Liver failure that produces hepatic encephalopathy within 6 months of initial diagnosis 50% of cases are caused by accidental or deliberate ingestion of toxic doses of acetaminophen other 50% include autoimmune hepatitis and acute HAV/HBV/ HBV+HDV infections

Pathology Of The Liver And Billary Tract 1 Flashcards by Scott Mitchell

What are common test findings that could be found in liver failure?

Increase in ALT/AST

Increase in serum lactate dehydrogenase

Increase in bilirubin (both unconjugated and conjugated) and serum ammonia

Increase in bile acids and alkaline phosphatase

Increase in PT/PTT times

Decrease in serum albumin and aminopyrine in the breath

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Acute liver failure

Liver failure that produces hepatic encephalopathy within 6 months of initial diagnosis

50% of cases are caused by accidental or deliberate ingestion of toxic doses of acetaminophen*
other 50% include autoimmune hepatitis and acute HAV/HBV/ HBV+HDV infections*

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Symptoms of acute liver failure

Nausea/vomiting

Jaundice

Fatigue

Life-threatening encephalopathy, coagulation defects and portal HTN w/ ascites

ALT/AST levels are within the thousands

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What are signs of hepatic encephalopathy

Ranges from subtle abnormal behavior to confusion/stupor or coma

Common neurological signs:

rigidity of movement
hyperreflexia
asterixis (nonrhythmic extension/flexion of head and extremities. “Hand flapping”)

elevated signs of ammonia levels is the best correlate to hepatic encephalopathy

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Chronic liver failure

Most commonly occurs as a result of extensive hepatic cirrhosis
- shows diffuse fibrosis (although this fibrosis can be reversible with cure/remission)

Leading causes are:

chronic HBV/HBC/HBV+HDV
alcoholic liver disease (accounts for 60% of cases)
non-alcoholic fatty liver disease

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Clinical features of chronic liver failure

40% are asymptomatic

Symptoms:

anorexia/ weight loss
weakness
jaundice
encephalopathy
coagulopathy
pruritis
portal HTN (ascites and esophageal varices)
hyperestrogenemia (spider angiomas of skin in females and hypogonadism/gynecomastia in males)

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What is the cancer most heavily tied to chronic liver disease?

Hepatocellular carcinoma (HCC)

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Alcoholic and nonalcoholic fatty liver disease

Almost indistinguishable and look exactly the same

Both present with

steatosis
hepatitis
fibrosis
cirrhosis

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How many chronic alcoholics develop fatty liver disease?

90-100%

10-35% of these develop alcoholic hepatitis
8-20% of these develop cirrhosis

10-20% of the ones to develop cirrhosis will develop HCC

as much as 80g of ethanol per day causes fatty liver changes to the liver

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What is the proposed mechanism surrounding hepatocellular steatosis

Ethanol metabolism by alcohol dehydrogenase and acetylaldehyde dehydrogenase generates large amounts of NADH

This large amounts of NADH increases shunting of substrates away from catabolism and toward lipid biosynthesis, however ethanol also impairs assembly and secretion of lipoproteins

lipid biosynthesis causes accumulation of intracellular lipids

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What 3 toxic byproducts of alcohol are believed to play a role in alcoholic hepatitis?

Acetaldehyde

Alcohol

ROS

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What is the estimated timeframe for developing alcoholic cirrhosis and alcoholic hepatitis?

Alcoholic cirrhosis = 15-20 years of excessive drinking

Alcoholic hepatitis = 3 weeks- months

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Alcoholic hepatitis symptoms/lab values

Symptoms:

malaise
anorexia
weight loss
upper-abdominal discomfort
tenderness in upper right quadrant
hepatomegaly
fever

Lab values:

hyperbilirubinemia
elevated serum alkaline phosphatase
leukocytosis
ALT/AST levels are elevated slightly (<500)

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What is the risk fo death with alcoholic hepatitis?

10-20%

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What are causes of death in alcoholic liver disease

Hepatic failure

Massive GI hemorrhages

Intercurrent infection

Hepatorenal syndrome

HCC (3-6%)

5-yr survival rates WITH abstinence of alcohol = 90% ; 5-yr survival rates WITHOUT abstinence of alcohol = 50-60%

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Nonalcoholic fatty liver disease (NAFLD)

Fatty liver develops without drinking alcohol
- can show steatosis/steatohepatitis or cirrhosis

is the most common cause of incidental elevation of serum transaminases

highly associated with insulin resistance and metabolic syndrome

also associated with type 2 diabetes, obesity, dyslipidemia, HTN

Treatment = lower obesity (lifestyle modifications) and reverse insulin resistance

Pathogenesis of NAFLD

Development of obesity and insulin resistance in adipose and liver tissues
- increases mobilization of free FAs from adipose tissue -> hepatocytes and stimulates synthesis of FA’s within hepatocytes

How to differentiate NAFLD from nonalcoholic steatohepatitis (NASH)?

Liver biopsy

Hemochromatosis

Caused by excessive absorption of iron
- iron excess is deposited into liver, pancreas, heart, joints, etc.

most commonly is hereditary hemochromatosis

acquired hemochromatosis is less common and is usually due to blood transfusions

normal body iron levels are 2-6gm, whereas severe hemochromatosis shows levels above 50gm often

What are the 3 liver based symptoms of hemochromatosis?

1) micronodular cirrhosis
2) diabetes mellitus
3) abnormal skin pigmentation

What is the purpose of hepcidin?

It is a peptide hormone that acts as a key negative regulator of intestinal iron uptake

several genes have been described in hemochromatosis, all of which function to lower efficacy of hepcidin functions*
this results in an increase of intestinal absorption of dietary iron (increases 0.5-1 gm/yr)

the cut off to get hemochromatosis is usually 20gm iron stores

What genes are most associated with hemochromatosis?

