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MD1 2016 - Abdominal > Hepatic Diseases > Flashcards

Hepatic Diseases Flashcards

1
Q

What are the three distinctive, albeit overlapping forms of alcoholic liver injury?

A

(1) hepatocellular steatosis or fatty change, (2) alcoholic (or steato-) hepatitis
(3) steatofibrosis (patterns of scarring typical for all fatty liver diseases including alcohol) up to and including cirrhosis in the late stages of disease

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2
Q

What is the morphological pattern of injury in alcoholic liver disease?

A

Changes begin in acinus zone 3 and extend outward toward the portal tracts with increasing severity of injury.

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3
Q

Describe the morphological histological changes in hepatic steatosis

A

lipid droplets accumulate in hepatocytes

The lipid begins as small droplets that coalesce into large droplets which distend the hepatocyte and push the nucleus aside

lip droplets most prominent around the central vein and extends outward to the portal tracts.

Some fibrosis (stained blue) can be present in a characteristic perisinusoidal chicken wire fence pattern

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4
Q

Describe the morphological macroscopicchanges in hepatic steatosis

A

the fatty liver in individuals with chronic alcoholism is a large (as heavy as 4 to 6 kg), soft orgqan that is yellow and greasy.

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5
Q

T/F Fatty change is completely reversible if there is abstention from further intake of alcohol.

A

Yes (phew there is hope for me)

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6
Q

What are the histological characteristics of Alcoholic (Steato-) Hepatitis ?

A
  1. Hepatocyte swelling and necrosis resulting from the accumulation of fat and water, as well as proteins that are normally exported.
  2. Mallory-Denk bodies that appear as clumped, amorphous, eosinophilic material in ballooned hepatocytes.
  3. Neutrophilic reaction as neutrophils permeate the hepatic lobule and accumulate around degenerating hepatocytes, particularly those having Mallory bodies.
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7
Q

What are Mallory bodies made of?

A

tangled skeins of intermediate filaments such in complex with other proteins such as ubiquitin

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8
Q

Mallory bodies are a specific characteristic of alcoholic liver disease. T/F?

A

No.
These inclusions are a characteristic but not specific feature of alcoholic liver disease, since they are also present in non-alcoholic fatty liver disease and in periportal distributions in Wilson disease and in chronic biliary tract diseases.

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9
Q

What is Alcoholic steatofibrosis?

A

Alcoholic hepatitis is often accompanied by prominent activation of sinusoidal stellate cells and portal fibroblasts, giving rise to fibrosis.

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10
Q

Describe the mechanisms of Alcoholic steatofibrosis

A

Fibrosis begins with sclerosis of central veins. Perisinusoidal scar then accumulates in the space of Disse of the centrilobular region, spreading outward, encircling individual or small clusters of hepatocytes in a chicken wire fence pattern.

These webs of scar eventually link to portal tracts and then begin to condense into central-portal fibrous septa. With developing nodularity, cirrhosis becomes established.

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11
Q

What is first described for end-stage alcoholic liver disease (When alcohol use continues without interruption over the long term)?

A

Laennec cirrhosis - the continual subdivision of established nodules by new webs of, perisinusoidal scarring leads to a classic micronodular or Laennec cirrhosis

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12
Q

Early stages of scarring can regress with cessation of alcohol use. T/F

A

Tru, but but the farther along toward cirrhosis the liver gets, the more vascular derangements prevent a full restoration of normal.

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13
Q

Is complete regression of alcoholic cirrhosis possible?

A

Yes but rare

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14
Q

What is the size cut off for micronodular cirrhosis?

A

3mm nodules

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15
Q

How much must one ingest short term to produce mild, reversible, hepatic steatosis?

A

80 gm of alcohol (six beers or 8 ounces of 80-proof liquor) over one to several days

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16
Q

How much alcohol ingested daily will generate significant risk for severe hepatic injury?

A

Daily intake of 80 gm or more of ethanol

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17
Q

How much alcohol is ingested to produce severe injury?

A

daily ingestion of 160 gm or more for 10 to 20 years

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18
Q

Factors that influence development of alcoholic liver disease

A

Gender
ethnic and genetic
Comorbid conditions (HBV, HCV, iron overload)

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19
Q

Why are women more susceptible to hepatic injury than men?

A

estrogen increases gut permeability to endotoxins, which, in turn, increase the expression of the LPS receptor CD14 in Kupffer cells. This predisposes to increased production of proinflammatory cytokines and chemokines

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20
Q

What is ALDH2 and what is the significance of people homozygous for ALDH2?

A

a variant of aldehyde-dehydrogenase (ALDH), found in 50% of Asians, has a very low activity. Individuals homozygous for ALDH*2 are unable to oxidize acetaldehyde and do not tolerate alcohol, leading to alcohol intolerance characterized by upper body flushing and, variably, nausea or lethargy.

