1. Hepatic Disease
Clinical Medicine I
Patrick Carter MPAS, PA-C
February 14, 2011

2. Objectives
 Discuss the major metabolic functions of the liver.
 Identify the categories of viral agents that cause hepatitis.
 For each of the following, describe the etiology, risk factors,
transmission, clinical features, diagnostic findings, treatment,
and prophylaxis:
◦ HAV
◦ HBV
◦ HCV
◦ HDV
◦ HEV
◦ HGV
 Discuss the possible complications of viral hepatitis.

3. Objectives
 Differentiate between toxic and drug induced
injury of the hepatic system.
 Define autoimmune chronic active hepatitis.
 Identify the typical clinical presentation of
alcoholic liver disease.
 Identify the pathophysiologic mechanisms of
alcohol injury to the liver.

4. Objectives
 Identify the typical treatment options for alcoholic
liver disease including pharmacological, dietary, and life
style treatments
 Discuss the association between alcoholic liver
disease and portal hypertension.
 State the major complications of alcoholic liver
disease including presentation, laboratory findings, and
treatment of: spontaneous bacterial peritonitis,
hepatorenal syndrome, and hepatic encephalopathy
 Indicate the prognosis for alcoholic liver disease.

5. Assessment Parameters
 Acute or chronic
 Focal or diffuse
 Mild or severe
 Reversible or irreversible
 Fulminant – development of hepatic
encephalopathy within 8 weeks
 Sub-fulminant -- development of hepatic
encephalopathy at 8 weeks – 6 months

6. Definitions
 Jaundice (Icterus)
◦ Yellow pigmentation of skin & sclera secondary to increased serum
bilirubin
 Bilirubin
◦ Yellow breakdown product of normal heme catabolism
 Unconjugated (Indirect) bilirubin
◦ Heme is turned into unconjugated bilirubin in the reticuloendothelial
cells of the spleen. It is then bound to albumin and sent to the liver.
 Conjugated (Direct) bilirubin
◦ In the liver bilirubin is conjugated with glucuronic acid by the enzyme
glucuronyltransferase. Much of it goes into the bile and thus out into
the small intestine
 Hepatitis
◦ Inflammation of the liver
 Cirrhosis
◦ Scarring and fibrosis of liver secondary to chronic liver disease

9. Hepatic Physiology
 Energy metabolism
◦ carbohydrates, lipid and protein
◦ glucose production
◦ cholesterol synthesis
 Protein synthesis functions
◦ plasma proteins (albumin, clotting factors)

10. Hepatic Physiology
 Solubilization, transport, and storage
◦ drug and poison detoxification
◦ solubilization of fats and fat-soluble vitamins
◦ synthesis of VLDL, HDL, LDL
◦ uptake and storage of Vit A, D, B12 and Folate

11. Hepatic Physiology
 Protective and clearance functions
◦ detox of ammonia
◦ detox of drugs
◦ clearance of damaged cells and proteins,
hormones, drugs and clotting factors
◦ clearance of bacteria and antigens

12. Etiology of Hepatic Disease
 Cholelithiasis
 Excessive alcohol intake
 Inherited disorders
 Viruses/bacterial Infection
 Medications
 Cirrhosis
 Cancer

13. Jaundice (Icterus)

14. Causes of Jaundice
CMDT 2011
Chapter 16

15. Jaundice
Pathology Smart Charts, Groysman; McGraw-Hill. 2001

16. Acute Hepatic Failure
 Fulminant
◦ Hepatic encephalopathy within 8 weeks after
onset of acute Liver Disease
 Subfulminant
◦ Hepatic encephalopathy between 8 weeks and
6 months after onset of acute Liver Disease

17. Acute Hepatic Failure
 Causes
◦ Acetaminophen toxicity is most common
accounting for at least 45%
◦ Idiosyncratic drug reactions 2nd most common
◦ Viral Hepatitis (only 12% of all cases)
◦ Poisonous mushrooms
◦ Shock
◦ Hyperthermia / Hypothermia
◦ Budd-Chiari syndrome
◦ Malignancies
◦ Wilson disease

18. Acute Hepatic Failure
 Risk of acute hepatic failure is increased in
patients with diabetes
 Outcome is worsened by obesity
 Symptoms & Signs
◦ Gastrointestinal
◦ SIRS
◦ Hemorrhagic phenomena
◦ Adrenal insufficiency
◦ Subclnical myhocardial injury

