ICL 10.2: Causes of Cirrhosis

Question 1

what is cirrhosis?

Answer 1

irreversible; End Stage Liver Disease

normal liver parenchyma is replaced by scar tissue

distortion of liver anatomy causes:

1. decreased blood flow through the liver and subsequent portal hypertension
2. hepatocellular failure that leads to impairment of biochemical functions (ex. decreased albumin and clotting factor synthesis)

Question 2

what does cirrhosis histology look like?

Answer 2

scars made up of diffuse bands of fibrosis and regenerative nodules

stellate cells produce fibrosis via TGF-Beta

hepatocytes produce regenerative nodules

Question 3

what are the functions of the liver?

Answer 3

1. removal of potentially toxic byproducts of certain medicatiosn
2. metabolizes nutrients from food to produce energy
3. helps body fight infection by removing bacteria from blood
4. reduces clotting factors
5. produces bile needed to digest far, absorb vitamin A, D, E and K
6. produces most proteins needed by the body
7. prevents shortages of nutrients by storing vitamins, mineral sand sugar

Question 4

what are the risk factors of hepatocellular carcinoma?

Answer 4

cirrhosis from any cause can lead to HCC

can also be associated with Chronic Hepatitis B infection and aflatoxins from Aspergillus

spreads hematogenously

Question 5

how do you diagnose hepatocellular carcinoma?

Answer 5

increased alpha-fetoprotein, ultrasound or contrast CT/MRI

biopsy shows nuclear atypia, prominent nucleoli, increased hepatocytes with invasion into blood vessels

Question 6

what liver tests are indicators of liver disease?

Answer 6

1. serum albumin, bilirubin, and prothrombin time - indicators of liver synthetic function
2. liver enzyme levels in thousands → indicates acute hepatitis
3. liver enzymes in hundreds → indicates chronic disease

ALT > AST in most causes of liver damage

Question 7

how does alcoholic liver disease progress?

Answer 7

this is the most common cause of liver disease in the West –> it leads to bacterial overgrowth and gut permeability in the GI tract and hepatocyte damage which lead to inflammation –> inflammation leads to liver injury and decreased BM function

normal –> steatosis –> statohepatitis –> fibrosis –> cirrhosis –> hepatocellular carcinoma

lab values: AST increased more than ALT by 1.5:1 ratio

AST - in mitochondria, alcohol is mitochondrial poison

Question 8

what is the histology of alcoholic cirrhosis?

Answer 8

swollen, necrotic hepatocytes with acute inflammation and Mallory bodies

damaged cytokeratin filaments that accumulate in cytoplasm

Question 9

what is NAFLD?

Answer 9

Nonalcoholic Fatty Liver Disease

liver disease independent of alcohol use

can be caused by metabolic syndrome (diabetes, hypertension, obesity and or hyperlipidemia)

fatty infiltration of hepatocytes can progress to cellular ballooning and necrosis

lab values: ALT > AST

Question 10

what are the causes of cirrhosis?

Answer 10

1. alcohol
2. nonalcoholic fatty liver disease
3. alpha 1 antitrypsin deficiency
4. Wilson disease
5. hemochromatosis
6. primary biliary cholangitis
7. primary sclerosis cholagnitis
8. HepB
9. HepC
10. autoimmune hepatitis
11. drug induced hepatotoxicity (DILI)
12. budd Chiari syndrome

Question 11

what is alpha 1 antitrypsin deficiency?

Answer 11

codominant inheritance, affects 1 in 2500 people

disease severity depends on number of mutated alleles

1. PiM = normal allele; PiZ = most common mutated allele
2. PIMM individuals have 2 normal copies; PIMZ heterozygotes can be asymptomatic
3. PiZZ homozygotes are at significantly increased risk for disease

normally, the liver produces alpha1-antitrypsin which neutralizes proteases produced by neutrophils and macrophages –> mutations cause misfolding of the protein which accumulates in the hepatocyte endoplasmic reticulum

seen on biopsy as PAS+ globules

uninhibited proteases in alveoli cause emphysema and accumulation in liver causes cirrhosis

Question 12

what is Wilson disease?

