-2- Cirrhosis

September-02-08 9:55 PM

Liver Cirrhosis
Epidemiology Among the ten most common cause of death Cirrhosis common. No particular susceptibility based upon race More common in blacks -> SEC Death rate in African Americans > Caucasians Most common non-neoplastic cause of death among hepatobiliary disorders Etiology Toxins: Remember INH can also cause cirrhosis -> patient with TB. Alcohol, INH, methotraxate & amiodarone Infections: Hepatitis C, B, echinoccosis & syphilis Autoimmune: Autoimmune chronic hepatitis Metabolic: Hemochromatosis, Wilsons disease, alpha1-antitrypsin deficiency & glycogen storage disease Biliary obstruction: Primary biliary cirrhosis, primary sclerosing cholangitis, neoplasms, iatrogenic biliary stricture & cystic fibrosis Presinosoidal fibrosis: Schistosomiasis & idiopathic portal fibrosis Post-sinosoidal fibrosis: Veno-occlusive disease, chronic right heart failure & Budd-Chiari syndrome Pathology The old term for micronodular cirrhosis is Micronodular: Laennec's -> Founder of modern chest medicine. Called Laennecs cirrhosis Started with first wooden steth. Seen in alcoholics The regeneration nodules are not larger than liver lobules: < 3 mm Macronodular: Post-necrotic The regeneration nodules are larger > 3 mm Mixed type Pathogenesis Cirrhosis should be viewed as a final common pathway of many types of chronic liver injury. It is an irreversible chronic injury of the hepatic parenchyma and include extensive fibrosis and formation of regenerative nodules. The central event leading to hepatic fibrosis is activation of the hepatic stellate cells (lipocytes) by factors released from hepatocytes and Kupffer cells. Activation of stellate cells can occur due to: Chronic inflammatory cells Kupffer cells, hepatocytes secreted factors Direct stimulation by toxins (alcohol)

Patient: 26 year old Pregnant Whitey Presents with Jaundice, Abdominal Pain, Lower extremity Swelling Differential diagnosis: Cholecystitis Cirrhosis due to drugs Tumor Hepatitis (viral) Hemolytic Anemia RHF Pulmonary Embolism Stones Thrombus (portal vein) History Start with Pain questions. - Diffuse upper, now settled into right side, worse with movement, better lying down, started about 10 days ago Then ask jaundice - 1 day ago Then ask about lower extremity swelling - 10-12 days ago. Cant get her shoes on, poor fatty. Physical - Hepatomegaly - 2+ pitting edema - Pregnant - Distressed Labs - Perform CBC first (start general) Liver enzymes Alkphos normal Electrolytes normal Negative hepatic panel - Coags Imaging - Ultrasound Enlarged liver, mild ascites - MRI/Angiography of liver Budd-Chiari

Alcohol gets endotoxins going within the body. These stimulate the kupffer cells directly and indirectly and eventually the stellate cells and you get leukocytes. So you get all those cytokines activating stellate cells.

The stellate cells assumes a myofibroblast-like conformation Under the influence of cytokines such as TGF-beta, Interleukin and TNF, stellate cells produce fibril-forming type I collagen, which results in distortion of hepatic architecture With fibrosis and liver damage the remaining hepatocytes are stimulated to regenerate and proliferate resulting in appearance of regenerating nodules. Alteration of composition of extracellular matrix also results in collapse of the supporting reticulin network. Loss of functioning hepatocellular mass results in: Jaundice, edema, coagulopathy & metabolic changes Fibrosis and distorted vasculature lead to: Portal hypertension One of the most devastating things of portal hypertension is GE Varices. Portal hypertension results in: Gastroesophageal varices, splenomegaly, caput medusa Hepatocellular failure & portal hypertension causes: Ascites and hepatic encephalopathy

Block I Page 1

Clinical Presentation Anorexia Weight loss Malnutrition Muscle loss Edema Ascites Easy bruising Spider angioma Muscle Loss

Why do these people lose muscle? Malnutrition mostly. So they start dissolving their muscles as a food source. They can have the generalized edema. They will have huge bruises. Some will be purple.

