Pathology
Lecture 49 Alcoholic Liver Disease and Cirrhosis of the Liver
1) Recognize that not all alcoholics get cirrhosis. More than 14 million Americans
meet criteria for alcohol abuse and/or dependence (7.4% prevalence). Approximately
40% of deaths from cirrhosis are attributed to alcohol-induced liver disease.
Cirrhosis develops in 10% of alcoholics.
2) Understand that not all cirrhotics are symptomatic.
Cirrhosis may be clinically silent, discovered only at autopsy or when stress such as
infection or trauma precipitates hepatic insufficiency. However, symptomatic
cirrhosis may include malaise, weakness, weight-loss, a loss of appetite proceeding
the appearance of jaundice, ascites, and peripheral edema (impaired albumin
synthesis). Patients also commonly show signs of portal hypertension including
vericeal hemorrhage.
3) Understand the pathologic changes of alcoholic liver disease.
Changes in alcoholic liver disease include:
Hepatic Steatosis (fatty liver) - a large, soft organ that is yellow and greasy.
Microscopicly, macrovesicular lipid accumulation compressing the nucleus to the
periphery of the hepatocyte.
Alcoholic hepatitis - hepatocyte swelling and necrosis (accumulation of fat, proteins,
and water), appearance of Mallory bodies (tangled cytokeratin and other proteins),
neutrophil accumulation, and fibrosis.
Alcoholic cirrhosis – initially cirrhotic liver is yellow-tan, fatty, and enlarged, over
several years, it becomes a brown, shrunken, and non-fatty organ. Regenerative
activity of entrapped parenchymal hepatocytes generates fairly uniform sized "micro
nodules" creating a "hobnail" appearance on the surface of the liver
4) Recognize the histologic changes of cirrhosis.
Histology: parenchymal necrosis severe enough to destroy the liver architecture with
nodular rather than lobular regeneration accompanied by fibrosis. The vascular
architecture is reorganized in the advanced state.
5) Vascular abnormalities in cirrhosis often control the clinical outcome of
cirrhosis. In advanced cases, hepatorenal syndrome, kidney failure secondary severe
vascular low flow and result in electrolyte abnormalities, are seen. Additionally,
resulting portal hypertension can result in esophageal varices, splenomegaly, and
ascites.
6) Understand the inflammatory changes and cirrhosis in hemochromatosis,
Wilson’s disease and in Alpha-1 antitrypsin deficiency.
Hemochromatosis is iron accumulation in the body due to excess intestinal resorption.
This results in heart damage (fetal arrhythmia), deposition of iron in endocrine cells,
and stimulation of melanocyte stimulating hormone (bronze diabetes).
Hemosiderosis may also occur from breakdown of RBCs and iron deposition in
macrophages. Genetic mutation on chromosome 6 associated with HLA A3, 11%
prevalence in US. Cirrhosis results from hepatocyte damage (inflammation and
fibrosis) due to iron generation of superoxide radicals (Fenton reaction).
Hemochromatosis cirrhotics develop hepatocellular carcinoma (25-30%).
Wilson's disease is copper overload related liver injury due to defective biliary
excretion. The genetic defect is a transmembrane copper-transporting ATPase. The
increase copper in blood binds with ceruloplasmin but when this enzyme is
exhausted, excess copper deposits in the iris and in neurons in basal ganglia in brain
causing abnormal movement. In the liver, toxic copper levels form reactive oxygen
species that may produce changes such as fatty liver, acute hepatitis (like viral
hepatitis), chronic hepatitis, or massive liver necrosis (rare and indistinguishable from
viral hepatitis)
Alpha-1 antitrypsin deficiency is an autosomal recessive disorder marked abnormally
low serum levels of this protease inhibitor. This gives rise to different proteins (M, N
or Z types) with different severity of disease. Alpha-1 antitrypsin inhibits elastase,
cathepsin G, and proteinase 3, which are normally released from neutrophils at sites
of inflammation. Lack of inhibition permits overactivity of these tissue-destructive
enzymes. This tissue-destruction leads to emphysema and liver disease.
7) Distinguish the differences of primary biliary cirrhosis, primary sclerosing
cholangitis and secondary biliary cirrhosis.
Disease
Pathogenesis
Primary biliary cirrhosis
Autoimmune cholangiolytic hepatitis
inflammatory injury of interlobular
bile ducts, middle-aged females (9:1)
Clinical
presentation
Insidious onset, pruritus, jaundice is
late, death in 20-30 years, elevated
serum cholesterol and alkaline
phosphatase, abnormal MHC class I
& II, T cell accumulation and B cell
expansion with production of
antimitochondrial antibody and
polyclonal hyperglobulinemia.
Duct lesions are granulomatous, late
lesions include cirrhosis,
intermediate changes include fibrosis
in bile duct proliferation.
Morphology
Primary sclerosing cholangitis
Inflammation and obliterative
fibrosis with segmental dilation of
intrahepatic and extrahepatic bile
ducts. Associated with IBD
(ulcerative colitis 70%) Male 2x
>Female
Does not have antimitochondrial
antibody, elevated serum
cholesterol and alkaline
phosphatase like PBC, higher
incidence of cholangiocarcinoma.
Secondary biliary cirrhosis
Extrahepatic bile duct
obstruction, anatomic.
Periductal fibrosis and segmental
stenosis of extrahepatic biliary
ducts
Portal tract edema,
inflammation in bile ducts and
bile duct proliferation are seen
Pruritus, jaundice, and dark
urine. Conjugated
hyperbilirubinemia.