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Liver Disease

Barbara Andrews, FNP-BC Hepatology Dept.

UC San Diego Medical Center

OBJECTIVE

• Anatomy & physiology of the liver

• Etiology of liver disease

• Complications of liver disease

• Treatment of liver disease

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Liver Function • Chemical Factory

– Proteins

– Carbohydrates

– Fats

– Bilirubin

– Production bile salts and clotting factors

• Warehouse

– Stores glycogen, bile , vitamins and minerals

– Filtering system

• Nutrients, drugs, toxins, bacteria, everything

• Blood reservoir for 10% total blood volume

Liver Function Tests Serum Proteins

• Total Protein • 6.0-8.0 g/dl

• Albumin • 3.5-5.0 g/dl

• Globulins • 2.6-4.1 g/dl

• Pre-Albumin • 17-40 mg/dl

Serum Ammonia • 19 – 60 mcg/dL

Bilirubin • Total Bilirubin

• 0.1 – 1.2 mg/dL

• Unconjugated Bilirubin • 0.1-1.0 mg/dL

• Conjugated Bilirubin • 0.1-0.2 mg/dL

Coagulation Studies • PT, PTT, INR, bleeding

time, ACT all indirectly reflect liver function.

Liver Enzymes

• ALP – 42 – 136U/L

• GGT – M: 0–85 – F: 0-70 U/L

• AST – M: 15-40 – F: 13-35 U/L

• ALT – M: 10-55 – F: 7-30 U/L

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ETIOLOGY of LIVER DISEASE

• Infectious

– viral hepatitis, schistosomiasis

• Metabolic:

– NASH, HFE, alpha-1 antitrypsin, Wilson's, glycogen storage disease, CF

• Cholestatic/Biliary:

– Chronic obstruction: PBC, PSC, chronic cholestasis. Byler disease

• Drug/Toxin: – alcohol, amiodarone,

methotrexate, vitamin A

• Vascular:

– Right-sided heart failure, hepatic vein occlusion

• Idiopathic:

– Cryptogenic

• Autoimmune:

– AIH

• Budd-Chiari syndrome

Chronic Liver Disease: Prevalence in United States

a. McCullough AJ. J Clin Gastroenterol 2006;40:S17-S29; b. Armstrong GL et al. Ann Intern Med. 2006;144:705-714; c. From

http://www.acg.gi.org/patients/cgp/pdf/alcohol.pdf. Accessed 04/05/08; d. From http://www.nhlbi.nih.gov/new/press/01-09-25.htm. Accessed 04/05/08; e.

From http://www.cdc.gov/ncidod/diseases/hepatitis/resource/PDFs/disease_burden.pdf. Accessed 04/05/08;

f. From http://seer.cancer.gov/statfacts/html/livibd.html. Accessed 04/05/08.

Disease Prevalence Rate

Nonalcoholic Fatty Liver Diseasea 17-33%

Nonalcoholic Steatohepatitisa 5.7%-17%

Chronic hepatitis Cb 1.3%

Alcoholic liver diseasec 0.8-1.3%

Hemochromatosisd 0.5%

Chronic Hepatitis Be 0.4%

2004 Prevalence

Hepatocellular Cancerf 19,429

Six Key Tests for Patients with Chronically Elevated Liver Enzymes

• Metabolic syndrome tests

– BMI

– HTN

– Lipids

– Glc fasting

– Waist circumference

• Medication and herbal, OTC history

• Alcohol history

– CAGE, MAST

• HCV antibody

• HBsAg

• Iron Saturation

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Key Tests for Acutely Elevated Liver Enzymes

• Tox screen

• Acetaminophen level

• HAV IgM

• HBV anti-HBc IgM

• Alcohol blood level

• Heart disease, shock

• Medication history

• F-actin

(HEV IgM if the 6 tests above are negative)

Physical Exam - Chronic Liver Disease

VIRAL HEPATITIS

• Hepatitis A Virus (HAV)

• Hepatitis B Virus (HBV)

• Hepatitis C Virus (HCV)

• Hepatitis D Virus (HDV)

• Hepatitis E Virus (HEV)

• Other viruses infecting the liver

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Who Should be Tested for Viral Hepatitis?