Investigation Blood chemistry: Liver Function Test: Elevated bilirubin, AST, ALT, alkaline phosphatase and GGT Hypoalbuminemia due to decrease in hepatic protein synthesis Prolonged bleeding time due to failure of hepatic synthesis of clotting factors CBC: Anemia (often macrocytic) Leukopenia or leukocytosis (infection) Thrombocytopenia Electrolytes: Hyponatremia due to volume overload Hypokalemia due to the effect of aldosterone Hypomagnesemia due to poor nutrition and renal loss Hypophosphatemia due to poor nutrition and renal loss Procedures Ascitic tap for spontaneous bacterial peritonitis Endoscopy for evidence of varices Portal pressure measurements

Be cautious that you can infect

Block I Page 2

 Portal pressure measurements EEG for encephalopathy

Be cautious that you can infect ascitis by injecting. So only do the tap when you have to.

Ultrasound: Assesses liver size Detects ascites that is undetectable by PE Together with color doppler analyzes blood flow changes in portal hypertension

Arteries are tortuous

Liver biopsy is the gold standard test for diagnosis, but beware of coagulopathy

Child-Pugh Classification Developed to assess severity of liver cirrhosis and chronic liver failure Class A: 5-6 score, Class B: 7-9 score, Class C: 10-15

Management Avoid exacerbating medications and substances: Avoid alcohol: most important principle Avoid NSAIDS: Risk of upper GI bleeding & renal failure Manage fluid and electrolyte disturbances Maintain adequate nutrition, but limit sodium and protein intake Treat underlying cause if possible Treat complications Liver transplantation Complications of Cirrhosis Ascites Spontaneous Bacterial Peritonitis Hepatorenal syndrome Hepatic encephalopathy Portal HT - Esophageal varices

Keep sodium and protein down to prevent encephelopathy

You can be total body fluid overloaded, and intravascularly depleted. Which is one of the

Block I Page 3

 Portal HT - Esophageal varices Hematological disorders Ascites Ascites may results in: Spontaneous bacterial peritonitis Umbilical hernia with risk of rupture Risk of rupture not that common Significant patient discomfort ' Extra 15 lbs. Respiratory compromise Especially when lying down at night Investigations: Paracentesis: Transudate fluid (protein < 2g/L) Ultrasound: Abdominal haziness

You can be total body fluid overloaded, and intravascularly depleted. Which is one of the most common states in the ICU. You have to know what the total body fluid situation is: Hyper-, isovolemic, or Hypo-. And intravascular can also be Hyper, Iso or Hypo

Ascites goes up: Intravascular leads to Renal perfusion leads to Plasma renin activity leads to Aldosterone. So eventually you retain sodium and free water. And ascites goes up. Feedback loop.

Intestinal wall thickens with chronic ascitis to try to protect the integrity of the bowel.

Management: Diet: Sodium and fluid restriction Maain treatment Diuretics: Spironolactone + furosemide Therapeutic paracentesis -(dont do it if they come back in a few days) Transjugular intrahepatic portosystemic shunt (TIPS): Liver transplantation: Consider in any patient with cirrhotic ascites. The big thing to look at is if they have a mental status change. If they have fever and mental status Spontaneous Bacterial Peritonitis change and something else -> bacterial peritonitis is number one differential. Etiology: Enterobacteriaceae & Pneumococci Clinical Findings: Fever, abdominal pain and tenderness, increasing ascites & progressive encephalopathy Investigation: Paracentesis: Ascitic fluid has PMNs > 250 cells/, and ascitic fluid culture is diagnostic. Treatment: Cephalosporin (Rocephin), Amp+CA (Unasyn), Imipenim + Cilastatin(Primxin) Dont use primxin on small things, its the elephant gun not the fly swatter. He used Unasyn most. Hepatorenal Syndrome Etiology: PGE2 will be huge in our careers. Viagra started as blood pressure Unknown medication. Theres lots of unintentional research on this. Pathogenesis: Intense renal vasoconstriction due to impaired synthesis of renal vasodilators (PGE2)*** Possible disturbance in nitric oxide-mediated vasodilation & endothelin-mediated vasoconstriction Clinical Features: Classic history is someone with ascites who took diueretics and whose urine stopped. Liver failure, oliguria, history of intense diuretic usage Investigations: Hyponatremia Elevated BUN & creatinine Elevated liver enzymes No diuresis with volume expansion (1.5 L of saline). Treatment: Treatment is generally ineffective Galambo's Cocktail: Albumin, Mannitol, Furosemide Trying to jumpstart the kidneys by giving them a bolus fluid to start the dieuresis. Molecular adsorbent recirculating system (MARS): A modified dialysis method that selectively removes water-bound and albumin-bound toxins. He never really used it, its just a fancy dialysis method. TIPS may be useful. Liver transplantation is the treatment of choice. Hepatic Encephalopathy Complex neuro-psychiatric syndrome Characterized by: Altered consciousness and behavior Fluctuating neurological signs Asterixis Typical EEG changes: triphasic slow waves