19. Acute Hepatic Failure
 Labs
◦ Serum aminotransferase levels are elevated
(>5000 in acetaminophen tox)
◦ Bilirubin may be normal or minimally elevated
initially then elevates as progresses
◦ Serum ammonia elevated – correlates with
encephalopathy & intracranial hypertension

20. Acute Hepatic Failure

21. Acute Hepatic Failure
 Treatment
◦ Correct coagulation defects
◦ Correct electrolyte defects
◦ Correct acid-base disturbances
◦ Correct hypoglycemia
◦ Correct encephalopathy (lactulose)
◦ Prophylactic antibiotics not routinely
recommended (only Sepsis)
◦ Steroids are uncertain in value
◦ Stress gastrophathy prophylaxis

22. Acute Hepatic Failure
 Treatment
◦ Treat intracranial hypertension (Mannitol)
◦ Administer acetylcysteine for acetaminophen
toxicity
◦ EARLY transfer to liver transplantation center
is crucial

23. Acute Hepatic Failure
 Prognosis
◦ Mortality up to 80% - except acetaminophen
toxicity
◦ Acetaminophen toxicity up to 65% transplant
free survival
◦ Be familiar with poor prognostic indicators for
acetaminophen and non-acetaminophen
hepatotoxicity in CMDT (page 608)

24. Acute Viral Hepatitis

25. Viral Hepatitis
 Essentials of diagnosis
◦ Prodrome of anorexia, nausea/vomiting,
malaise, aversion to smoking
◦ Fever, enlarged and tender liver, jaundice
◦ Normal to low WBCs, markedly elevated
aminotransferases early in the course
◦ Liver biopsy rarely indicated, but might show
hepatocellular necrosis

26. Acute Viral Hepatitis
 Symptoms
◦ Icteric phase – jaundice after 5-10 days
◦ Convalescent phase – gradual disappearance of
symptoms
 Signs
◦ Hepatomegaly
◦ Liver tenderness
◦ Splenomegaly in about 15% of cases

27. Hepatitis A Virus (HAV)
 Fecal/oral transmission
 Poor sanitation or crowded living
situations
 Contaminated water & food
 ~ 30 days incubation
 Low level of mortality
 Fulminant cases are rare
 Never chronic

29. Hepatitis B Virus (HBV)
 Blood and blood products
 Sexual transmission
 Maternal-fetal transmission
 Prevalent in homosexuals and IV drug
users
 Incidence has decreased by 75% since the
1980’s
 Onset is more insidious than HAV

30. Hepatitis B Virus (HBV)
 6 week – 6 month incubation
 Aminotransferase levels higher than in
HAV
 Risk of fulminant hepatitis is less than 1%
but has a 60% mortality rate
 Infection persists in 1-2%, higher in
immunocompromised

31. Hepatitis B Virus (HBV)
 Patients with chronic HBV have substantial
risk of cirrhosis and hepatocellular
carcinoma (up to 40%)
 HBsAg – first evidence of infection
 Anti-HBs – signals recovery from HBV
infection and immunity
 Vaccination exists

33. Hepatitis B Virus (HBV)
CMDT 2011
Chapter 16

34. Hepatitis C Virus (HCV)
 Transmission
◦ IV drug use
◦ Body piercings
◦ Blood transfusion
 Low risk of transmission
◦ Sexual
◦ Maternal/fetal

35. Hepatitis C Virus (HCV)
 30 – 50% of HIV patients are coinfected
with HCV
◦ Faster progression of chronic HCV to cirrhosis
 Incubation period is 6-7 weeks
 Clinical illness is generally mild or
asymptomatic
 80% will become chronic

36. Hepatitis C Virus (HCV)
 Screening to detect HCV antibodies
 Confirmation by an assay for HCV RNA
 About 20% of patients infected with HCV
will clear the infection
 No vaccination available
 Treatment exists with varying results

38. Hepatitis D (Delta agent)
 Defective RNA virus that causes hepatitis
ONLY in association with HBV
 Usually percutaneous exposure
 As superinfection with HBV, may cause
fulminant hepatitis or severe chronic
hepatitis
 In US, occurs mainly in IV drug users
 3 x risk of hepatocellular carcinoma