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21
Q

What does exposure to alcohol cause?

A

steatosis, dysfunction of mitochondrial and cellular membranes, hypoxia, and oxidative stress

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22
Q

Why do hepatocytes accumulate lipid droplets (How does Hepatocellular steatosis result)?

A

(1) shunting of normal substrates away from catabolism and toward lipid biosynthesis, as a result of increased generation of reduced nicotinamide adenine dinucleotide (NADH) by the two major enzymes of alcohol metabolism, alcohol dehydro­genase and acetaldehyde dehydrogenase;
(2) impaired assembly and secretion of lipoproteins; and
(3) increased peripheral catabolism of fat, thus releasing free fatty acids into the circulation.

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23
Q

What is Alcoholic liver disease?

A

a chronic disorder featuring steatosis, hepatitis, progressive fibrosis, and marked derangement of vascular perfusion.

In essence, alcoholic liver disease can be a regarded as a maladaptive state in which cells in the liver respond in an increasingly pathologic manner to a stimulus (alcohol) that originally was only marginally harmful.

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24
Q

What are causes of alcoholic hepatitis?

A

Acetaldehyde - induces lipid peroxidation and acetaldehyde-protein adduct formation, further disrupting cytoskeletal and membrane function.

Cytochrome P-450 metabolism produces reactive oxygen species (ROS) that react with cellular proteins, damage membranes, and alter hepato­cellular function.

Decreased glutathione levels due to impaired hepatic metabolism of methionine, thereby sensitizing the liver to oxidative injury.

Increased alcohol catabolism in the endoplasmic reticulum due to the induction of cytochrome P-450 enzymes by alcohol enhances the conversion of other drugs (e.g., acetaminophen) to toxic metabolites.

release of bacterial endotoxin from the gut into the portal circulation, inducing inflammatory responses in the liver, due to the activation of NF-κB, and release of TNF, IL-6, and TGF-α.

stimulates the release of endothelins from sinusoidal endothelial cells, causing vasoconstriction and contraction of activated, myofibroblastic stellate cells, leading to a decrease in hepatic sinu­soidal perfusion

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25
Q

What is Nonalcoholic Fatty Liver Disease (NAFLD)?

A

a spectrum of disorders that have in common the presence of hepatic steatosis (fatty liver) in individuals who do not consume alcohol or do so in very small quantities

NAFLD contributes to the progression of other liver diseases such as HCV and HBV infection, hepatocellular carcinoma

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26
Q

histologic hallmarks of NAFLD

A

most consistently associated with the metabolic syndrome

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27
Q

What is the criteria for metabolic syndrome?

A 
One of: 
diabetes mellitus
impaired glucose tolerance
impaired fasting glucose 
insulin resistance

and two of:
blood pressure >140/90 mmHg
dysplipidemia: triglycerides >1.695 mmol/L and HDL 90 (male) >0.85 female or BMI > 30kg/m2
microalbuminuria - urinary albumin excretion rate of >20ug/min or albumin-to-creatinine ratio >30mg/g

28
Q

What is the pathogenesis for NAFLD?

A

2 hit model:
Insulin resistance gives rise to hepatic steatosis

Hepatocellular oxidative injury resulting in liver cell necrosis and the inflammatory reactions to it.

In individuals with established insulin resistance and metabolic syndrome, the visceral adipose tissue not only increases, but also becomes dysfunctional, with reduced production of the lipid hormone, adiponectin, and increased production of inflammatory cytokines such as TNF-α and IL-6. These changes in turn promote hepatocyte apoptosis. Fat laden cells are highly sensitive to lipid peroxidation products generated by oxidative stress which can damage mitochondrial and plasma membranes, causing apoptosis.

29
Q

What are the histological differences between non-alcoholic steatohepatitis (NASH) and alcoholic hepatitis?

A

In NASH, compared with alcoholic hepatitis, mononuclear cells may be more prominent than neutrophis and Mallory-Denk bodies are often less prominent.

Steatofibrosis in NAFLD shows precisely the same features and progression as it does in alcoholic liver disease, although portal fibrosis may be more prominent.

30
Q

How is diagnosis for NAFLD and NASH?

A

liver biopsy is the most reliable diagnostic tool for NAFLD and NASH, and for assessment of scarring.

Viral, autoimmune and other metabolic diseases of the liver must be excluded before the diagnosis can be made.

31
Q

What are some symptoms of NAFLD/NASH?

A

fatigue or right-sided abdominal discomfort caused by hepatomegaly.

32
Q

What is a common sequelae of NAFLD?

A

Because of the association between NASH and the metabolic syndrome, cardiovascular disease is a frequent cause of death in patients with NASH.

33
Q

How do you treat patients with NAFLD?

