Chronic liver disease
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Chronic Liver Disease. Chronic Liver Disease. Outline: Definition Epidemiology Clinical Presentation History/PE Labs Radiographs Management of complications Ascites (including HRS, SBP) HE Variceal hemorrhage HCC. CLD- Pathophysiology.

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Chronic Liver Disease

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Chronic Liver Disease

Chronic Liver Disease




Clinical Presentation

  • History/PE

  • Labs

  • Radiographs

    Management of complications

  • Ascites (including HRS, SBP)

  • HE

  • Variceal hemorrhage

  • HCC

CLD- Pathophysiology

When the liver is injured, inflammatory cells infiltrate into the liver leading to the damage of hepatocytes, which is termed ‘‘hepatitis.’’

When the injury, regardless of its cause, is prolonged, numerous mechanisms are initiated to promote healing.

Injured areas become surrounded by scar tissue formed by excessive deposition of extracellular matrix as a result of activated fibrogenic mechanisms.

These processes may lead to fibrosis, which after a period of time leads to irreversible distortion of the hepatic architecture, termed ‘‘cirrhosis.’’

Fibrosis develops in almost all patients who have chronic liver injury, albeit at variable rates depending on numerous patient factors and the underlying liver disease.

Over time, progressive fibrosis ultimately may cause cirrhosis.

CLD/Cirrhosis - Definition

The word cirrhosis, derived from the Greek term ‘‘kirrhos,’’ refers to a diffuse process in the liver characterized by the development of extensive fibrosis and replacement of the normal hepatic architecture by structurally abnormal nodules of fibrotic tissue.

This structural change in the hepatic architecture eventually leads to functional changes that are characterized collectively as the syndrome of chronic liver failure (CLF).

Presence of these changes for more than 6 months distinguishes CLF from acute liver failure

Chronic Liver Disease


Decompensation HCC Malnutrition Pulmonary

(HE, ascites, VH) Compl.


Burden of Liver Disease in U.S.

Prevalence of 5.5 million cases of CLD/cirrhosis in U.S.

Rate of 2030 cases per 100,000 persons

Over 60% of cases are male

Over 80% are between the ages of 25 and 64 years

Little variation in prevalence among different racial or ethnic groups

Leading Causes of Death in U.S.

  • Chronic liver disease and cirrhosis ranks 12th

  • Age 35-44 years, ranks 7th

  • Age 45-54 years, ranks 4th

  • Age 55-64 years, ranks 7th

  • Among Hispanics, ranks 7th

  • Among Native Americans, ranks 6th

    • Among Native Americans ages 35-44 years, cirrhosis is the 2nd leading cause of death

Economic Impact of Chronic Liver Disease in the U.S.

  • $1.5 billion in direct annual costs

  • Inpatient stays

    • $134 million in physician fees

    • $1.1 billion in facility fees

  • Office visits $64.8 million

  • Medications used to treat CLD/cirrhosis $16.9 million

  • $234 million in indirect annual costs

Etiology Chronic Liver Disease


Nonalcoholic Fatty Liver Disease (NAFLD/NASH)

Alcoholic liver disease

Chronic hepatitis C (CHC)

Chronic hepatitis B (CHB)

Etiology Chronic Liver Disease

Less Common:

  • Autoimmune hepatitis

  • Primary biliary cirrhosis (PBC)

  • Primary sclerosing cholangitis (PSC)

  • Drug-induced hepatitis

  • Genetic

    • Hereditary hemochromatosis

    • α 1 antitrypsin deficiency

    • Tyrosinemia

    • Urea cycle disorders

    • Glycogen storage diseases

Etiology Chronic Liver Disease


Secondary biliary cirrhosis


Polycystic liver disease


Idiopathic portal fibrosis (hepatoportal sclerosis)

Cardiac cirrhosis

Veno-occlusive disease (sinusoidal obstruction syndrome)

Budd-Chiari Syndrome

Etiology of Newly Diagnosed CLD in U.S. GI Practices

(Am J Gastro 2008)

Deaths due to CLD

  • HCC:

  • 16,780 deaths in U.S. in 2007

  • Third leading cause of death from cancer worldwide

Hepatology 2006

Clinical Presentation


  • Usually asymptomatic

  • Primary focus is on risk factors of CLD

    • Alcohol history

    • Jaundiced illnesses

    • IVDU, blood transfusions pre-1991, tattoos, incarcerations

    • Metabolic syndrome

    • IBD

    • Other autoimmune disease

    • Family history

    • Medications including OTCs and CAM

Clinical Presentation

Physical Exam:

  • “stigmata of chronic liver disease”

