151. Pathology Liver: Metabolic Liver Disease, Viral Hepatitis, Cirrhosis

Question 1

Hemochromatosis

• what is it
• histo/gross
• hereditary form (who has it, gene problem)
• how does disease form?
• triad of organs affected by Fe overload
• causes of secondary hemochromatosis

Answer 1

Excess Fe deposited in tissues (20-40g)
Histo: Fe Deposits in hepatocytes, Kupffer cells, biliary tree (accumulates more in periportal zones - zone 1) - H&E stain (brown), Fe Stain (blue = iron/hemosiderin)
Gross: micronodular cirrhosis

Hereditary hemochromatosis: M>F, C282Y mutation of HFE (regulates intestinal Fe absorption = increased uptake)

Hepcidin - regulates Fe absorption (low hepcidin = Fe overload)

Pathophys: 2-3mg/day Fe absorbed instead of 1mg - need 20-40g for clinical disease (Fe accumulation SLOW AND PROGRESSIVE - takes 40-50yrs for sx to present)

Sx: Cirrhosis (liver), Bronze Skin, Diabetes (pancreas)

Secondary: non-genetic Fe overload due to disorders w/ ineffective erythropoiesis, multiple blood transfusions, injectable Fe, hemolytic anemias

Question 2

alpha-1 antitrypsin deficiency

• what is it
• genotypes
• fx of A1AT
• histo
• tx

Answer 2

AR disorder w/ low levels of A1AT
A1AT: protease inhibitor (gene is Pi), synthesized by liver secreted to blood
in lung: inhibits leukocyte elastase (low levels = EMPHYSEMA)
Genotype: PiMM (wildtype), PiSS (moderate levels, no sx), PiZZ (severe reduction, high disease risk), PiMZ (codominant - intermediate levels)

Histo: mutated protein in ROUND INCLUSIONS (accumulates in hepatocytes with diff sizes and shapes) - visible with PAS-D Stain!!!

Tx: liver tx - produce functional A1AT = halt lung disease

Question 3

Wilson’s Disease

• gene
• sx
• how is mLc transported/lead to overload in liver
• histo
• labs
• tx

Answer 3

Mutated ATP7B gene (encodes Cu transporting ATPase = impaired excretion of Cu to bile, failure to incorporate Cu into ceruloplasmin)
Sx: Cu accumulation in brain (encephalopathy), eyes (Keyser-Fleischer Rings), liver (cirrhosis)
Transport: Cu binds albumin/histamine in blood/PV to get into liver; Cu must bind a2-globulin to form ceruloplasmin to go to blood for excretion or transported to bile (no ceruloplasmin)
Overload in liver: free Cu ions = oxidative damage (unbound Cu ions in blood damage eye/brain)

Histo: steatosis (macro/microvesicular), glycogenated nuclei (WHITE SPOTS), fibrosis, necrosis
Gross: micronodular cirrhosis

Labs: low ceruloplasmin, high urinary Cu

Tx: dx early! (cirrhosis = transplant), chelation therapy - prevent neuro damage and heal iris

Question 4

Non-hepatotropic viruses

• most common viruses
• who does it affect
• disease type
• histo

Difference between hepatotropic viruses and those causing chronic hepatitis

Answer 4

Most common: CMV, HSV, adenovirus, EBV (herpesvirus family)
Who: immunosuppressed/immunocompromised
Disease: fulminant or acute hepatitis
Histo: mixed inflammatory infiltrate, NO fibrosis (NOT chronic), viruses with characteristic viral occlusions (CMV - Owl’s eye - nuclear inclusions and bright on CMV immunostain)

Chronic Hepatitis caused by ONLY SUBGROUP of hepatotropic viruses (HBV, HCV, HDV)

HAV, HEV are hepatotropic but do not progress to chronic hepatitis

Question 5

HAV

• genome
• transmit
• incubation
• type of infection (adults vs. kids)
• chronicity

Answer 5

ssRNA
fecal-oral
2-7 week incubation
community-acquired infection in epidemics/endemics
30% of infected children show sx
70% infected adults show sx (more robust immune response)

NO CHRONICITY

Question 6

HEV

• genome
• transmit
• type of infection
• vulnerable population
• chronicity

Answer 6

ssRNA
fecal-oral
sporadic/epidemic in developing countries (SE Asia/Africa)
Affects primarily young adults
High mortality in 2/3rd trimester of pregnancy!!
NO CHRONICITY (except immunosuppressed - organ tx)

Question 7

HBV

• genome
• transmit
• epidemiology
• outcomes

Answer 7

dsDNA
vertical tx (mom to child), horizontal tx (blood, sex, IDU)
epi: 1/3 world infected, 400Mil chronic infected, 0.5mil die due to HCC 2/2 HBV
Outcomes:
1. Acute HBV w/ complete recovery/clearance
2. Fulminant hepatitis w/ massive necrosis
3. Non-progressive chronic HBV: persistence of HBsAg
4. Progressive chronic HBV = cirrhosis (RF for HCC! HBV can integrate to host dna and disrupt signalling)
5. Carrier state (asx)

VACCINE EXISTS!!! PREVENTABLE!

Question 8

HCV

• genome
• transmission
• epidemiology
• complications
• risk factors

Answer 8

ssRNA
parenteral/blood/sex
Epi: major cause of liver disease worldwide, MOST COMMON BLOODBORNE INFECTION, HALF of ppl with chronic disease in USA
complications: majority progress to chronic liver disease, 20-30% become cirrhotic

RF: IDU, multiple sex partners, needle sticks, multiple contacts w/ HCV infected person, employment in medical/dental field

Question 9

Histo features of Acute Viral Hepatitis (3)

Answer 9

1. Necrosis in lobules (b/w CV and portal tracts): ballooning degeneration, hemorrhage, apoptotic bodies, inflammation (lymphocyte)
2. Bridging necrosis (severe only - central-central or portal-portal)
3. Massive necrosis - in fulminant hepatitis

Question 10

Histo Features of Chronic Viral Hepatitis (5)

Causes of Micronodular and Macronodular Cirrhosis

Answer 10

1. MONONUCLEAR PORTAL INFILTRATION (near portal tract!!!)
2. Interface hepatitis (inflammation into hepatocytes near portal tract)
3. Ground Glass Hepatocytes = HBV
4. Focal Fatty Changes = HCV
5. Fibrosis of Portal Tract

Micronodular (<3mm): alcoholism
Macronodular (3-10mm): HBV, HCV, wilson’s disease, A1AT deficiency