39. Hepatitis E (HEV)
 Rare in the US
 Endemic areas are India, Burma,
Afghanistan, Algeria and Mexico
 Waterborne
 Illness is self-limited
 Mortality rate of 10-20% in pregnant
women

40. Hepatitis G (HGV)
 Percutaneously transmitted and associated with
chronic viremia lasting at least 10 years
 Has been detected in
◦ 1.5% of blood donors
◦ 50% of IV drug users
◦ 30% of hemodialysis patients
◦ 20% of hemophiliacs
◦ 15% of patients with chronic hepatitis B or C

41. Hepatitis G (HGV)
 Does not cause important liver disease
 Does not affect the response of patients
with chronic hepatitis B or C to antiviral
therapy
 HGV coinfection may improve survival in
patients with HIV infection

42. Viral Hepatitis
 Symptoms
◦ Prodromal phase
 General malaise, myalgia, arthralgia, fatigue and
anorexia
 Distaste for smoking
 Nausea/vomiting
 Serum sickness in HBV
 Fever, usually low-grade
 RUQ or epigastric pain, usually mild

43. Acute Viral Hepatitis
 Prevention
◦ Thorough handwashing
◦ Universal precautions
◦ Screening of blood supply
◦ Vaccinations
 HAV – close contacts of infected patients, persons
traveling to endemic areas
 HBV – universal vaccination of infants and children,
healthcare workers

44. Chronic Viral Hepatitis
 Defined as chronic necroinflammation > 3-6
months
 Causes
◦ Hepatitis B
◦ Hepatitis C
◦ Hepatitis D
◦ Autoimmune Hepatitis
◦ Alcoholic & Non Alcoholic Hepatitis
◦ etc…
 Prognosis is variable depending upon disease

45. Chronic Hepatitis B
 4 Phases
1. Immune Tolerant
2. Immune Clearance
3. Inactive Carrier State
4. Reactivated Chronic Hepatitis B

46. Chronic Hepatitis B
 Risk Factors
◦ Male
◦ Increased Age
◦ ETOH Use
◦ Cigarrette Use
◦ Coinfection with:
 HBV +/- HDV, HCV, autoimmune hepatitis, Wilson’s
disease, etc.
◦ HIV with low CD4 count

47. Chronic Hepatitis B
 Treatment
◦ Peginterferion alpha 2a
 4 years for treatment
 Injections weekly
 Increased survival 40%
◦ Oral Nucleosides & Nucleoside Analogues
 Entecavir = 1st line choice
 Decreased resistance
 Orally administered
 Up to 70-80% supression

48. Chronic Hepatitis C
 Develops in up to 85% with Acute HCV
 About 20% will progress to cirrhosis in 20
years
 Men with EtOH use more than 50 g/day
increases risk of cirrhosis
 Age > 40 when acquire HCV increases risk
 Tobacco & Cannabis increases risk
 African Americans have increase rate of
Chronic HCV but less fibrosis (poor
responders)

49. Chronic Hepatitis C
 Treatment
◦ Age less than 70 with minimal fibrosis
◦ Combination therapy with peginterferon alpha
2a or 2b and ribavirin
◦ Response rates up to 55-80%
◦ May reduce the risk of hepatocellular
carcinoma
◦ Mexican American & African American are
poor responders to therapy

50. Autoimmune Hepatitis
 Young – middle aged women
 Increased Risk for Cirrhosis & Carcinoma
 Signs/Symptoms
◦ Healthy Appearance
◦ Multiple spider nevi
◦ Cutaneous striae
◦ Acne
◦ Hirsutism
◦ Hepatomegaly
◦ Amenorrhea

51. Autoimmune Hepatitis
 Associated Disease
◦ Arthritis
◦ Sjogren’s syndrome
◦ Thyroiditis
◦ Nephritis
◦ Ulcerative colitis
◦ Coombs (+) Hemolytic Anemia

52. Autoimmune Hepatitis
 Labs
◦ AST/ALT > 1000
◦ Elevated Total bilirubin
◦ Positive ANA/Smooth Muscle Antibody
◦ May cause FALSE positive Anti-HCV
 Liver biopsy needed to establish diagnosis
and evaluate severity and need for
treatment