• Patients typically enter this diagnostic group with a history of

– Elevated liver tests

or

– Risk events, immigrant status, blood exposure

or

– For HCV: Birth cohort 1945 -1965

• Also, few symptoms are specific for liver disease, thus an evaluation should take place if there are signs of liver failure

*Dependent on hepatitis B virus (HBV) for replication. Vaccine against hepatitis B available. CDC. Viral Hepatitis A to E: An Overview. Available at: www.cdc.gov/ncidod/diseases/hepatitis/slideset. Accessed March 13, 2006.

Overview of Viral Hepatitis

Type of Hepatitis A B C D* E

Source of virus Feces Blood/body

fluids

Blood/body

fluids

Blood/body

fluids

Feces

Route of

transmission

Fecal-oral Percutaneous

permucosal

Percutaneous

permucosal

Percutaneous

permucosal

Fecal-

oral

Chronic

infection

No Yes Yes Yes No

Prevention Pre/post-

exposure

immunization;

ensure safe

food and

drinking water

Pre/post-

exposure

immunization;

risk behavior

modification

Blood donor

screening; risk

behavior

modification

Pre/post-

exposure

immunization

against HBV;

risk behavior

modification

Ensure

safe food

and

drinking

water

Vaccine

available Yes Yes No No

Yes

(regional)

*Requires HBV infection

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Hepatitis A

• Hepatitis A can be found in the feces, bile, and sera of infected individuals

• Usually transmitted by the fecal-oral route

• Risk factors

• Crowded, unsanitary conditions

• Food and water contamination

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Hepatitis B Worldwide • 2 Billion exposed • 400 million infected

worldwide • 2 million infected in the

US* • Death rate due to

cirrhosis or liver cancer

– 25-30% in patients with vertically acquired HBV

– 7% in patients with adult acquired HBV

*Kowdley KV, et al. Hepatology 2012. In press : Hepatology. 2011 Nov 22. doi: 10.1002/hep.24804. [Epub ahead of print] Assume it will come out in 2012 issue

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HBV Epidemiology

Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C Institute of Medicine Report, Colvin & Mitchell, Editors (2010)

• Incidence of acute HBV 43,000 annually

– 1,000 from vertical transmission

• Estimated 40-45,000 emigrate to US annually from HBV-endemic countries

• Nearly 1/2 of US foreign-born

(6% of population) originate

from HBV-endemic countries

CDC Yellow Book, 2006

Groups who should be screened • Individuals born in endemic regions

• US born, not vaccinated, children of parents from endemic regions

• Household & sexual contacts of HBsAg+

• IV drugs

• Multiple sexual partners, STDs

• Men who have sex with men

• Inmates

• Hemodialysis

• Pregnant women

• HIV or HCV positive

• Abnormal AST/ALT

• Persons needing immunosuppressive therapy Weinbaum MMWR Recomm Rep 2008

Seronegative persons should be vaccinated

Approved Therapies for HBV

• Interferon-a, Pegylated interferon-a

• Lamivudine

• Adefovir

• Entecavir

• Telbivudine

• Tenofovir

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Hepatitis C

• Is a very tricky, stubborn virus

• Changes, mutates easily

• Six different “strains” or genotypes, and over 50 subtypes

• No vaccine or post-exposure treatment

• Usually NO symptoms, sometimes flu-like symptoms/fatigue

• Accounts for 60-70% of chronic hepatitis

• Leading cause of cirrhosis; most common reason for liver transplantation in U.S.; most common blood-borne infection

• Increased risk of liver cancer

Hepatitis C (HCV)

• Transmission: human blood & body fluids

• Rare but not absent

• Do not share razors or toothbrushes

• Clean up blood spills with 9:1 bleach

• Keep cuts and sores covered

• Safely dispose of contaminated needles

• CANNOT transmit by hugging, kissing, coughing, food, water, etc.

