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Pathology > Liver Path > Flashcards

Liver Path Flashcards

1
Q

normal liver

A

The surface is uniform and smooth.

Aging itself does not really affect the appearance of the liver, so it should look like this even as a person ages.

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2
Q

cirrhosis

A

Note the darkened appearance and many nodules of scar tissue that have developed, deforming the appearance of the liver.
When the liver cells turn into scar tissue, they no longer can function normally, and liver failure develops.

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3
Q

zones of liver

A

On the basis of blood flow, three zones can be defined, zone 1 being the closest to the blood supply and zone 3 being the farthest. Pathologists refer to the regions of the parenchyma as “periportal, midzonal, and centrilobular,” the last term owing to the historical concept that the terminal hepatic vein was at the center of a “lobule.”

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4
Q

Hepatic injury 1 &2

A
  1. Degeneration and intracellular accumulation
    Swelling (moderate is reversible), iron and copper accumulation, and steatosis
    2a. Cell death
    Necrosis is zonal
    -Centrilobular: (most obvious) characteristic of ischemic damage and drug and other toxic reactions
    -Midzonal and periportal are rare (latter seen in eclampsia)
    2b. Apoptotic death
    Councilman bodies contain fragmented nuclei from apoptotic cells
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5
Q

Hepatic Injury 3-5

A
  1. Inflammation
    Injury associated with an influx of acute or chronic inflammatory cells is called hepatitis
  2. Regeneration
    Occurs in all but the most fulminant diseases
    Can occur as long as the tissue framework is intact
    May not necessarily be anatomically normal
  3. Fibrosis
    Generally an irreversible consequence of hepatic damage
    With continuing fibrosis the liver becomes nodular
    -Regenerating hepatocytes are surrounded by scar tissue
    -This is observed in cirrhosis (covered later)
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6
Q

Jaundice

A

Presents as a yellowish discoloration of the skin, mucous membranes, and body fluids
Occurs when the equilibrium between BR production and clearance is disturbed due to:
-Excessive production
-Reduced hepatocyte uptake
-Impaired conjugation
-Decreased hepatocellular excretion
-Impaired bile flow (intra- and extrahepatic)

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7
Q

Bilirubin metabolism

A

~ 70% of bilirubin is produced in macrophages in the spleen, liver, and bone marrow from the destruction of senescent RBCs
The remaining 30% derives from metabolism of hepatic hemoproteins and destruction of RBCs in the bone marrow (ineffective hematopoiesis)

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8
Q

Unconjugated (indirect) bilirubin (UCB)

A

Reversibly binds with albumin (less tightly with newborns)
Drugs and radiographic contrast media can displace the (UCB) from albumin (particularly in newborns)
-Imposes a risk for kernicturus (bilirubin encephalopathy)
*A condition with severe neural symptoms associated with high levels of bilirubin in the blood with subsequent UCB accumulation in the brain

An increase in UCB may occur with ↑’d production or impaired uptake or conjugation

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9
Q

Conjugated bilirubin (CB)

A

An ↑ in CB may be due to impaired secretion into the canaliculi or obstruction of the common bile duct
-Obstruction results in backflow of CB to the hepatocyte and then to the sinusoidal blood
*Allows water-soluble CB access to blood (jaundice) and urine (bilirubinuria)
*Results in :
+The absence of urobilin pigment (produces light-colored stools [ clay-colored stools]) and
+The absence of urobilinogen in the urine

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10
Q

Clinical aspects of jaundice

A

Is clinically detectable when total BR exceeds 2-3 mg/dL
Elastic tissue in the sclera has a high affinity for BR
In patients with predominant ↑ in UCB, the urine and stools may be darker than normal
-Due to increased urobilin pigment
In obstructive jaundice,
-The urine is darker than normal owing to CB
-Stools are lighter since no urobilin is present
-The reappearance of normally colored urine and stool marks the end of the cholestatic (obstructive) phase

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11
Q

Pathophysiologic classification

A

Thus, NOT ALL CAUSES OF JAUNDICE ARE THE DIRECT RESULT OF LIVER DISEASE
-E.g., extravascular hemolysis,and extrahepatic bile duct obstruction
Most diseases involving jaundice are acquired
-Viral hepatitis represents the most common cause in adults
-Physiologic jaundice of the newborn is the most common cause in children
A few genetic diseases also directly involve the liver (e.g., Gilbert syndrome, Wilson’s disease)

