellate cell

Become activated in response to injury and lead to ed expression of fibril-forming collagen

Above process is influenced by Kupffer cells which activate stellate cells by eliciting production of cytokines

Sinusoidal fenestrations are obliterated because of ed collagen and EC matrix synthesis

CIRRHOSIS: PATHOPHYSIOLOGY

Prevents normal flow of nutrients to hepatocytes and increases vascular resistance

Initially, fibrosis may be reversible if inciting events are removed

With sustained injury, process of fibrosis becomes irreversible and leads to cirrhosis

CAUSES OF CIRRHOSIS

Alcohol

Viral hepatitis

Biliary obstruction

Veno-occlusive disease

Hemochromatosis

Wilsons disease

Autommune

Drugs and toxins

Metabolic diseases

Idiopathic

CLASSIFICATION OF CIRRHOSIS

WHO divided cirrhosis into 3 categories based on morphological characteristics of the hepatic nodules

1. Micronodular

2. Macronodular

3. Mixed

MICRONODULAR CIRRHOSIS

Nodules are

MACRONODULAR & MIXED CIRRHOSIS

Nodules are >3 mm in diameter and vary considerably in size

Usually contain portal tracts and efferent veins

Liver is usually normal or reduced in size

Mixed pattern if both type of nodules are present in equal proportions

CIRRHOSIS - ALCOHOL

Also known as Laennecs cirrhosis

>50% of pts. with alcoholic cirrhosis die within 4 yrs of diagnosis

Develops in only 10% to 30% of heavy drinkers

Morphologically, micronodular pattern

Multifactorial - genetic, nutritional, drug use and viral

CIRRHOSIS - ALCOHOL

Fatty liver, alcoholic hepatitis

Histology - megamitochondria, Mallory bodies, inflammation, necrosis, fibrosis

Key mediator is acetaldehyde (ADH), the product of alcohol metabolism by alcohol dehydrogenase

ADH directly activates stellate cells, inhibits DNA repair and damage microtubules

NAFLD/NASH

Nonalcoholic Fatty Liver Disease and Steatohepatitis

Becoming more common

Infiltration of the liver with fat inflammation

Pathologically similar to alcoholic liver but in absence of alcohol

Associated with obesity, hyperlipidemia, NIDDM,

VIRAL HEPATITIS

Most common cause of cirrhosis worldwide (>50% of cases)

Incidence of cirrhosis in Hepatitis B pts. is 1% and 10% in Hepatitis C pts.

Incidence increases to 70-80% in HBV +ve pts. who are superinfected with HDV

DIAGNOSIS

Can be asymptomatic for decades

History

Physical findings: Hepatomegaly, jaundice, ascites, spider angioma, splenomegaly, palmar erythema, fetor hepaticus, purpura etc.

Elevated LFTs, thrombocytopenia,

DIAGNOSIS

Definitive diagnosis is by biopsy or gross inspection of liver

Noninvasive methods include US, CT scan, MRI

Indirect evidence - esophageal varices seen during endoscopy

MANIFESTATIONS OF CIRRHOSIS

Hepatorenal syndrome

Hepatic encephalopathy

Portal hypertension

Water retention

Hematologic

Hepatocellular carcinoma

PORTAL HYPERTENSION (PH)

Portal vein pressure above the normal range of 5 to 8 mm Hg

Portal vein - Hepatic vein pressure gradient greater than 5 mm Hg (>12 clinically significant)

Represents an increase of the hydrostatic pressure within the portal vein or its tributaries

PATHOPHYSIOLOGY OF PH

Cirrhosis results in scarring (perisinusoidal deposition of collagen)

Scarring narrows and compresses hepatic sinusoids (fibrosis)

Progressive increase in resistance to portal venous blood flow results in PH

Portal vein thrombosis, or hepatic venous obstruction also cause PH by increasing the resistance to portal blood flow

PATHOPHYSIOLOGY OF PH

As pressure increases, blood flow decreases and the pressure in the portal system is transmitted to its branches

Results in dilation of venous tributaries

Increased blood flow through collaterals and subsequently increased venous return cause an increase in cardiac output and total blood volume and a decrease in systemic vascular resistance

With progression of disease, blood pressure usually falls

PORTAL VEIN COLLATERALS

Coronary vein and short gastric veins -> veins of the lesser curve of the stomach and the esophagus, leading to the formation of varices