53. Autoimmune Hepatitis
 Treatment
◦ If Asymptomatic with Normal LFT no Treatment
indicated
◦ If Asymptomatic with abnormal LFT or
Symptomatic then:
 Prednisone
 (+) Azathioprine
◦ Response rate up to 80% with combination
◦ Fibrosis may reverse with treatment and rarely
progresses
◦ Non-responders may need other meds or
transplant

54. Drug & Toxin Induced Liver Disease
1. Direct hepatic toxins
◦ Dose related severity
◦ Latent period following exposure
◦ Susceptibility in all individuals
◦ Examples
 Acetaminophen, EtOH, carbon tetrachloride,
chloroform, heavy metals, mercaptopurine (6-MP),
tetracycline, vitamin A
Note: Statins may cause elevation of
aminotransferase but rarely cause hepatitis and are
NO LONGER contraindicated in liver disease

55. Drug & Toxin Induced Liver Disease
2. Drug induced idiosyncratic reactions
◦ Sporadic
◦ Not dose associated
◦ Occasionally features suggest allergic reaction
(fever and eosinophilia)
◦ Examples
 Amiodarone, ASA, carbamazepine, chloramphenicol,
diclofenac, halothane, isoniazid, ketoconazole,
phenytoin, etc.

56. Drug & Toxin Induced Liver Disease
3. Cholestatic Reactions
◦ Drug induced cholestasis
◦ Drug induced inflamation of portal arewas
with bile duct injury
◦ Often associated with allergic features
4. Acute or Chronic Hepatitis
◦ Result in acute or chronic hepatitis
◦ Histologically & Clinically indistinguishable
from autoimmune hepatitis

57. Alcoholic Hepatitis
 Acute or chronic inflammation and
parenchymal necrosis of the liver induced
by EtOH
 Often Reversible
 Most common cause of cirrhosis in the US
 Tumor necrosis factor alpha and
acetaldehyde induces immune response to
proteins in liver

58. Alcoholic Hepatitis
 Frequency estimated at 10-15% of daily
drinkers (more than 50 g) for over 10
years
 50 g = 4 drinks (4 oz. 100 proof whiskey,
15 oz. wine or 48 oz. beer)
 Women > men
 Concurrent HBV or HCV increases risk

59. Alcoholic Hepatitis
 Signs and symptoms
◦ Asymptomatic to Rapidly Fatal Acute Illness
◦ Enlarged liver
◦ Anorexia and nausea
◦ Hepatomegaly and jaundice
◦ Abdominal pain
◦ Splenomegaly
◦ Ascites
◦ Fever
◦ Encephalopathy

60. Abdominal pain

61. Recent
Heavy
Abdominal pain
Drinking
Splenomegaly
Anorexia
Ascites
Nausea
Fever
Hepatomegaly
Encephalopathy
Jaundice

62. Treatment
 Strict EtOH abstinence - ESSENTIAL
 Caloric supplement and nutritional
support
 Vitamin supplement – folic acid and
thiamine
 Glucose administration increases Vitamin
B1 needs and can precipitate Wernicke-
Korsakoff syndrome – must co-administer
thiamine

63. Alcoholic Hepatitis
 Labs
◦ Mild elevation of AST < 300
◦ AST > ALT at least 2 fold
◦ Alk Phos mildly elevated < 3 times normal
◦ Increased Total Bilirubin in 60-90%
◦ Macrocytic Anemia
◦ 10% may have Thrombocytopenia
 If Total Bili > 10 and INR > 6 = Poor
Prognosis with up to 50% mortality

64. Alcoholic Hepatitis
 Differential
◦ Mimics
 Cholecystitis
 Cholelithiasis
 Drug induced hepatitis

65. Treatment
 Stop ETOH
 Nutritional Support
 Prednisone 32 mg/day for 1 month
◦ May reduce short-term mortality for patients
with alcoholic hepatitis and encephalopathy or
greatly elevated bilirubin
 Pentoxifylline 400 mg TID for 4 weeks may
decrease risk of hepatorenal syndrome

66. Treatment
 Liver transplant
◦ Usually requires abstinence for 6 months prior
to transplant
◦ Absolute contraindications
 Malignancy, advanced cardiopulmonary disease and
sepsis
◦ Relative contraindications
 Age > 70, HIV infection, portal vein thrombosis,
active substance abuse, severe malnutrition