    • Hepatomegaly/splenomegaly

    • Palmar erythema

    • Vascular spiders

    • Dupuytren’s contracture

    • Terry’s nails/leukonychia

    • Gynecomastia

    • Asterixis

    • Ascites

    • Fetor hepaticus

Clinical Presentation


  • “liver function” is a misnomer

  • LFT at NMCSD includes: t.bili, d.bili, alt, ast, alk phos, ldh, albumin, t.protein

  • Markers of hepatic synthetic function include: prothrombin time, albumin, bilirubin

  • Important considerations:

    • Duration of abnormality

    • Degree of elevation (mild ALT<250, severe ALT>1000)

    • Pattern: hepatocellular, cholestatic, mixed

Clinical Presentation


  • Hepatocellular pattern:

    • Elevation in ALT and AST

    • ALT(xULN)/AP(xULN) ratio = 5 or greater

  • Cholestatic pattern:

    • Elevation in alkaline phosphate (+/-t.bili)

    • Other cholestatic enzymes include GGT and 5’NT

    • ALT/AP ratio = 2 or less

  • Mixed pattern:

    • Elevation in transaminases and alkaline phosphatase

    • ALT/AP ratio = >2 and < 5

Clinical Presentation


  • Viral hepatitis

  • AIH


  • ALD

  • DILI

  • Hereditary (HH, A1AT, Wilson’s, celiac sprue)

  • Ischemic hepatopathy

  • Congestive hepatopathy

  • Budd-Chiari


  • Celiac


  • Extrahepatic biliary obstruction

  • PSC

  • PBC

  • DILI

  • Sepsis

  • Post-operative, benign

  • Infiltrative (sarcoid, lymphoma, tb, amyloid)

Clinical Presentation

Labs (specific serologies):



PBC: Antimitochondrial Ab (AMA)

AIH: ANA, anti smooth muscle Ab (ASMA), IgG

HH: ferritin, iron saturation, HFE mutation

Wilson’s: ceruloplasmin, 24h urine copper

A1AT deficiency: A1AT level/phenotype

Celiac: anti-ttg

Clinical Presentation

Labs (nonspecific):

  • AST:ALT of > 1 (even in setting of normal values)

  • APRI (AST to platelet ratio index)

    • (AST/AST ULN)/Plt count x 100

    • APRI threshold of 0.5 has sens. of 81% and spec of 50% of predicting advanced fibrosis in patients with CHC

  • Low albumin

  • Prolonged PT/INR

  • Thrombocytopenia/Leukopenia

  • Macrocytosis

Clinical Presentation

Radiographic Studies:

  • Ultrasound

    • First study of choice (inexpensive, easy)

  • CT

    • Liver protocol (triple phase constrast study)

  • MR

    • With gadolinium enhancement

    • Can combine with MRCP

Clinical Presentation

Radiographic Studies (findings):

  • Hepatomegaly

  • Increased echogenicity (hallmark of steatosis)

    • Hypodense compared to spleen (steatosis on CT)

  • Nodular contour liver edge

  • Left/Caudate lobe hypertrophy

    • Caudate/Right lobe ratio > 0.65 is 90% specific for cirrhosis

  • Splenomegaly

    • Spleen length > 12cm consistent with Portal HTN

Clinical Presenation

Radiographic Studies (findings):

  • Portal vein diameter

    • >12 mm consistent with Portal HTN

  • Ascites

    • Can detect as little as 50ml

  • Venous collaterallization

    • Recanalized umbilical vein, varices

  • Portal vein thrombosis

  • Bowel wall thickening

    • 64% of cirrhotics vs. 7% controls

  • HCC

    • Early aterial enhancing nodules with venous phase washout

Chronic Liver Disease


Decompensation HCC Malnutrition Pulmonary

(HE, ascites, VH) Compl.


Cirrhosis: management(general principles)

  • Addressing underlying disease

  • Assessing severity

    • Prognosis

    • Natural history

  • Screening/Surveillance of HCC and varices

  • Treat decompensation (ascites, HE, etc.)

  • Preventive

Assessing Severity of Underlying Liver Disease

  • An accurate assessment of extent and severity of liver disease is required for every cirrhotic

  • Two commonly used clinical scoring schemes have both been found to correlate with liver-related mortality

    • Child-Turcotte-Pugh (CTP)

    • Model for End-Stage Liver Disease (MELD)

Assessing Severity of Underlying Liver Disease


  • 1964, Child & Turcotte introduced a scoring system to predict mortality in patients undergoing portocaval shunt surgery

  • 5 significant factors that affected mortality

    • Ascites

    • Albumin

    • Bilirubin

    • Encephalopathy

    • Nutritional status

      • 1972, Pugh substituted the most subjective factor (nutritional status) with prothrombin time