A

reverse the steatosis and prevent cirrhosis by correcting the underlying risk factors, such as obesity and hyperlipidemia, and to treat insulin resistance.

34
Q

T/F The most common metabolic disorder is nonalcoholic fatty liver disease

A

True

35
Q

What is Hemochromatosis caused by?

A

excessive iron (red meat) absorption, most of which is deposited in parenchymal organs such as the liver and pancreas, followed by heart, joints, and endocrine organs

36
Q

Why do symptoms of hemochromatosis usually first appear in the fourth to fifth decades of life in men and later in women?

A

Iron accumulation in hereditary forms is lifelong but the injury caused by excessive iron is slow and progressive

In women, menstrual bleeding counterbalances the accumulation until menopause.

37
Q

What is the pathogenesis of hemochromatosis?

A

Excessive iron appears to be directly toxic to tissues. Mechanisms of liver injury include:

(1) lipid peroxidation via iron-catalyzed free radical reactions,
(2) stimulation of collagen formation by activation of hepatic stellate cells, and
(3) interaction of reactive oxygen species and iron itself with DNA, leading to lethal cell injury and predisposition to HCC.

38
Q

What regulates iron absorption?

A

hepcidin secreted by the liver

Transcription of hepcidin is increased by inflammatory cytokines and iron, and decreased by iron deficiency, hypoxia, and ineffective erythropoiesis. Hepcidin binds to the cellular iron efflux channel ferroportin, causing its internalization and proteolysis, thereby inhibiting the release of iron from intestinal cells and macrophages.

39
Q

What happens when there is increased hepcidin?

A

lowers plasma iron levels

40
Q

What are the histological characteristics of hereditary or secondary hemochromatosis?

A

(1) deposition of hemosiderin
(2) cirrhosis; and
(3) pancreatic fibrosis.

In the liver, iron becomes evident first as golden-yellow hemosiderin granules in the cytoplasm of periportal hepatocytes that stain with Prussian blue

41
Q

What tissues does hemosiderin get deposited in?

A

in the following organs (in decreasing order of severity) the liver, pancreas, myocardium, pituitary gland, adrenal gland, thyroid and parathyroid glands, joints, and skin

42
Q

What happens in the liver with increasing iron load?

A

progressive involvement of the rest of the lobule, along with bile duct epithelium and Kupffer cell pigmentation.

Iron is a direct hepatotoxin and inflammation is characteristically absent.

The parenchymal architecture is normal.

43
Q

What are the macroscopic changes of the liver in hemochromatosis?

A

In early stages of accumulation, the liver is typically slightly larger than normal, dense, and chocolate brown.

Fibrous septa develop slowly, leading ultimately to a small, shrunken liver with a micronodular pattern of cirrhosis.

The liver parenchyma in later stages is often dark brown to nearly black due to overwhelming iron accumulation.

44
Q

What are the morphological features of the heart in hemochromatosis?

A

The heart is often enlarged and has hemosiderin granules within the myocardial fibers, producing a striking brown coloration to the myocardium. A delicate interstitial fibrosis may appear.

45
Q

What are the morphological features of the pancreas in hemochromatosis?

A

The pancreas becomes intensely pigmented, has diffuse interstitial fibrosis, and may exhibit some parenchymal atrophy.

Hemosiderin is found in both the acinar and the islet cells, and sometimes in the interstitial fibrous stroma.

46
Q

What are the principal manifestations of classic hemochromatosis?

A

hepatomegaly
abdominal pain
abnormal skin pigmentation (particularly in sun-exposed areas)
deranged glucose homeostasis or diabetes mellitus due to destruction of pancreatic islets,
cardiac dysfunction (arrhythmias, cardiomyopathy)
and atypical arthritis.

47
Q

What is Neonatal hemochromatosis (also called congenital hemochromatosis)?

A

a disease of unknown origin manifested by severe liver disease and extrahepatic hemosiderin deposition (not inherited)

48
Q

The most common caues of secondary hemochromatosis are…?

A

disorders associated with ineffective erythropoiesis, such as thalassemia and myelodysplastic syndromes

In these disorders, the excess iron results not only from transfusions, but also from increased absorption.

Transfusions alone, when given repeatedly over a period of years (e.g., in patients with chronic hemolytic anemias), can also lead to systemic hemosiderosis and parenchymal organ injury.

49
Q

What is Wilson disease?

A

autosomal recessive disorder caused by mutation of the ATP7B gene, resulting in impaired copper excretion into bile and a failure to incorporate cop

50
Q

What are the clinical presentations of Wilson disease?

A

Initial presentation may either be with acute or chronic liver disease.
Neurologic involvement presents as movement disorders (tremor, poor coordination, chorea or choreoathetosis) or rigid dystonia (spastic dystonia, mask like facies, rigidity and gait disturbances); these symptoms may be confused with Parkinsonism.