67. Cirrhosis
 12th Leading Cause of Death in U.S.
 Hepatocellular injury that leads to:
◦ Fibrosis
◦ Nodular Regeneration
 Risk Factors
◦ Chronic Viral Hepatitis
◦ Alcoholic Hepatitis
◦ Drug Toxicity
◦ Autoimmune Hepatitis

68. Cirrhosis
 Clinical Features are Secondary to:
◦ Portal HTN
◦ Hepatic Cell Dysfunction
◦ Portosystemic Shunting

69. Portal Hypertension
Pathology Smart Charts, Groysman; McGraw-Hill. 2001

70. Signs of Portal HTN

72. Major Complications
 Ascites
◦ Diagnostic paracentesis indicated for new
ascites
 Cell count and culture
 Albumin level
◦ Restriction of dietary sodium and fluid intake
◦ Diuretics – spironolactone +/- Lasix
◦ Large-volume paracentesis (4-6 L)
◦ TIPS (transjugular intrahepatic portosystemic
shunt

73. Major Complications
 Spontaneous bacterial peritonitis
◦ Abdominal pain, increasing ascites, fever
and progressive encephalopathy
◦ Paracentesis shows high WBC count
◦ Cultures are usually positive – most
common E. coli or pneumococci

74. Major Complications
 Spontaneous bacterial peritonitis
◦ Treatment with IV cefotaxime 2 g q 8-12 hours
for 5 days
◦ Overall mortality rate is up to 70% in 1 year
 Hepatorenal syndrome
◦ Azotemia in the absence of shock or
significant proteinuria in a patient with end-
stage liver disease

75. Major Complications
 Hepatorenal syndrome
◦ Does not improve with IV isotonic saline
◦ Oliguria and hyponatremia
◦ Diagnosis of exclusion
◦ Cause is unknown
◦ Treatment is generally ineffective
◦ Mortality is high without liver transplant
◦ TIPS procedure may buy time until transplant

76. Major Complications
 Hepatic encephalopathy
◦ Disordered CNS function due to failure of the
liver to detoxify noxious agents originating in
the gut
◦ Ammonia is most readily identified
◦ Dietary protein withheld during acute episodes
◦ Lactulose to acidify colon contents
NH4+ NH3 + H+

77. Major Complications
 Hepatic encephalopathy
◦ NH4+ is not absorbable
◦ Lactulose should be dosed at 30 mL 3 or 4
times daily
◦ Avoid opioids and sedatives that are
metabolized or excreted by the liver
◦ Zinc deficiency should be corrected if present

78. Prognosis
Points Class One year survival Two year survival
5-6 A 100% 85%
7-9 B 81% 57%
10-15 C 45% 35%

79. Non-Alcoholic Fatty Liver Disease
(NAFLD)
 Up to 30% US population
 Etiology
◦ Obesity
◦ Diabetes
◦ Hypertriglycerides
◦ Corticosteroids
 Physical Activity protects against NAFLD
 Don’t worry about NASH

80. Non-Alcoholic Fatty Liver Disease
(NAFLD)
 Signs & Symptoms
◦ Asymptomatic
◦ Mild Right Upper Quadrant Pain
◦ Hepatomegaly (up to 75%)
 Chronic Liver Disease uncommon

81. Non-Alcoholic Fatty Liver Disease
(NAFLD)
 Laboratory Findings
◦ Mild elevated Aminotransaminases & Alkaline
Phosphatase levels
◦ Ratio ALT to AST > 1 (opposite ETOH)
◦ Ratio does decrease if fibrosis/cirrhosis
develop
 Imaging
◦ CT/MRI/US demonstrate fatty liver
◦ Does not distinguish hepatitis

82. Non-Alcoholic Fatty Liver Disease
(NAFLD)
 Liver Biopsy
◦ Percutaneous
◦ Diagnostic & “Standard Approach”
◦ Assess degree of inflammation & fibrosis
 BARD Score used to predict advanced
fibrosis

83. Non-Alcoholic Fatty Liver Disease
(NAFLD)
 Treatment
◦ Remove offending factors
◦ Weight Loss
◦ Exercise
◦ Fat Restriction
◦ Gastric Bypass with BMI > 35
 Statins are NOT contraindicated

84. Questions?