Block I Page 4

Classic Triphasic waves have an initial small-amplitude, sharp-negative component followed by a large-amplitude, sharppositive wave; they end with a slow negative wave. Hepatic Encephalopathy Pathogenesis: It is due to hepatocellular dysfunction and portosystemic shunting. The liver fails to detoxify noxious agents of GI origin Ammonia is the most important noxious agent Encephalopathy may result from: GI bleeding due to breakdown of blood protein Increased intake of protein Sepsis with increased endogenous protein breakdown Clinical presentation Asterixis flapping tremors Rigidity Hyper-reflexia Seizures rare Fetur hepaticus And you will smell the ammonia

Clinical stages of Hepatic Encephalopathy

He never used this, just be aware of it.

Treatment: Restriction of dietary proteins Control of GI bleeding Lactulose (acidifies ammonia to NH4+) Neomycin for ammonia-producing intestinal flora The two cornerstones of treatment Zinc for zinc deficiency (zinc is need for urea cycle) Eradication of H. pylori (it produces ammonia) Sodium benzoate or ornithine aspartate (lower ammonia level) Avoid opioids, sedatives and hypnotics Hematological Disorders Anemia: Pathogenesis: Suppression of erythrocytosis by alcohol Folate, B12 deficiency Hypersplenism Hemolysis GI bleeding (causes microcytic anemia) Treatment: Folic acid in alcohol induced anemia For iron deficiency: ferrous sulfate, transfusion in severe cases Thrombocytopenia: Pathogenesis: Alcoholic marrow suppression Folate deficiency Splenic sequestration Sepsis Treatment: Platelet transfusion Vitamin K takes at least 2 days to kick in, if not longer. Coagulation factors deficiency: If they are bleeding give them fresh frozen plasma and plateletes if they need it. Pathogenesis: Lack of synthesis due to hepatocytes damage Def of Vit K due to malabsorbtion Treatment: Vitamin K Fresh frozen plasma in active bleeding & before invasive procedures Portal HT Esophageal varices Caput medusa Splenomegaly Ascites

Portal hypertension can come anatomically from multiple places: Constrictive pericarditis, Restrictive cardiomyopathy, valvular disease

Block I Page 5

Esophageal Varices Dilated submucosal veins due to portal hypertension If the pressure gradient exceeds 12 mmHg, portal hypertension will result Serious GI bleeding may occur Bleeding esophageal varices have a higher morbidity and mortality rate than any other source of GI bleeding. 1/3 of patients die from acute bleeding within 2 weeks More than 2/3 of survivors have recurrent bleeding within one year Clinical Features: Painless massive hematemesis with or without melena Postural hypotension & shock Investigations: Barium swallow Endoscopy MRI Doppler sonography Venous phase celiac arteriography

Endoscopy

Treatment of EV Acute intervention: Resuscitation with fluid and blood products Use fresh frozen plasma or platelets if: Active bleeding AND INRs > 2 OR Platelet count of < 50,000/L With active bleeding, insert endotracheal tube to prevent aspiration Perform emergency endoscopy after the patient is hemodynamically stable Types of endoscopic intervention: Banding: Lower overall morbidity and mortality than sclerotherapy Sclerotherapy: Injection of ethanolamine or tetradecyl sulfate

Block I Page 6

Banding: You are basically thrombosing it with a rubber band.

Sclerotherapy: trying to cause thrombosis by irritation.

Pharmacologic therapy: Agents: Vasopressin + nitroglycerin Octreotide / Somatostatin If they are actively bleeding, you have to scope. Both of these agents controls acute bleeding Combined therapy with endoscopy is superior than either modality alone Vitamin K indicated with increased INR (Inc PT) Balloon Tamponade is indicated when bleeding continues despite of pharmacologic and endoscopic intervention. It has high complication rate especially rebleeding.

Portal decompressive procedures: Indicated when bleeding is not controlled with pharmacologic and endoscopic intervention TIPS (transjugular intrahepatic portosystemic shunt) Emergency portosystemic shunt if TIPS is not available

Treatment of EV: Antibiotic prophylaxis: Cirrhotic patients with upper GI bleeding have > 50% chance of severe infection. Common infections are bacterial peritonitis, pneumonia, UTI & sepsis Use cephalosporin Treatment of EV Prevention of first bleed: Do endoscopy every year If large varices give blockers Prophylactic banding Treatment of EV: Prevention of rebleeding: Once the initial bleeding is stopped, the risk of rebleeding is 80% without further treatment Pharmacological treatment: Beta-blocker or nitrates To decrease afterload Combination therapy of beta-blocker + nitrates more effective

Someone comes in with Esoph varices: Do all your cultures. You are not sure what triggered the event. It may be underlying coagulopathies, but lots of times they will have combinant infections.