Inferior mesenteric vein -> rectal branches which, when distended, form hemorrhoids

Umbilical vein ->epigastric venous system around the umbilicus (caput medusae)

Retroperitoneal collaterals ->gastrointestinal veins through the bare areas of the liver

ETIOLOGY OF PH

Causes of PH can be divided into

1. Pre-hepatic

2. Intra-hepatic

3. Post-hepatic

PRE-HEPATIC PH

Caused by obstruction to blood flow at the level of portal vein

Examples: congenital atresia, extrinsic compression, schistosomiasis, portal, superior mesenteric, or splenic vein thrombosis

POST-HEPATIC

Caused by obstruction to blood flow at the level of hepatic vein

Examples: Budd-Chiari syndrome, chronic heart failure, constrictive pericarditis, vena cava webs

BUDD-CHIARI SYNDROME

Caused by hepatic venous obstruction

At the level of the inferior vena cava, the hepatic veins, or the central veins within the liver itself

result of congenital webs (in Africa and Asia), acute or chronic thrombosis (in the West), and malignancy

BUDD-CHIARI SYNDROME

Acute symptoms include hepatomegaly, RUQ abdominal pain, nausea, vomiting, ascites

Chronic form present with the sequelae of cirrhosis and portal hypertension, including variceal bleeding, ascites, spontaneous bacterial peritonitis, fatigue, and encephalopathy

Diagnosis is most often made by US evaluation of the liver and its vasculature

Cross-sectional imaging using contrast-enhanced CT or MRI

BUDD-CHIARI SYNDROME

Gold standard for the diagnosis has been angiography

Management has traditionally been surgical intervention (surgical decompression with a side-to-side portosystemic shunt)

Minimally invasive treatment using TIPS may be first-line therapy now

Response rates to medical therapy are poor

PORTAL VEIN THROMBOSIS

Most common cause in children (fewer than 10% of adult pts.)

Normal liver function and not as susceptible to the development of complications, such as encephalopathy

Diagnosis by sonography, CT and MRI

Often, the initial manifestation of portal vein thrombosis is variceal bleeding in a noncirrhotic patient with normal liver function

PORTAL VEIN THROMBOSIS - CAUSES

Umbilical vein infection (the most common cause in children)

Coagulopathies (protein C and antithrombin III deficiency),

Hepatic malignancy, myeloproliferative disorders

Inflammatory bowel disease

pancreatitis

trauma

Most cases in adults are idiopathic

PORTAL VEIN THROMBOSIS

Therapeutic options are esophageal variceal ligation and sclerotherapy

Distal splenorenal shunt

Rex shunt in patients whose intrahepatic portal vein is patent (most commonly children)

SPLENIC VEIN THROMBOSIS

Most often caused by disorders of the pancreas (acute and chronic pancreatitis, trauma, pancreatic malignancy, and pseudocysts)

Related to the location of the splenic vein

Gastric varices are present in 80% of patients

Occurs in the setting of normal liver function

Readily cured with splenectomy (variceal hemorrhage), although observation for asymptomatic patients is acceptable.

COMPLICATIONS OF PH

GI bleeding due to gastric and esophageal varices

Ascites

Hepatic encephalopathy

VARICES

Most life threatening complication is bleeding from esophageal varices

Distal 5 cm of esophagus

Usually the portal vein-hepatic vein pressure gradient >12 mm Hg

Bleeding occurs in 25-35% of pts. With varices and risk is highest in 1st yr.

PREVENTION OF VARICES

Primary prophylaxis: prevent 1st episode of bleeding

Secondary prophylaxis: prevent recurrent episodes of bleeding

Include control of underlying cause of cirrhosis and pharmacological, surgical interventions to lower portal pressure

PREVENTION OF VARICES

Beta blockade: Beta blockade (Nadolol, Propranolol)

Nitrates:Organic nitrates

Surgery: No longer performed*

Endoscopy: Sclerotherapy (no longer used*) and variceal ligation

* Refers to primary prophylaxis

TREATMENT OF VARICES

Initial Management:

1. Airway control

2. Hemodynamic monitoring

3. Placement of large bore IV lines

4. Full lab investigation (Hct, Coags, LFTs,)

5. Administration of blood products

6. ICU monitoring

PHARMACOLOGIC TREATMENT OF VARICES

Decreases the rate of bleeding

Enhances the endoscopic ability to visualize the site of bleeding

Vasopressin - potent splanchnic vasoconstrictor; decreases portal venous blood flow and pressure