Household Transmission

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U.S. Centers for Disease Control and Prevention

HCV Sexual Transmission

• Occurs, but rare between long-term steady partners (approx. 5% lifetime risk)

• Persons with one long-term sexual partner:

– Should discuss with partner

• Risk is low but not absent

– Do not need to change their sexual practices

• But some couples might choose to use barrier precautions to lower the limited risk further

Factors Affecting Disease Progression

• Male gender • Older than 40 at the

time of infection • Duration of illness

• Alcohol intake

• Immunosuppressed individuals?

• Co-infection with hepatitis B or HIV

Goals of HCV Treatment

• Primary: “Sustained Response = CURE”

– Permanently clear/kill virus ( virus still not detectable 6 mos. after stopping treatment)

• Secondary: – Slow down disease progression – Reduce or reverse liver damage – Reduce risk of liver cancer – Reduce need for liver transplantation – Improve quality of life

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Hepatitis • Hepatitis D

• Depends on hepatitis B for replication

• Hepatitis E • Fecal-oral transmission

• Developing countries

• Hepatitis G • Recently discovered

• Parentally and sexually transmitted

COMPLICATIONS OF LIVER DISEASE

• CIRRHOSIS – PORTAL HYPERTENSION – ASCITES – HEPATIC ENCEPHALOPATHY – UPPER GI BLEED – HEPATORENAL SYNDROME

• JAUNDICE • HEPATOPULMONARY SYNDROME • INFECTION • ACUTE LIVER FAILURE

What is Cirrhosis?

• When liver tissue is damaged and inflamed, liver cells die and are replaced by bands of scar tissue

• Cirrhosis is extensive scarring, causing liver shrinkage & deformities

• Blood flow is restricted, and loss of liver function develops

• 20% chance of death within 10 years of developing cirrhosis

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Cirrhosis • Irreversible inflammatory disease that disrupts

liver function and even structure

• Decreased hepatic function due to nodular and fibrotic tissue synthesis (fibrosis)

• Biliary channels become obstructed and cause portal hypertension.

• Due to the hypertension, blood can be shunted away from the liver, and a hypoxic necrosis develops

Cirrhosis due to chronic

hepatitis

Normal

“Liver Function Tests”

• Prolonged prothrombin time (INR)

– Factor V level

• Bilirubin > 2 mg/dL

• Albumin < 3.5 mg/dL

• Cholesterol < 100 mg/dL

• Ammonia: very poor test !

• Surrogate: Platelets < 100,000/mm3

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Portal Hypertension Portal hypertension is abnormally high blood pressure in the portal venous system due to resistance to portal blood flow

•Consequences •Varices

•Lower esophagus, stomach, rectum

•Splenomegaly •Ascites •Hepatic encephalopathy

Causes of Portal Hypertension

• Prehepatic: portal vein thrombosis or congenital atresia

• Intrahepatic: hepatic fibrosis and cirrhosis

• Posthepatic: obstruction at any level between the liver and right heart, including hepatic vein thrombosis, inferior vena cava thrombosis, inferior vena cava congenital malformation and contrictive pericarditis

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Portal Hypertension Diagnosis & Treatment

• HPV pressure gradient to >5mmHg.

• Pressure is not measured directly until the decision to place a transjugular intrahepatic portosystemic shunt (TIPS)

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Portal Hypertension Treatment

• Prophylaxis of variceal bleeding

– beta blockers and EGD with banding

• Management of active bleeding

– blood transfusion; vasoactive drugs (somatostatin, octreotide or terlipressin), endoscopic banding ligation, balloon tamponade and TIPS.

• Management of ascites

– salt restriction, diuretics (spironolactone), paracentesis, transjugular intrahepatic portosystemic shunt (TIPS) and peritoneovenous shunt.

