Toxic, Metabolic, and Cholestatic Liver Disorders

Question 1

What is the pathogenesis of alcoholic liver disease?

Answer 1

Ethanol and acetaldehyde cause:
1. Fatty liver -> increased fatty acid uptake and synthesis, with decreased oxidation and decreased lipoprotein secretion

2. Hepatocyte injury and necrosis -> direct toxic effects, ROS, induces a hypermetabolic state, and induces ischemia

Question 2

How does a fatty liver (hepatic steatosis) appear grossly and microscopically?

Answer 2

Grossly - large, greasy, yellow liver

Microscopically - microvesicular (multiple per cell, implies active turnover) to macrovesicular (takes up entire cytoplasm, nuclei pushed to side) lipid vacuoles in hepatocytes

Question 3

When does alcoholic hepatitis happen?

Answer 3

More acute event, frequently following a drinking binge in an individual with a long history of heavy alcohol intake

Question 4

How does alcoholic hepatitis appear pathologically?

Answer 4

Swollen and necrotic hepatocytes with a neutrophilic inflammatory infiltrate.

Mallory-Denk bodies -> alcoholic hyaline - eosinophilic cytoplasmic inclusions which are inclusions of damage keratin filaments

Can be some centrilobular fibrosis

Question 5

What are the clinical findings of alcoholic hepatitis?

Answer 5

Fatigue, nausea, anorexia, low-grade fever, hepatomegaly with mild liver tenderness (inflammatory infiltrate), jaundice / icterus (compression of bile ducts)

Question 6

What are the laboratory findings of alcoholic hepatitis?

Answer 6

Mild to moderate increase in serum transaminases, especially AST > ALT. “Make a toAST with alcohol”

Elevated bilirubin, alkphos, GGT with cholestasis, and mild leukocytosis due to neutrophils

Question 7

What type of cirrhosis is alcoholic cirrhosis, and where does the fibrosis usually start? What else can be seen microscopically?

Answer 7

Classically a micronodular cirrhosis which leads diffusely nodular liver.

Fibrosis starts around central veins, then spreads, as abnormally regenerative nodules form between

Question 8

What are the complications of alcoholic cirrhosis?

Answer 8

Same as other types of cirrhosis:

Complications due to portal HTN: i.e. ascities, extrahepatic portosystemic shunts, congestive splenomegaly, encephalopathy

Complications due to hepatic failure: jaundice, hypoalbuminemia, coagulopathy, encephalopathy, hepatorenal syndrome, hyperestrogenism

Increased risk of HCC

Question 9

What is the cause of non-alcoholic fatty liver disease?

Answer 9

Obesity and insulin resistance (metabolic syndrome)

Gives rise to the same spectrum of liver pathology

Question 10

What is the most prevalent genetic metabolic error in white people and what causes it?

Answer 10

Hereditary Hemochromatosis, cause by autosomal recessive mutation on HFE gene of chromosome 6
-> increased intestinal absorption of dietary iron, with increased storage of iron in parenchymal cells and cell injury
(abnormal functioning of hepcidin, ferroportin, and transferrin due to HFE product interaction)

Question 11

Are men or women more susceptible to hemochromatosis and why?

Answer 11

Men -> they do not have menstruation or loss of iron in pregnancy to help them get rid of some of their iron

Women develop clinical consequences less frequently and later in life

Question 12

How can secondary hemochromatosis be told from primary based on pathology, and what are the etiologies of secondary?

Answer 12

In secondary, the iron overload will be properly managed by the RES first due to no impairment in iron storage / transport -> hemosiderin-laden macrophages

In primary, iron management is messed up and iron will accumulate in hepatocytes quickly

Etiology: long-term increased iron intake, multiple blood transfusions

Question 13

Where does iron tend to accumulate in hemochromatosis and what are the consequences?

Answer 13

Bronze diabetes
Liver - micronodular cirrhosis and HCC

Pancreas - diabetes mellitus

Myocardium - restrictive -> dilated cardiomyopathy

Joint synovial tissue - arthropathy

Pituitary - hypogonadism

Skin - increased melanin in epidermis, increased hemosiderin in dermis

Question 14

How is primary hemochromatosis diagnosed?

Answer 14

elevated transferrin saturation (typically over 45%) since transferrin will go down and ferritin goes up, and transferrin will become more saturated with iron overload

Genetic testing and liver biopsy may also be indicated

Question 15

What is the treatment for primary vs secondary hemochromatosis?

Answer 15

Primary - periodic phlebotomies and avoidance of food with very high iron content

Secondary - can’t do phlebotomies because anemia is generally the reason why you’re iron overloaded -> need oral iron chelation

Question 16

What is Wilson disease also known as and what causes it?

Answer 16

Hepatolenticular degeneration
-> lenticular refers to basal ganglia

Caused by autosomal recessive mutation in copper-transporting ATPase

Question 17

What is the pathogenesis of Wilson disease?

Answer 17

Defective transport of copper in liver -> decreased incorporation of copper into ceruloplasmin -> decreased excretion of excess copper into bile -> toxic copper accumulation

Question 18

When does Wilson disease present? Where does copper tend to build up in this disease?

Answer 18

Childhood or early adulthood (sooner than hemochromatosis)

Builds up in liver, brain (esp. basal ganglia), cornea, kidneys, bones / joints, and blood

Question 19

What are the consequences of copper excess in all liver and CNS in Wilson disease?

Answer 19

Liver - fat and glycogen accumulation -> hepatitis -> cirrhosis

CNS - neuronal injury -> neurologic and psychiatric manifestations.

Basal ganglia involvement: Temors, rigidity, dysarthria

Elsewhere: depression, anxiety, psychosis

Question 20

What are the consequences of copper excess in cornea, kidneys, and blood?