Somatostatin: decrease splanchnic blood flow indirectly; fewer side effects

Octreotide: Initial drug of choice for acute variceal bleeding

ENDOSCOPIC THERAPY FOR VARICES

Endoscopic Sclerotherapy: complications occur in 10-30% and include fever, retrosternal chest pain, dysphagia, perforation

Endoscopic variceal ligation: becoming the initial intervention of choice; success rates range from 80-100%

BALLOON TAMPONADE

Sengstaken-Blakemore tube

Minnesota tube

Alternative therapy for pts. who fail pharmacologic or endoscopic therapy

Complications: aspiration, perforation, necrosis

Limited to 24 hrs; works in 70-80%

TIPS

Transjugular inrahepatic portasystemic shunt

1st line treatment for bleeding esophageal varices when earlier-mentioned methods fail

Performed in IR

Success rates 90-100%

Significant complication is hepatic encephalopathy

SURGICAL INTERVENTION

Liver transplantation: only definitive procedure for PH caused by cirrhosis

Shunts

Totally diverting (end-side portacaval)

Partially diverting (side-side portacaval)

Selective (distal splenorenal shunt)

Devascularization

SEVERE COMPLICATIONS

such as spontaneous bacterial peritonitis or ascites that is refractory to diuretic therapy, occur in the most advanced disease and are associated with a median life expectancy of less than 1 year.

Cirrhosis, even if early and stable, predisposes to development of primary hepatocellular carcinoma in as many as 3% of patients per year.

Until recently, little could be done to alter the prognosis of patients with cirrhosis and most died of complications. Today, the outlook has begun to change because of advances in orthotopic liver transplantation and development of therapies to prevent and treat complications.

BIOLOGIC BASIS OF HEPATIC FIBROSIS

Hepatic fibrosis is a wound-healing response

The same cell type produce hepatic fibrosis regardless of the underling cause.

hepatic fibrosis follows chronic,but not self-limited,injury.

Fibrosis occurs earliest in regions where injury is most severe.

ANTIFIBROTIC THERAPIES :RATIONALE AND SPECIFIC AGENT

The paradigm of satellite cell activation provides an important framework to define potential sites of antifibrotic therapy follows

1.Cure the primary disease to prevent injury.

2.Reduce inflammation or the host response to avoid stimulating satellite cells.

3.Directly down regulate stellate cell activation

ANTIFIBROTIC THERAPIES :RATIONALE AND SPECIFIC AGENT

4.Neutralize the proliferative,fibrogenic,contractile,and proinflammatory responses of stellate cells.

5.Stimulate apoptosis of stellate cells.

6.Increase the degradation of scar martix,either by stimulating cells that produce matrix proteases,down-regulating their inhibitors ,or directly administering matrix proteases.

DIAGNOSTIC APPROACH

Unless the diagnosis is already established, specific serologic tests and often a liver biopsy are required to establish the cause of the cirrhosis .

DIAGNOSTIC APPROACH

In addition, patients should undergo laboratory testing to document the severity of the disease and assessment of whether ascites or hepatic encephalopathy is present ..

DIAGNOSTIC APPROACH

Obtaining this information helps to determine prognosis, the possibility of specific therapy, and the possible necessity for screening family members for inherited diseases or chronic viral hepatitis

SPECIFIC THERAPY MAY BE INDICATED

Antiviral therapy for chronic hepatitis C and B,

Corticosteroids (with or without immunosuppressive therapy) for autoimmune hepatitis,

Phlebotomy for hereditary hemochromatosis,

Penicillamine for Wilson's disease.

In some cases, even hepatic fibrosis can be reversed; examples include abstinence from alcohol in alcoholic liver disease and immunosuppressive therapy in autoimmune hepatitis

30 - 50 Years

Progression of Hepatitis B Infection

Short-term

Infection

Long-term

HepatitisCirrhosis

Liver

CancerDeath

Long-term

Carrier

Resolution

Cirrhosis

Resolution

Death

Silent

Cirrhosis

INITIAL TESTING SHOULD CONSIST OF THE FOLLOWINGMeasurement of serum aminotransferases, bilirubin, alkaline phosphatase, albumin, creatinine, and sodium (otherwise unexplained hyponatremia is a marker of severe disease), the blood urea nitrogen, platelet count, and prothrombin time

.