51
Q

What is α 1 -Antitrypsin Deficiency?

A

α 1 -Antitrypsin deficiency is an autosomal recessive disorder of protein folding marked by very low levels of circulating α 1 -Antitrypsin (α 1 AT).

52
Q

What is the clinical sequelae of alpha 1 antitrypsin deficiency?

A

α 1 AT deficiency leads to the development of pulmonary emphysema, because the activity of destructive proteases is not inhibited.

It also causes liver disease as a consequence of hepatocellular accumulation of the misfolded protein.

53
Q

What are the functions of α 1 -Antitrypsin?

A

inhibition of proteases, particularly neutrophil elastase, cathepsin G, and proteinase 3, which are normally released from neutrophils at sites of inflammation.

54
Q

What is the clinical presentation of a-1-antitrypsin deficiency?

A

Neonatal hepatitis with cholestatic jaundice

In adolescence, presenting symptoms may be related to hepatitis, cirrhosis or pulmonary disease.

55
Q

When does jaundice occur?

A

bilirubin overproduction, hepatitis, or obstruction of the flow of bile, any of which can disturb the equilibrium between bilirubin production and clearance

56
Q

Describe briefly the steps of bile production

A

Intracellular heme oxygenase converts heme to biliverdin which is immediately reduced to bilirubin by biliverdin reductase.

Bilirubin thus formed outside the liver is released and bound to serum albumin.

Albumin binding is necessary to transport bilirubin because bilirubin is virtually insoluble in aqueous solutions at physiologic pH.

Hepatic processing of bilirubin involves carrier-mediated uptake at the sinusoidal membrane (step 3), conjugation with one or two molecules of glucuronic acid by bilirubin uridine diphosphate (UDP) glucuronyl transferase (UGT1A1, step 4) in the endoplasmic reticulum, and excretion of the water-soluble, nontoxic bilirubin glucuronides into bile.

Most bilirubin glucuronides are deconjugated in the gut lumen by bacterial β-glucuronidases and degraded to colorless urobilinogens.

The urobilinogens and the residue of intact pigment are largely excreted in feces.

Approximately 20% of the urobilinogens formed are reabsorbed in the ileum and colon, returned to the liver, and reexcreted into bile. A small amount of reabsorbed urobilinogen is excreted in the urine.

57
Q

Where does bile come from?

A

The majority of daily production is derived from breakdown of senescent red cells by the mononuclear phagocytic system, especially in the spleen, liver, and bone marrow.

Most of the remainder of bilirubin is derived from the turnover of hepatic heme or hemoproteins (e.g., the P-450 cytochromes) and from premature destruction of red cell precursors in the bone marrow.

58
Q

What is the pathophysiology of jaundice resulting from unconjugated bilirubin accumulation?

A

unbound bilirubin may diffuse into tissues, particularly the brain in infants, and produce toxic injury.

The unbound plasma fraction may increase in severe hemolytic disease or when drugs displace bilirubin from albumin.

59
Q

What is kernicterus?

A

accumulation of uncon­jugated bilirubin in the newborn brain, which can cause severe neurologic damage caused by hemolytic disease (erythroblastosis fetalis)

60
Q

What is Crigler-Najjar syndrome

A

Crigler-Najjar syndrome type 1 is caused by severe UGT1A1 deficiency and is fatal around the time of birth

Crigler-Najjar type II and Gilbert syndrome there is some UGT1A1 activity and the phenotypes are much milder.

61
Q

What is Dubin-Johnson syndrome

A

Impaired biliary excretion of bilirubin glucuronides due to mutation in canalicular multidrug resistance protein 2 (MRP2)

autosomal recessive and inocuous

62
Q

What is Gilbert syndrome?

A

Autosomal recessive condition of decreased UGT1A1 activity

innocuous

63
Q

What is Cholestasis?

A

impaired bile formation and bile flow that gives rise to accumulation of bile pigment in the hepatic parenchyma.

64
Q

What causes cholestasis?

A

extrahepatic or intrahepatic obstruction of bile channels, or by defects in hepatocyte bile secretion

65
Q

What is the clinical presentation of cholestasis?

A

jaundice
pruritus
skin xanthomas (focal accumulation of cholesterol), or symptoms related to intestinal malabsorption, including nutritional deficiencies of the fat-soluble vitamins A, D, or K

66
Q

Causes of acute liver failure (ABCDEF)

A

A: Acetaminophen, hepatitis A, autoimmune hepatitis
B: Hepatitis B
C: Hepatitis C, cryptogenic
D: Drugs/toxins, hepatitis D
E: Hepatitis E, esoteric causes (Wilson disease)
F: Fatty change of the microvesicular type (fatty liver of pregnancy, valproate, tetracycline)

MD1 2016 - Abdominal (5 decks)

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