Lecture 3: Cirrhosis and Choleostasis

Question 1

Major determinants of Liver Disease: metabolic consequences of liver disease

Answer 1

-toxic accumulations of
metabolic waste (especially ammonia & bilirubin)
-drugs & toxins
-endogenous hormones (especially estrogen)

bleeding, associated with a deficiency of coagulation factors

edema, associated with a deficiency of albumin

failure to absorb intestinal fat because of a deficiency of bile acids

Viral hepatitis is a common contagious disease

Cirrhosis is the final endpoint for many liver diseases

Portal HTN is the most important consequence of cirrhosis & can be associated with liver failure & severe hemorrhage

Stones often form in the gallbladder & may pass into & obstruct the bile duct

Question 2

What is intrahepatic cholestasis?

Answer 2

Anything that impairs liver function – hepatitis, infection, drugs, toxins

May give mixed hyperbilirubinemia

Distinguish from extrahepatic causes as there is no obstruction in intrahepatic

Question 3

What is extrahepatic cholestasis?

Answer 3

Mechanical obstruction of biliary drainage

Question 4

Where is the problem?

Prehepatic to intra to extra for cholestasis

Answer 4

Prehepatic
Before the liver = hyperbilirubinemia = jaundice

Intrahepatic Cholestasis
From uptake into the hepatocyte to delivery into biliary canaliculi = cholestasis = hyperbilirubinemia = jaundice

Extrahepatic Cholestasis
From canaliculi to small bowel = cholestasis = hyperbilirubinemia = jaundice

Question 5

Symptoms and Signs of cholestasis

Answer 5

Jaundice, dark urine, pale stools, and generalized pruritus

Chronic cholestasis may produce:
muddy skin pigmentation
excoriations from pruritus
a bleeding diathesis, bone pain, and cutaneous lipid deposits

Question 6

Lab results confirming cholestasis

Answer 6

↑ serum bilirubin
↑ serum amylase
↑ ↑ alkaline phosphatase (ALP)
↑ ↑ gamma glutamyl transpeptidase (GGT)
Mild ↑ liver transaminases (ALT, AST 2X normal)

Question 7

Morphological signs of cholestasis

Answer 7

“backup” of bile – hepatocyte, liver canaliculus, biliary tract

Deposition of bilirubin and other bile constituents due to backup

Question 8

Intrahepatic vs extrahepatic cholestasis in terms of symptoms or causes

Answer 8

Intrahepatic cholestasis is suggested by symptoms of hepatitis, heavy alcohol ingestion, recent use of potentially cholestatic drugs, or signs of chronic hepatocellular disease (eg, spider nevi, splenomegaly, ascites).

Extrahepatic cholestasis is suggested by biliary or pancreatic pain, rigors, or a palpable gallbladder.

Question 9

Describe Primary biliary cirrhosis

Answer 9

Slowly progressive autoimmune liver disease

90% females

Peak incidence in 40’s

Portal inflammation and autoimmune destruction of intrahepatic bile ducts

Leads to cirrhosis and liver failure

90-95% have antimitochondrial antibody (confirms PBC)
Primary biliary cirrhosis

(PBC) is a chronic cholestatic liver disease

Question 10

Pathological stages of PBC

Answer 10

1 Destruction of bile ducts in portal tracts

2 Inflammation beyond portal tracts

3 fibrous septa link portal triads

4 Cirrhosis

Question 11

PBC: Cholestatic liver disease (ALP) Diagnosis

Answer 11

AMA titer 1:80 or greater (95% sens/spec)

IgM > 1.5 upper limits of normal

Liver biopsy: bile duct destruction

Symptoms: Pruritus and Fatigue

Question 12

Stages of Cirrhosis

Answer 12

Starts as hepatocelluar neocrosis and inflammation

Complete loss of normal architecture,

Replaced by extensive fibrosis (bridging fibrous septa) with,

Regenerating hepatocytes from nodules.

Question 13

Etiology of Cirrhosis

Answer 13

1. Alcoholic liver disease

2. Viral Hepatitis

Question 14

Pathogenesis of Cirrhosis

Answer 14

Hepatocyte injury leading to necrosis.
(Alcoholic, infections including virus, drugs, genetic etc.).

Chronic inflammation - (hepatitis).

Bridging fibrosis

Regeneration of remaining hepatocytes.

Proliferate as round nodules.

Loss of sinusoids, vascular arrangement rendering regenerating hepatocytes ineffective.

Question 15

Cirrhosis Features

Answer 15

Hepatocyte injury & fibrosis

Hepatocyte regeneration but non functional.

Vascular disruption Porta systemic shunts (blood bypasses hepatocyte) – Liver failure

Portal hypertension

Encephalopathy

Question 16

Clinical Features of Cirrhosis

Answer 16

Hepatocellular failure.
Malnutrition, low albumin & clotting factors, bleeding.
Hepatic encephalopathy.

Portal hypertension.
Ascites, Porta systemic shunts, varices, splenomegaly.

Question 17

Early Stage Cirrhosis

Answer 17

GI disturbances, dull pain in RUQ/epigastrium, fever, malaise, enlargement of liver & spleen

Question 18

Late Stage Cirrhosis

Answer 18

Jaundice, skin lesions (spider angiomas, palmar erythema), hematologic problems, endocrine disturbances, peripheral neuropathy

Question 19

Complications of portal hypertension

Answer 19

Compression
=
Portal vein,hepatic veins, sinusoids
=
Obstruction of portal blood flow
=
Portal Hypertension
=
Increased venous pressure, splenomegaly, collateral circulation, ascites, systemic hypertension, esophageal varices

Question 20

Diagnosis of Cirrohosis

Answer 20

Liver enzymes elevation – ALP, AST, GGT
↑ globulin (due to infection/globin)
↓ cholesterol levels, total protein, albumin
Prolonged PT
Bilirubin metabolism abnormalities
Liver biopsy
Liver scan

Question 21

why does cirrhosis cause INCREASED globulins but DECREASED albumin

Answer 21

Globulins: Due to the diminished removal of immunoglobulins by diseased liver allowing gut antigens and endotoxins that bypass the liver and reach the antibody-producing cells.

Albumin: is made by liver, so with less hepatocyte mass of functional cells, less albumin made.