Modified Child-Pugh Score


*Class A = 5-6 points, B = 7-9 points, C = 10-15 points

**For cholestatic disorders (eg, PBC) assign 1 point for bilirubin < 4mg/dl, 2 points for 4-10mg/dl, and 3 points for >10mg/dl

Assessing Severity of Underlying Liver Disease


  • Originally devised as a prognostic measure of short term mortality in patients undergoing transjugular intrahepatic portosystemic shunt¹

  • Patients are assigned a score of 6-40

  • The score incorporates 3 biochemical variables

    • Total bilirubin

    • Serum creatinine

    • INR

(¹Malinchoc, Hepatology 2000)


Assessing Severity of Underlying Liver Disease


  • Prospectively validated as a prognostic marker of mortality in cirrhosis, acute alcoholic hepatitis, acute variceal bleeding

  • Possible use in acetaminophen-induced liver injury, HRS, cirrhosis with sepsis, and UNOS Status 1

  • Feb. 2002 – MELD was adopted by UNOS for the purpose of donor liver allocation

Cirrhosis: Prognosis

  • 1 year survival:

    • Child’s A: 100%

    • Child’s B: 80%

    • Child’s C: 45%

  • 2 year survival

    • Child’s A: 85%

    • Child’s B: 60%

    • Child’s C: 35%

Cirrhosis: Prognosis

Cirrhosis: Prognosis

  • The median survival of patients with compensated cirrhosis is 7-10 years from the time of diagnosis

  • 2 year survival after clinical decompensation is below 50%

  • Decompensation event rates range between 5 and 10% annually

Cirrhosis: Prognosis

Cirrhosis: Prognosis

Decompensation/Disease-related complications

  • 8% annual risk of developing esophageal varices

  • 5-15% annual risk of variceal hemorrhage

  • 5-6% annual risk of developing hepatic encephalopathy and/or ascites

  • 1-6% annual risk of developing hepatocellular carcinoma

Cirrhosis: Prognosis

Management of Selected Complications of Cirrhosis: Varices

Acute Variceal Hemorrhage:

  • 40% risk reduction in mortality in AVH in 2000 compared to historical controls from the 1960s (using endoscopic variceal ligation and pharmacologic therapy)

    Primary prophylaxis:

  • Nonselective Beta blockers reduce the risk of first bleeding from 25% to 15% (RRR 40%, NNT 10)

    Secondary prophylaxis:

  • Combination EVL plus NSBB is better than either alone

  • Recent randomized trial (combo v EVL) reduced rebleeding rate from 38% to 14%

Management of Selected Complications of Cirrhosis: Varices

  • All cirrhotics eligible for the benefits of 1° prophylaxis should undergo EGD to exclude the presence of esophageal varices

  • When no or small EV are found in Child A cirrhotics, 1° prophylaxis not recommended and EGD should be repeated at 2-3 yr intervals

  • EVL may be used as 1° prophylaxis for those who are intolerant of NSBB

Management of Selected Complications of Cirrhosis: Varices

  • Management of acute variceal hemorrhage should include:

    • EVL

    • Vasoactive drug therapy for at least 5 days (Octreotide 50mcg bolus then 50mcg/h gtt)

    • antibiotic prophylaxis (oral norfloxacin 400 mg twice daily for 7 days or intravenous ceftriaxone 1g/d)

Management of Selected Complications of Cirrhosis: Ascites and SBP

  • Primary treatment of patients with cirrhosis and ascites is:

    • (1) sodium restriction

    • (2) oral diuretics.

  • Sodium restriction (not fluid restriction) results in weight loss as water follows sodium passively.

  • Dietary sodium restriction and diuretic therapy is successful in controlling ascites in 90% of patients.

Management of Selected Complications of Cirrhosis: Ascites and SBP

Sodium Restriction:

  • The goal is to restrict intake to less than 2000mg/day (88 mmol/d). To reduce or stabilize accumulation of ascites, net urinary excretion of sodium needs to be at least 78 mmol/d.

    • (88mmol – 10mmol (insensible losses)) = 78 mmol/d.

  • A random “spot” urine Na:K > 1 correlates with a 24 hour Na excretion of > 78 mmol/d with approximately 90% accuracy

Management of Selected Complications of Cirrhosis: Ascites and SBP


  • Aldosterone Antagonists

    • Increased aldosterone levels contribute to avid retention of sodium and the development of ascites, drugs that block aldosterone (spironolactone) are 1st line agents in producing diuresis in the setting of ascites.

  • Loop diuretics

    • Loop diuretics inhibit chloride reabsorption in the ascending limb of the loop of Henle which increases the sodium, chloride, and water delivered to the distal tubule. It is this action that limits the use of loop diuretics as single agents given that all of the sodium delivered to the distal tubule will be reabsorbed because of unopposed action of aldosterone. However when combined with spironolactone, loop diuretics result in marked natruiresis.