Answer 20

Cornea - Kayser-Fleischer rings and sunflower cataracts

Kidneys - Fanconi syndrome

Blood - Hemolytic anemias

Question 21

How is Wilson disease diagnosed and treated?

Answer 21

Diagnosis - decreased serum ceruloplasmin and increased urinary copper excretion

Treatment - copper chelation therapy (penicillamine), and oral zinc (blocks intestinal absorption of copper and binds free copper)

Question 22

Who should be screened for A1AT deficiency?

Answer 22

All adults with persistent COPD and unexplained liver disease. Often presents as dyspnea without a history of smoking in young patients

Question 23

What is the genetic defect in A1AT deficiency?

Answer 23

Autosomal codominant disorder of SERPINA1 gene, homozygous ZZ being the worst -> leads to abnormal accumulation of polymerized protein

Question 24

What causes damage in A1AT deficiency? What type of damage is it in the lungs?

Answer 24

Abnormal, polymerized A1AT protein accumulates in ER of hepatocytes -> hepatic damage

Protease inhibitor deficiency (i.e. anti-elastase) also leads to pulmonary injury, especially in smokers. This is a PANlobular emphysema worse in the bases where there is more blood flow.

Question 25

How does the liver appear pathologically in A1AT deficiency and what does it stain with?

Answer 25

Variable presentation, but often leads to cirrhosis due to damage and chronic hepatitis from the protease in hepatocytes

Stains PAS+ (A1AT is a glycoprotein), as well as eosinophilic cytoplasmic granules

Question 26

What is the treatment for A1AT deficiency?

Answer 26

Aggressive smoking cessation, modification of risk factors (i.e. infection makes lack of A1AT worse), IV enzyme replacement, and liver transplant if need be

Question 27

What is the cause of primary biliary cholangitis (PBC) and who tends to get it?

Answer 27

Probably an autoimmune disease characterized by progressive T-cell mediated destruction of small to medium sized intrahepatic ducts

As it is autoimmune, it is classically seen in middle-aged women with other autoimmune disorders (i.e. Sjogren’s, RA, Hashimoto)

Question 28

What is the progression of disease in primary biliary cholangitis? What is the pathognomonic lesion?

Answer 28

Portal tract disease -> progressive parenchymal damage -> biliary cirrhosis

Pathognomonic = florid duct lesion, giant cells around a duct

Question 29

What characterizes portal tract disease pathologically in PBC?

Answer 29

Portal tract disease -> granulomatous destruction of small to medium-sized bile ducts via a chronic inflammatory infiltrate (giant cells can be seen in florid duct lesion)

Question 30

What characterizes progressive parenchymal damage vs biliary cirrhosis pathologically in PBC?

Answer 30

Progressive parenchymal damage -> periportal inflammation and hepatocyte necrosis (feathery degeneration) . Developing portal fibrosis with biliary ductular proliferation (compensatory), along with cholestasis and disappearance of normal bile ducts.

Biliary cirrhosis -> micronodular cirrhosis with considerable cholestasis

Question 31

What is seen in the lab values / tests for PBC?

Answer 31

Cholestatic lab profile (increased alk phos, GGT, cholesterol, conjugated bilirubin)

Increased IgM levels -> antimitochondrial antibodies and lipoprotein X (type of LDL only seen in bile diseases)

Question 32

What is the early vs late presentation of PBC?

Answer 32

Early - asymptomatic or fatigue / pruritus from bile salts

Late - Jaundice, xanthomas / xanthelasmas, malabsorption leading to steatorrhea, osteoporosis and osteomalacia, complications of cirrhosis (liver failure, portal HTN)

Question 33

What is the treatment for PBC?

Answer 33

Ursodeoxycholic acid -> protects against bad bile acids, and symptomatic treatment of complications (i.e. vitamin D, cholestyramine, portal HTN treatments like octeotide)

Question 34

What is the pathogenesis and a few causes of secondary biliary cholangitis?

Answer 34

Long-standing extrahepatic biliary obstruction -> increased pressure in intrahepatic ducts -> injury / fibrosis due to bile stasis

Common causes: bile duct strictures, choledocholithiasis, chronic pancreatitis (causes scarring)

Question 35

What does liver pathology show for SBC?

Answer 35

Similar to primary in progressive pathology:

Prominent bile stasis in all ducts / canaliculi with feathery degeneration which may progress to bile lakes

Biliary ductular proliferation

Portal inflammation, often with acute component

Portal fibrosis -> leads to micronodular cirrhosis overtime

Question 36

What ducts are destroyed in primary sclerosing cholangitis (PSC) and who tends to get it?

Answer 36

Progressive destruction of large intrahepatic and extrahepatic bile ducts

Found mostly in middle-aged men, strongly associated with ulcerative colitis

Question 37

How does pathology appear in PSC?

Answer 37

Think sclerosing + targetting bile ducts

Alternating areas of stricture (concentric, “onion-skin” fibrosis around ducts) and dilatation “beads”.

Basically strictures of fibrosis that look like hyperplastic arteriolosclerosis of ducts, and dilations that are like beads

Question 38

How is PSC best visualized? What is often positive in the disease?

Answer 38

Via endoscopic retrograde cholangiopancreatography (ERCP) with characteristic beading of the barium column

Patients are often p-ANCA positive (like microscopic polyangiitis)

Question 39

What are the complications of PSC?

Answer 39

Progressive biliary obstruction and portal fibrosis -> biliary cirrhosis, like PBC and SBC.

Also, increased risk of cholangiocarcinoma (bile duct cancer due to inflammation) and gallbladder cancer