INITIAL TESTING SHOULD CONSIST OF THE FOLLOWING

Abdominal ultrasonography to assess the portal circulation. In one study, the severity of liver disease correlated with portal vein blood velocity as determined by ultrasound

Portal hypertension is the most common and lethal complication of chronic liver disease

Esophageal varices and hemorrhage ascites renal dysfunction hypersplenism portal-systemic encephalopathy

P H.. PPG>5mmHg

HEPATOCELLULAR CARCINOMA

The issue of periodic surveillance of such patients with serum alpha-fetoprotein (AFP) measurements (values above 20 g/L being abnormal) and ultrasound examinations remains a contentious issue from the viewpoint of cost-effectiveness since an improvement in survival has not yet been demonstrate

All patients with cirrhosis should be evaluated for the presence of varices because of the beneficial effect of prophylaxis with propranolol or nadolol

Patients with most forms of cirrhosis, particularly due to hepatitis B and C, hereditary hemochromatosis, and alcoholic liver disease, are at high risk (1 to 6 percent per year) for the development of hepatocellular carcinoma

A.CURE THE PRIMARY DISEASE

Clear chronic viral infection

Abstinence from alcohol,stop toxic drugs

Remove iron ,copper in overload disease

Eradicate schistosomiasis

Reverse biliary obstruction

Revers jejunoileal bypass

NONALCOHOLIC STEATOHEPATITIS NASH

NASH is a disorder diagnosed by liver biopsy. The biopsy findings are indistinguishable from those of alcoholic hepatitis described above but the patient lacks a history of significant alcohol consumption. The liver disease is stable in most patients but a minority progress to cirrhosis

CIRRHOSIS & PORTAL HYPERTENSION

SURGICAL COMPLICATIONS

Turner Lisle

Resident Teaching Conference

May 2008

CIRRHOSIS

End result of anything that causes hepatocellular

injury

Toxins, viruses, prolonged cholestasis, autoimmunity, metabolic disorders

Pathologic response is uniform

Hepatocellular necrosis

Fibrosis

Nodular regeneration

CIRRHOSIS - WHY DO WE CARE

Hepatic failure

Portal hypertension - variceal bleeding

Ischemia & autoimmune factors thought

to play a role, although mechanism is not

clear

ANATOMY

Dual blood supplyHepatic arterial Portal venous

Total hepatic blood flow ~1500 mL/min or 25% of cardiac output

Portal vein 2/3 of total hepatic blood flow

Hepatic artery>1/2 of O2

PORTAL HYPERTENSION

Usually due to increased portal venous resistance

Classification based on site of increased resistance

Prehepatic

Intrahepatic

PREHEPATIC PORTAL HTN

Portal vein thrombosis most common

Isolated splenic vein thrombosis

Usually caused by pancreatic inflammation or neoplasm

Results in gastrosplenic HTN with ensuing formation of gastric varices

Normal superior mesenteric & portal vein pressure

Easily reversed by splenectomy alone

INTRAHEPATIC PORTAL HTN

Often a combination of pre-, intra-, or post-sinusoidal

Presinusoidal Schistosomiasis Nonalcoholic cirrhosis

Sinusoidal EtOH

Postsinusoidal - overall rare EtOH Budd-Chiari syndrome (hepatic vein thrombosis) Constrictive pericarditis Heart failure

PORTAL HYPERTENSION

Portal pressure > 5 mmHg

Portal pressure > 8 mmHg needed for collateralization

COLLATERALIZATION

EVALUATION OF THE CIRRHOTIC

1) Dx of underlying liver disease

2) Estimation of fxn hepatic reserve

3) Definition of portal venous anatomy

4) Hepatic hemodynamic evaluation

5) If present, identification of site of UGI bleeding

EVALUATION OF THE CIRRHOTIC

Physical Exam

Jaundice

Ascites

Caput medusae

Asterixis

Spider angiomas

Palmer erythema

Testicular atrophy

Gynecomastia

+/- Palpable spleen (portal HTN)

Lab tests

Anemia

Thrombocytopenia

Coagulopathy

Hypoalbuminemia

AST/ALT

Bili

Alk Phos

GGT

Hepatitis serologies

-fetoprotein

LIVER BIOPSY

Cause of cirrhosis

Activity of liver disease

Approaches

Percutaneous (avoid with ascites or INR)

Transjugular venous

Laparoscopic

Open

HEPATIC FUNCTIONAL RESERVE

CHILD-PUGH Encephalopathy grade Amount of ascites Bilirubin Albumin PT (INR)