  • Typically begin Aldactone 100mg/d with Lasix 40mg/d and titrate up in that ratio

Management of Selected Complications of Cirrhosis: Ascites and SBP

  • Spontaneous bacterial peritonitis (SBP) is present in 3.5% of hospitalized outpatients and increases to 10-30% in inpatients

  • Mortality has decreased from 30-50% to 8-17% with advances in diagnosis and treatment

  • All hospitalized patients with ascites (especially those with GI bleed) should undergo diagnostic paracentesis

Management of Selected Complications of Cirrhosis: Ascites and SBP

SBP Treatment:

  • Intial therapy typically includes 3rd generation cephalosporin for 5 days

    • Cefotaxime has been most extensively studied (2g IV every 8 hours

    • 100% penetration of ascitic fluid and sterilizes the fluid in 94% of cases after single dose

  • Intravenous albumin at 1.5g/kg on day 1 and 1g/kg on day 3

    • Has shown to decrease frequency of renal impairment and reduce short and intermediate-term mortality in single prospective randomized trial

      (Sort, NEJM 1999)

Management of Selected Complications of Cirrhosis: Ascites and SBP

SBP prophylaxis:

  • Any cirrhotic with acute GI bleed

  • History of SBP

    • Patients with previous episode of SBP have 70% chance of recurrence at 1 year

  • Hospitalized cirrhotics with low protein (<1g/dl) ascites

    • Single study of norfloxacin reduced incidence incidence of SBP from 22.5% to 0%

      (Soriano, Gastroenterology 1999)

Management of Selected Complications of Cirrhosis: Ascites and SBP

SBP prophylaxis:

  • Cirrhotics with low protein ascites (<1.5) and advanced liver failure (CPT ≥ 9) with bili ≥ 3mg OR Cr ≥ 1.2, BUN ≥ 25 or Na ≤ 130

    • Single study using daily norfloxacin reduced 1 year probablility of SBP and HRS as well as improved 3 month and 1 year survival

      (Fernandez, Gastroenterology 2007)

Management of Selected Complications of Cirrhosis: Encephalopathy

Portosystemic Encephalopathy:

  • Pathogenesis is complex but ammonia is a key factor

  • The diagnosis is one of exclusion

  • Precipitating factors: electrolyte disturbances (hypokalemia), alkalosis, hypovolemia, medications (benzos, narcotics), infection (UTI, SBP), GI bleeding, constipation, surgery

Management of Selected Complications of Cirrhosis: Encephalopathy

PSE management:

  • Fix/remove precipitating factors

  • Nonabsorbable dissacharides

  • Antibiotics

  • Don’t restrict protein!

    • No clinical evidence to support this practice and has potential to complicate postoperative course (often have preexisting malnutrition)

    • Need 1-1.5g/kg/d

  • Miscellaneous: BCAA, probiotics, flumazenil, Zinc, melatonin

Management of Selected Complications of Cirrhosis: Encephalopathy

PSE management:

  • Lactulose

    • Paucity of placebo controlled clinical trials but extensive clinical experience

    • Cheap!

  • Rifaximin

    • Metanalysis showed rifaximin to be as effective and in many studies for effective than nonabsorbable dissacharides

      (Lawrence, Pharmacotherapy 2008)

    • Recent study showed fewer hospitalizations, fewer days hospitalized, fewer total weeks hospitalized and lower hospitalization charges per patient (rifaximin v. lactulose)

      (Leevy, Dig Dis Sci 2007)

Management of Selected Complications of Cirrhosis: Hepatocellular Carcinoma

  • HCC screening is recommended in high risk patients

  • Recent analysis of HCC screening practices across 3 VA centers showed

    • 28% received any screening test within 3 years

    • 7% had two sequential tests reflecting actual surveillance guidelines

      (Dawla, J Clin Gastroenterol 2007)

  • Adherence to surveillance strategy has shown a 37% reduction in HCC-related mortality

    (Zhang, J Cancer Res Clin Oncol 2004)

High risk groups requiring screening:

CHB (+HBsAg)

Asian males > 40

Asian females > 50

All cirrhotics

Family history of HCC

Africans over age 20

Nonhepatitis B cirrhosis

Hepatitis C

Alcoholic cirrhosis



Possible (A1AT, NASH, AIH)

AASLD guidelines:

AFP + ultrasound every 6-12 months

EASL guidelines:

AFP + ultrasound every 6 months

APASL guidelines:

HBV patients every 3-6 months

Method not specified

Management of Selected Complications of Cirrhosis: Hepatocellular Carcinoma

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