• Management of Hepatic Encephalopathy

Esophageal Varices

Banding Procedure

Ascites • Normal amount of fluid in the

peritoneal cavity- 150 ml; any fluid in excess- ascites

• 50% of all cirrhotics will develop ascites (compared to 25% who develop Gd III- IV varices)

• There is no single effective therapy

• 10% of these patients will have refractory ascites

• Mortality of this condition is 50% @ 1 year and 80% @ 2 years

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Ascites Diagnosis: Physical Exam

• Fluid wave – 53% sensitive; 90%

specific – Requires ~ 15 liters of

ascites

• Shifting dullness – 88% sensitivity; 56%

specific – Requires ~ 1.5-2 L of

ascites

• Ultrasound • Paracentesis

Evaluation of the patient with ascites • Indicated

• hospitalized patient, signs of infection, abdominal pain, encephalopathy, or gastrointestinal bleeding

• Crucial to determine hepatic reserve • (Child score, MELD score)

• Investigate dietary history, encephalopathy, medication intake

• Careful physical examination • icterus, temporal wasting, caput medusae, fluid wave-

broad degree of hepatic insufficiency

• Basic labs • Urine Na excretion • Ascitic fluid examination

Large volume paracentesis

• Respiratory compromise

• Abdominal discomfort

• Diuretic refractory or resistant

• Up to 4 liters probably safe without albumin

• 8-10 gm of albumin (25%)/L ascites if > 2L

– Other expanders (Hespan, Dextran) not as helpful

• Consider indwelling catheter (palliative)

• PleurX Catheter for home drainage

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Hepatorenal Syndrome (HRS)

• Most common type of renal failure in ESLD

• Renal vasoconstriction with reduced perfusion and diminished GFR

• Three types recognized: – Type I, rapidly progressive over 2 weeks. Often

precipitated. More advanced liver failure.

– Type II, slowly progressive. Diuretic resistant ascites. Less advanced liver failure.

– Type III, very slowly declining renal function

Hepatorenal Syndrome

• Generally described in patients who acutely decompensate in setting of cirrhosis or alcoholic hepatitis

• Precipitated by event such as SBP, GI bleed, circulatory disturbance

• Median survival is 1 month without therapy

• Type II- usually occurs in patients with refractory ascites in which renal function deteriorates over weeks to months.

• Decline in renal function is regarded as a progression of RA.

Diagnosis of HRS: International Ascites Club

• Major criteria (all required)

– Low GFR: creatinine >1.5mg/dl or CrCl <40mL/min.

– Absence of shock, ongoing bacterial infection, fluid losses, or nephrotoxic drugs.

– No sustained improvement with diuretic withdrawal and volume expansion (1.5L)

– Proteinuria <500mg/day; Normal kidneys on U/S

• Minor Criteria (supportive)

– Urine volume <500mL/day, UNa <10, Uosm > SOsm, Urine RBCs <50/hpf, Serum Na<130

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Treatment of HRS

• Liver transplantation

• TIPS

• Medical therapy: peripheral vasoconstriction with volume expansion – Terlipressin and albumin

– Octreotide, midodrine, and albumin

– Norepinephrine and albumin

• Molecular adsorbent recirculating system (MARS)

Management of HRS

• First step- replenish the intravascular volume (precipitating cause in many cases)

• Central venous monitoring; Swan-Ganz catheter

• Discontinue diuretics, NSAIDs, aminoglycosides

• Paracentesis to r/o SBP

• LVP- may decrease intra-abdominal pressure

• Fluid replacement (colloids and crystalloids)

• IV albumin has been used with variable success

Roberts, et al. Mayo Clinic Proceedings. 1996 71;(9)

Hepatic Encephalopathy (HE) Defined as a disturbance in central nervous system (CNS) function due to hepatic insufficiency (acute and chronic liver failure)

•Manifests as a spectrum of neuropsychiatric disturbances

– Alteration of consciousness that often undergoes spontaneous fluctuations

– Potentially reversible

•Related to a range of pathophysiological mechanisms

•Symptoms influenced by clinical factors

– Infection, hypoxemia, gastrointestinal (GI) hemorrhage, electrolyte disturbances

Blei AT et al. Am J Gastroenterol. 2001;96:1968-1976.