Answer 12

autosomal recessive disease of copper metabolism

mutations in the ATP7B gene lead to impairment of copper excretion into bile and into ceruloplasmin (a copper binding protein necessary for excretion)

copper accumulates in liver cells causing hepatocytes injury → copper leaks into plasma and accumulates in various organs (kidney, cornea, brain)

Question 13

how do you treat wilson disease?

Answer 13

penicillamine to chelate the copper and zinc to reduce intestinal uptake

Question 14

what is the clinical presentation of Wilson’s disease?

Answer 14

1. proximal renal tubular dysfunction
2. cardiac accumulation
3. hepatomegaly, jaundice, acute hepatitis, fulminant hepatic failure, portal HTN, cirrhosis
4. arthritis, rickets
5. Kayser Fleischer rings in the eye
6. deterioration in school performance, behavioral changes, resting and intention tremors, dystonia, dysarthria, excessive salivation, mask like facies, dysphagia

Question 15

whats hemochromatosis? how do you treat it?

Answer 15

autosomal recessive disease of iron metabolism

excessive iron absorption in the intestine leads to increased accumulation of iron in various organs

treatment = repeated phlebotomies to remove iron along with treating any complications

women present later because they’re getting rid of iron with menstruations

Question 16

how are organs effected in hemochromatosis?

Answer 16

1. liver: cirrhosis, increased risk of hepatocellular carcinoma
2. pancreas –> Diabetes mellitus
3. heart –> cardiomyopathy (CHF, arrhythmias)
4. joints –> arthritis
5. skin –> hyperpigmentation

hemochromatosis often referred to as “bronze diabetes”

Question 17

what is primary biliary cholangitis?

Answer 17

autoimmune disease characterized by destruction of intrahepatic bile ducts with portal inflammation and scarring

positive anti-mitochondrial antibodies found in 90-95% of patients; associated with other autoimmune disorders like RA, Celiacs, etc.

typically effects middle-aged women

clinical features:
1. fatigue

2. pruritus (early)
3. jaundice (late)
4. xanthomata and xanthelasmata
5. osteoporosis
6. cirrhosis/Portal hypertension

Question 18

how do you treat primary biliary cholagnitis?

Answer 18

ursodeoxycholic acid may slow progression

liver transplant is the only cure

Question 19

what is primary sclerosis cholagnitis?

Answer 19

chronic idiopathic disease of intrahepatic and/or extrahepatic bile ducts that causes thickening of the walls and narrowing of lumen

alternating strictures and dilation leads to “beading” of ducts

causes concentric “onion skin” bile duct fibrosis

strong association with ulcerative colitis –> can lead to cholangiocarcinoma,cholangitis and/or gallbladder cancer so always do a colonoscopy in patients with PSC!!!

Question 20

how do you treat primary sclerosis cholagnitis?

Answer 20

no curative treatment other than liver transplant

Question 21

what is Hepatitis B?

Answer 21

DNA, partially dsDNA

transmitted parenterally, sexually, and perinatally

long incubation period with initial symptoms of fever, arthralgias, and rash

Question 22

what are the symptoms of acute HepB infections?

Answer 22

1. jaundice
2. fever
3. increased liver enzymes

viral hepatitis = ALT > AST, especially in acute infection

Question 23

what is the prognosis of a HepB infection?

Answer 23

most people fully resolve their infection, indicated by anti-HB surface Ab and envelope Ag IgG antibodies

carrier state detected by presence of Hep B surface antigen

presence of Hep B envelope Ag (HBeAg) indicates high infectivity

Question 24

what is the histology of a HepB infection?

Answer 24

granular eosinophilic “ground glass” appearance

Question 25

how do you treat HepB infections?

Answer 25

1. tenofovir | 2. entacavir

Question 26

what is HepC?

Answer 26

RNA virus transmitted via blood with a long incubation period; also sometimes sexually 60-80% of patients develop stable chronic infection multiple extrahepatic manifestations possible

Question 27

what is the histology of HepC infection?