Operative mortality A (5%) B (10-15%) C (25%)

Subjective

MELD Bilirubin INR Creatinine Cr Max = 4.0 mg/dL On dialysis calculate with CR = 4.0 mg/dL

Calculators on the web

MELD 5-20

1% increase in mortality with each integer rise in

MELD score

MELD >20

Additional 2% increase in mortality with each integer

rise in MELD score

DIAGNOSIS OF BLEEDING

NGT decompression & lavage

Endoscopy - key procedure for UGIB

UGIB with portal HTN

90% due to varices

10% other causes (Mallory-Weiss tears, ulcers, etc)

Majority are esophagogastric varices

Isolated gastric varices

Likely splenic vein thrombosis

VARICEAL HEMMORRHAGE

Single most life threatening complication of portal HTN

Risk of death is related to the underlying hepatic functional reserve

Pathogenesis of rupture incompletely understood

Multifactorial

Portal pressure >12mmHg

Treatment

Control the bleeding

Control the portal HTN

TREATMENT OF ACUTE VARICEAL BLEEDING

Emergency tx should be non-operative

Resuscitation first

Endoscopy Successful in >85%

Pharmacotherapy Vasopressin +/- NTG Somatostatin/Octreotide (fewer complications)

Balloon tamponade (rare)

TIPS

ENDOSCOPIC TREATMENT

Most common treatment modality for acute bleeding as well as prevention

Sclerosis

Ligation

Complications Esophageal ulceration Perforation Worsening hemorrhage Aspiration

Failure after two unsuccessful attempts

Equally efficacious (80-90%)

Potentially lethal complications

as pharmacotherapy and endoscopy

Has been shown to be as effective

-esophageal perforation-ischemic necrosis of esophagus

May be life saving

Deflation followed by

high re-bleeding rate

Sengstaken-Blakemore tube

TIPS

Portal decompression without surgery (nonselective shunt)

Not recommended as initial therapy for acute variceal bleeding

Preferred tx when pharmacotherapy and endoscopic means have failed

Best when used as a bridge to transplant

Problems include shunt stenosis/occlusion, encephalopathy (50% at 1-year)

Transjugular Intrahepatic Portosystemic Shunt

EMERGENCY SURGERY

Indications

Failure of acute endoscopic tx

Failure of TIPS placement

Hemorrhage from gastric varices

Esophageal transection rapid/simple

Portacaval shunt or splenorenal shunt

Operative mortality >25% in most series

PREVENTION OF RECURRENT HEMORRHAGE

Likelihood of repeat episodes >70%

Goals Prevention of recurrent bleeding Maintenance of satisfactory hepatic function

Options Pharmacotherapy (-blockers +/- nitrates) Chronic endoscopy (successful in 2/3) TIPS (less bleeding, more encephalopathy) Operative shunts Transplantation

PORTOSYSTEMIC SHUNTS

Most effective means of preventing recurrent bleeding in patients with portal hypertension

Problems

Encephalopathy

Accelerated hepatic failure

Types

Nonselective - End-to-end/side portocaval

Selective - Distal splenorenal

Partial - Small diameter PTFE

NONSHUNT PROCEDURES

ObjectivesAblation of varices Extensive interruption of collateral vessels

Options Transection and reanastamosis of the distal esophagus Extensive esophagogastric devascularization + esophageal transection and splenectomy

Rebleeding rates similar to endoscopic

experience

ASCITES

Usually an indicator of advanced cirrhosis

Initiated by altered hepatic and splanchnic hemodynamics

Intravascular volume deficit resulting in increased aldosterone..

Central goal is to achieve a NEGATIVE sodium balance

ASCITES TREATMENT

Dietary restriction

Dietary restriction + Diuretics spironolactone +/- lasix

5-10% are refractory Intermittent paracentesis TIPS Peritoneovenous Denver shunt (rarely used)

SBP PMN >250/mm3 or positive culture

ENCEPHALOPATHY

Variety of manifestations

Pathogenesis - circulating cerebral toxins Ammonia

Mercaptans -aminobutyric acid

Precipitated by multiple factors Shunts, hemorrhage, excessive diuresis, azotemia, infection, increased

dietary protein, sedatives

Management Eliminate/treat precipitating factors Lactulose, neomycin (decrease absorption of intestinal ammonia)

May you success in any path you have chosen.