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HE causes

• 20-30% unknown cause

• Excessive nitrogen load: GI bleed, increase protein intake, renal failure, constipation

• Electrolyte or metabolic disturbance: hyponatremia, hypokalemia, alkalosis, dehydration, hypoxia

• Drugs and medications: sedatives, alcohol withdrawl,

• Infections: pneumonia, UTI, SBP

• Others: surgery, EtOH hepatitis, acute Hepatitis A

Most Patients With Cirrhosis Develop Some Degree of HE

TIPS=transjugular intrahepatic portosystemic shunt. 1. Bajaj JS. Expert Rev Gastroenterol Hepatol. 2008;2(6):785-790. 2. Poordad FF. Aliment Pharmacol Ther. 2007;25(suppl 1):3-9.

• Up to 80% of patients with cirrhosis1

• 30%-45% of patients with cirrhosis2

• 10%-50% of patients with TIPS2

MHE (Subclinical or Latent HE)

OHE

HE

Neurocognitive disturbances, with or without mental status changes

Principles of HE Assessment

Identify known or suspected structural liver disease and/or identification of portosystemic shunts Detect and characterize CNS abnormalities by clinical manifestations and specialized testing as needed Exclude other causes of neurologic abnormalities Identify and resolve precipitating factors

1

2

3

4

Mullen KD et al. Semin Liver Dis. 2007;27(suppl 2):32-47.

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West Haven Criteria Used to Grade HE Severity1-3

Grade 0 • Lack of detectable changes in personality or behavior

• No asterixis

Grade 1

• Trivial lack of awareness, shortened attention span,

sleep disturbance, altered mood

• Asterixis may be present

Grade 2

• Lethargy, disorientation to time, amnesia of recent events,

impaired simple computations, inappropriate behavior,

slurred speech

• Asterixis is present

Grade 3

• Somnolence, confusion, disorientation to place, bizarre

behavior, clonus, nystagmus, and positive Babinski sign

• Asterixis is usually absent

Grade 4 • Coma; unresponsive to verbal or noxious stimuli

1. Blei AT et al. Am J Gastroenterol. 2001;96:1968-1976. 2. Ferenci P et al. Hepatology. 2002;35:716-721. 3. Mullen KD et al. Semin Liver Dis. 2007;27(suppl 2):32-47.

HE Treatment • Stages 3 & 4 are at risk of obstructing the airway,

tranferred to ICU, often intubation, placement of NG tube safe adm med’s & nutrients

• Treatment depends on underlying cause:

– Type A: acute liver failure.

– Type B post TIPPS procedure,

– Type C typically from infection.

• Lactulose is not absorbed from the digestive tract. They are thought to

improve the generation of ammonia by bacteria, render the ammonia inabsorbable by converting it to ammonium (NH4).

• Rifaximin nonabsorbable antibiotic

Lactulose for HE

• Current first-line pharmacologic treatment1,2

– Efficacy generally accepted, although not well demonstrated, in randomized, controlled trials (RCTs)

– Only agent FDA approved for use in HE

• Can be administered orally, via nasogastric tube, or enema1,2

• Side effects include abdominal cramping, diarrhea, flatulence, and excessively sweet taste1,2

1. Blei AT et al. Am J Gastroenterol. 2001;96:1968-1976.

2. Mullen KD et al. Semin Liver Dis. 2007;27(suppl 2):32-47.

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Diagnostic Tools for HE

Tools for Detecting HE1-3

Psychometric Testing1,2

Neurophysiologic Testing1,2

Neuroimaging3 Blood Ammonia

Levels2

Neuro- psychological assessments

Computerized tests

EEG CAT scan

MRI

MRS

PET scan

CAT=computerized axial tomography; EEG=electroencephalogram; MRI=magnetic resonance imaging; MRS=magnetic resonance spectroscopy; PET=positive emission tomography. 1.Bajaj JS. Expert Rev Gastroenterol Hepatol. 2008;2(6):785-790. 2.Blei AT et al. Am J Gastroenterol. 2001;96:1968-1976. 3.Ferenci P et al. Hepatology. 2002;35:716-721.