Answer 27

lymphoid aggregates with focal areas of macrovesicular steatosis macrovesicular steatosis - fat in cytoplasm displaces the nucleus of hepatocyte

Question 28

how do you treat HepC?

Answer 28

NS5A inhibitors and Protease inhibitors the NS5A protein has a substantial role in viral replication, packaging, assembly and complex interactions with cellular functions HepC is NOT cured by liver transplantation!!!!! once they have cirrhosis, you would transplant them but they'd still have hepC so you have to treat them with medications

Question 29

what is autoimmune hepatitis?

Answer 29

chronic autoimmune disease symptoms include fatigue, muscle aches, fever, jaundice, right upper quadrant pain strongly associated with anti-smooth muscle antibodies and other autoimmune antibodies associated with other autoimmune diseases

Question 30

what is the histology associated with autoimmune hepatitis?

Answer 30

plasma cells and lymphocytes infiltrates with intact bile ducts

Question 31

how do you treat autoimmune hepatitis?

Answer 31

immunosuppressive glucocorticoids and/or Azathioprine and liver transplant

Question 32

which drugs can cause drug induced hepatotoxicity?

Answer 32

1. Rifampin 2. Isoniazid 3. Statins 4. Fibrates 5. Acetaminophen 6. Amanita phalloides - death cap mushroom 7. Valproic acid 8. Antibiotics (bactrim and augmentin)* 9. Methotrexate

Question 33

how can acetaminophen cause liver toxicity?

Answer 33

overdose causes hepatic necrosis normal metabolism -- most acetaminophen is metabolized by glucuronidation to a non-toxic metabolite excreted in bile a small amount is converted into the toxic metabolite NAPQI and conjugated with glutathione to an inactive metabolite that can be excreted if you take too much tylenol it can't do this and you're left with toxic compounds that damage the liver alcohol intake lowers the toxicity threshold --> Chronic alcoholics may be more susceptible to liver injury because of decreased glutathione levels - toxic dose of acetaminophen saturates the normal glucuronide pathway → larger amount of acetaminophen is shuttled to cytochrome pathway - increased amounts of NAPQI are produced that deplete the liver reserves of glutathione - unconjugated NAPQI leads to oxidative stress on liver - causes hepatic necrosis

Question 34

what is budd Chiari syndrome?

Answer 34

obstruction of the hepatic vein (thrombosis, tumor, compression) can lead to liver infarction → necrosis clinical presentation triad: 1. abdominal pain 2. hepatomegaly 3. ascites

Question 35

what are the risk factors for budd chiari syndrome?

Answer 35

1. hypercoagulable states 2. polycythemia vera 3. postpartum state 4. hepatocellular carcinoma

Question 36

how do you manage liver disease?

Answer 36

1. Tteat underlying cause abstain from alcohol, give medication for Hepatitis B and/or C avoid agents that may cause injury to the liver such as alcohol or acetaminophen 2. treatment of hepatic encephalopathy: lactulose: acidifies the GI tract, trapping ammonia as ammonium which is excreted in stool rifaximin (antibiotic): kills intestinal bacteria which produce ammonia 3. best treatment is prevention, but once cirrhosis develops, aim treatment at managing symptoms and complications 4. screening for complications such as HCC and varices 5. liver transplant is the only curative treatment

Question 37

which of the following is (are) appropriate treatments for cirrhosis of the liver? A. cessation of alcohol use B. treating the underlying cause C. maintenance of proper nutrition D. liver transplantation E. all of the above

Answer 37

E. all of the above in uncomplicated cirrhosis, treatment includes cessation of alcohol use, maintenance of proper nutrition and treating the underlying cause patients with uncomplicated cirrhosis may have a relatively benign course of illness for many years once the patient has an episode of decompensation like fluid retention, vatical bleeding, encephalopathy, spontaneous bacterial peritonitis or hepatorenal syndrome, mortality is high without transplantation