Block I Page 7

Combination therapy of beta-blocker + nitrates more effective TIPS: Reserved for those who failed endoscopic intervention and pharmacotherapy Higher incidence of encephalopathy (because you are bypassing the liver) You poke through the neck of the hepatic vein, into the liver, and come out through the portal vein.

Surgical portosystemic shunts: Rebleeding rate is significantly lower than endoscopy Role of surgery is less clear with advent of TIPS Higher incidence of encephalopathy

They have a lot fo complications: Bleeding at time of stent (poking through) Infection Hepatic Encephalopathy

Ashburn has seen Side-to-side done the most. And has never seen the C shunt.

Hepatopulmonary Syndrome Pathogenesis: Inability of liver to clear circulating pulmonary vasodilators Clinical Features: Dyspnea in a cirrhotic patient Investigation: Arterial blood gases (ABG): Hypoxemia Contrast enhanced echo: Pulmonary vascular dilation Ventilationperfusion lung scan: Confirms the diagnosis Treatment: Medical: little currently Supportive: Normal ICU care Not useful, but IV methylene blue increases oxygenation by inhibiting nitric oxide-induced vasodilation Surgical: Liver transplantation Greater than 90% mortality rate Hepatocellular Carcinoma Epidemiology: Uncommon in North America One of the most common cancers worldwide Mean age between 55-62 years Male to female ratio 3-4:1

If liver and lung fail, mortality rate is over 90% If liver and kidney, mortality rate is over 60% This is in the acute setting. All you can do is support them, fight infections, correct electrolytes. These people really wont do well.

Block I Page 8

Male to female ratio 3-4:1 May occur in up to 5% of cirrhotic patients per year. The risk of hepatoma is increased 100 times in chronic HBV carriers.

Clinical findings: Symptoms: Fatigue, anorexia, hematemesis (esophageal varices), upper abdominal pain, abdominal fullness Signs: Fever, jaundice, hepatomegaly, hepatic arterial bruit, ascites, and feminization Metastasis: Lung, bone & brain Investigations: Liver function tests: Elevated Tumor markers: Alpha-fetoprotein (AFP), the single most important marker for screening and diagnosis

Always check the patient out when pain is changing. Or fatigue, etc.

Investigations (cont'd..): Liver biopsy: Diagnostic method of choice, but be aware of bleeding Abdominal X-ray: Sunburst calcifications Chest X-ray: For evidence of metastasis Gallium scan Laparoscopy Exploratory laparotomy

Neovascularization

Hepatocellular Cancer Treatment: Liver resection: Choice treatment. Liver transplant: For surgically inoperable, but not metastatic tumor Complimentary therapies: Systemic/arterial chemotherapy Hepatic arterial embolization Percutaneous ethanol injection Radiofrequency ablation

Wont need to remember all the different stages. Just be aware.

Block I Page 9

 Radiofrequency ablation Cryotherapy

In this pic they are trying to freeze it, ultrasound guided. The problem is you rarely have the opportunity to catch them when they are small and resectable. It wont cause bleeding, pain, or any other symptoms.

Embolization: trying to embolize the new vascular blood supply

Ethanol to try to kill it.

Notes By:
Prognosis: Unresectable liver cancer patients survives < 6 months 70% of children & 40% of adults with no cirrhosis survive with curative surgery 15-20% survives for 2 years after liver transplantation Liver Transplantation Liver Transplantation When to consider transplantation: Worsening functional status Rising liver function tests Decreasing albumin level Worsening coagulopathy Refractory ascites Recurrent variceal bleeding Diseases that may recur after transplantation: Hepatocelluar carcinoma, hepatitis B & C, and Budd-Chiari syndrome Contraindications: Absolute: Advanced liver malignancy Advanced cardiopulmonary disease Sepsis Relative Age > 70 Portal and mesenteric vein thrombosis Active drug and alcohol abuse AIDS Severe malnutrition These relative contraindications are pretty absolute since theres such few livers Five year survival rate after liver transplantation is 80%

Transplantation: Takes 8 hours.

Block I Page 10