Evoked potentials

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JAUNDICE (icterus)

Is a yellowish pigmentation of the skin, the conjuntival membranes on the sclera of the eye and mucus membranes caused by hyperbilirubinemia.

Clinical Definitions

• Liver failure –Failure of the liver to perform its

biosynthetic functions.

• Fulminant hepatic failure –Coagulopathy with encephalopathy

without a previous history of chronic liver disease

• Cirrhosis –Fibrosis of the liver with regenerative

nodules

–Cirrhosis is typically a sequelae of chronic hepatitis.

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Fulminant Hepatic Failure

• Description

– Severe and sudden liver cell dysfunction

–Coagulopathy

–Hepatic encephalopathy

–Mortality rate very high, 75% to 80%

– Liver transplantation is definitive treatment

Fulminant Hepatic Failure

• Etiology

– Infections

–Drugs

– Toxins

–Hypoperfusion

–Metabolic disorders

– Surgery

Fulminant Hepatic Failure • Pathophysiology

– Sudden onset of acute liver failure • Liver usually healthy before illness

– Occurs over a 1- to 3-week period – Hepatic encephalopathy within 8 weeks

• Usually less than 2 weeks between liver failure and onset of encephalopathy

– Massive necrosis of hepatocytes • Impaired bilirubin conjugation

– Result: jaundice

• Decreased clotting factor production – Result: bleeding

• Depressed glucose synthesis – Result: hypoglycemia

• Decreased lactate clearance – Result: metabolic acidosis

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Fulminant Hepatic Failure Assessment and Diagnosis

• Early recognition is important

• Hepatic encephalopathy (staging)

• Laboratory studies – Serum bilirubin, liver enzymes (aspartate

aminotransferase, alkaline phosphatase), serum ammonia, serum albumin

– Coagulation studies, prothrombin time, international normalized ratio, coagulation factors

– Arterial blood gases

Fulminant Hepatic Failure

• Medical management –Ammonia levels

• Remove or decrease nitrogenous waste in large intestine

• Lactulose, rifaximin

–Complications • High risk for gastrointestinal bleeding

• Stress ulcer prophylaxis

Fulminant Hepatic Failure

• Treat acute bleeding

–Vitamin K

– Fresh frozen plasma

–Coagulation factor replacement

–Blood transfusions

–Platelets

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Fulminant Hepatic Failure

• Multisystem organ involvement

– Brain: cerebral edema

– Kidneys: renal failure

– Lungs: respiratory failure

– Cardiovascular system: hemodynamic instability

• Liver transplantation

– Only definitive treatment

Fulminant Hepatic Failure

• Nursing management

–Protect the patient from injury

–Maintain surveillance for complications

• Neurologic condition

• Respiratory failure

–Educate patient and family

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Fulminant Hepatic Failure

• Nursing management

– Elevate head 30 degrees & keep head steady

– Avoid volume overload (early renal support)

– Goal PCO2 30-40 mm Hg ( first 48hrs)

– Avoid factors that may increase ICP

• Fever, seizure activity, agitation, hypertension, neck flexion, unnecessary stimulus (suctioning), vasodilating drugs

Acknowledgments

• Dr. Heather Patton

• Dr. Alex Kuo

• Dr. Michel Mendler

• Dr. Yuko Kono

• Dr. Robert Gish

• Dr Bruce Runyon

• Dr Todd Frederick