HFE gene located on chromosome 6

most common is cysteine -> tyrosine substitution at amino acid 282 (C282Y)
HFE gene = upregulated hepcidin
this mutation inactivates HFE protein and is in over 70% of patients diagnosed with hereditary hemochromatosis*
most common in European populations

What are the direct effects of hemochromatosis on the liver

Lipid peroxidation via free ROS

Stimulation of collagen formation (scarring/cirrhosis) by hepatic stellate cells in the liver

DNA damage to cells via ROS which increases risks of HCC

3 morphology effects:
1) tissue deposition of hemosiderin in the following organs: liver, pancreas, heart, pituitary gland, adrenal glands, thyroid, joints skin

2) cirrhosis of the liver
3) pancreatic fibrosis

What are extrabillary morphological changes in the body with respect to hemochromatosis?

Pancreas = becomes chocolate brown and fibrotic as well

Heart = enlarged with brown granules
- mild fibrosis may appear as well

Skin pigmentation = appear slate-gray usually due to hemosiderin and melanin production

Joint - acute synovitis and sometimes pseudogout

Testies = atrophic

Epidemiology of hemochromatosis

Symptoms appear earlier in men than women and is 7:1 more likely in men - its hypothesized that women get this less (and when they have it appears later) due to bleeding from periods (usually appears after menopause for this reason) Usually appears 50-60s Death is usually caused by cirrhosis or cardiac failure (if not caugh) *having untreated hemochromatosis = 200x risk for HCC* **having the HFE (C282Y) homozygous mutation shows penetrance (so having this mutation does not guarantee you have hemochromatosis)**

Symptoms of hemochromatosis

Symptoms: - hepatomegaly - abdominal pain - skin pigmentation - erratic glucose levels - frank diabetes mellitus (obstruction of pancreatic islets) - cardiac dysfunction - atypical arthritis - amenorrhea - hypogonadism* (often the #1 compliant in men)

Treatment for hemochromatosis

Regular phlebotomy remains mainstay

Wilson disease

Autosomal recessive disease caused by loss of function mutations in the ATP7B gene on chromosome 13 which results in impaired copper excretion into bile and failure to incorporate copper properly into ceruloplasmin - accumulation of toxic levels of copper is seen in liver/brain/eyes Causes impaired transport of copper and inability to bind copper to apoceruloplasmin - high copper in liver and very low plasma ceruloplasmin levels - also very high levels of excreted copper and hemolysis is seen

What is the normal pathway of copper?

1) 40-60% of ingested copper is absorbed via proximal mall intestine and complexed with albumin and histidine and taken to the liver - other amounts are excreted by feces 2) free copper is then taken up by hepatocytes where it is then used as cofactors for various enzymes and taken up by apoceruloplasmin to from ceruloplasmin. 3) cereuloplasmin is released into blood and carries 90-95% of plasma copper and deposits it where it is needed 4) circulating ceruloplasmin is then reuptake by liver and degraded with lysosomes. Any excess copper is excreted via bile and eliminated **these steps are the primary route for copper elimination**

How does copper cause liver injury?

Fenton reaction with copper produces ROS

Clinical features of Wilson disease

Usually show onset at 6-40years of age. (Highly variable) Symptoms: - liver disease symptoms - kayser-fleischer rings - hemolysis symptoms - spasticity, seizures, drooling and other neuropsychiatric symptoms (copper deposits in basal ganglia) Tests: - low levels of serum ceruloplasmin - increase hepatic and urinary copper content * most specific test is urinary, however Most sensitive is hepatic copper content* Treatment = copper chelation therapy (Trientine/d-penicillamine) w/ zinc-based therapy * zinc prevents copper uptake by small intestine in high levels* * *liver transplant is also needed if cirrhosis is present

A1-anti-trypsin deficiency

Autosomal recessive disorder marked by very low levels fo circulating a1-anti trypsin - cause by mutations on chromsome 14 that result in the misfolding of a1- antitrypsin * Major function of a1 AT is to inhibit proteases, especially neutrophil elastase, cathepsin G and proteinase 3.* - these all are used to increase inflammation **primary development from a1-anti-trypsin deficiency is pulmonary emphysema due to destructive proteases**

How does a1-anti-trypsin deficiency cause liver disease?

Misfolded proteins accumulate in the hepatocytes

What is the most common genotype mutation of AT-deficiency?

PiMM wild type - shown in 90% of cases - has a 50-50% chance of developing disease **most clinically significant is PiMZ or PiZZ Mutations (only seen in 10%) - very high risk for developing actual clinical disease - PiMZ is the heterozygote geneotype (so leads severe and only have intermediate levels of plasma a1AT - PiZZ is most common Europeans and is seen in 1:1800 ratio births

Why is the PiZZ genotype so dangerous?

It is the most proned to misfolding and aggregation of a1AT proteins - caused by glutamine -> lysine substitution at residue 342 (E342K) *causes endoplasmic reticulum stress and apoptosis ultimately* ** increases risks of liver cirrhosis and emphysema**

Clinical features of a1AT defciency

Symptoms are most closely related to decreased pulmonary functions and hepatitis/cirrhosis of the liver - can be silent however *10-20% of affected neonates will show neonatal hepatitis w/ cholestatic jaundice* **HCC develops in 2-3% of PiZZ patients (only one to have a chance)** Treatment = avoid smoking, symptomatic treatment - if liver disease is prominent = liver transplant

How is the blood supply to the liver split?

60-70% = from portal vein 30-40% = from hepatic artery