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12
Q

Hereditary hyperbilirubinemias

A

In rare instances, there may be a genetic deficiency of the enzyme bilirubin UGT 1A1 (UDP-glucuronosyl-transferase)
Crigler-Najjar syndrome type I
-A functional enzyme is completely absent
*Multiple genetic defects in the locus coding for UGT 1 may give rise to this disorder
*The liver is incapable of synthesizing a functional enzyme
-It is invariably fatal
*Causes death within 18 months due to kernicterus
-By both light and electron microscopy, the liver appears normal

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13
Q

Hereditary hyperbilirubinemias

A

Crigler-Najjar syndrome type II
Gilbert syndrome
Dubin-Johnson syndrome

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14
Q

Crigler-Najjar syndrome type II

A

Is less severe than type I and nonfatal
Exhibits a partial defect in bilirubin conjugation
The major consequence is extraordinarily yellow skin
The mutation involves a disruption of the hydrophobic core of the signal peptide for bilirubin UGT
Almost all patients develop normally, but there is a risk for neurologic damage from kernicterus

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15
Q

Gilbert syndrome

A

Is relatively common, benign, somewhat heterogeneous
Hereditary condition presenting with mild, fluctuating hyperbilirubinemia
The primary cause is a reduction in hepatic BR glucuronidating activity to ~ 30% normal levels
-Missense mutations and molecular anomalies in the promotor regions of the UGT1A1 gene result in reduced expression of the enzyme
Some 6% of the population is affected and may go undiscovered for years
When detected in adolescence or adult life, it is typically in association with stress (e.g., intercurrent illness, strenuous exercise, or fasting)
There is no clinical consequence except for possible anxiety from being jaundiced

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16
Q

Dubin-Johnson syndrome

A

Results from a defect in hepatocellular excretion of glucuronides across the canalicular membane
-Attributed to an absence of the canalicular transport protein for BR glucuronides and related organic ions
The liver is darkly pigmented due to coarse pigmented granules within the cytoplasm of the hepatocyte
The liver is otherwise normal
Most patients are asymptomatic other than having fluctuating jaundice

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17
Q

viral hepatitis may be secondary to

A

Hematogenous spread (e.g., via the portal vein or arterial system)
Transperitoneal spread (e.g., certain helminthic infections)
Spread from neighboring organs (e.g., subphrenic abscess)
Inflammations may be secondary to systemic viral infections
Viruses associated with secondary hepatitis include:
-yellow fever (in tropical countries[zone 2 necrosis]), Epstein –Barr (in acute phase of infectious mononucleosis), cytomegalovirus (particularly in the newborn or immunosuppressed), and infrequently, (in the newborn or immunosuppressed), herpesvirus, adenovirus, and enteroviruses

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18
Q

Overall, primary hepatitis is the most common liver infection in the U.S.

A

At least 5 major types occur: hepatitis viruses A (HAV), B (HBV), C (HCV), D (HDV [delta agent]), and E (HEV)
Non-A, non-B (NANB) is a term for hepatitis that may be caused by one or more types of viruses that have no serologic markers for either HAV or HBV
-Most NANB hepatitis is due to HCV

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19
Q

Carrier state

A

The patient is without clinically apparent disease or has chronic hepatitis
Individuals with impaired immunity are likely to become carriers
Best characterized for HBV
-Infection early in life leads to carrier state in 90-95% of cases
-Only 1-10% of adults become carriers

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20
Q

Asymptomatic infection

A

Serologic evidence only is present or see mildly elevated transaminases

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21
Q

Acute viral hepatitis

A

The disease is more or less the same regardless of the etiological agent
Four phases
1. incubation period
2. symptomatic preicteric phase (pre-jaundice)
3. Symptomatic icteric or jaundiced (CB hyperBRemia)
-Usual in adults, but not in children with HAV
-Absent in ½ cases the cases of HBV and most cases of HCV
4. Convalescence
-Can begin after a few weeks or months
-Jaundice and symptoms clear

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22
Q

prodromal phase

A

Most types of hepatitis have a prodromal phase that lasts for 1-2 weeks before the onset of jaundice

Characterized by a low-grade fever (HAV most commonly), “flu-like” symptoms (headache, myalgias), abdominal discomfort, and a loss of taste for coffee or cigarettes

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23
Q

icteric phase

A

The prodrome progresses to an icteric phase

  • Characterized by dark urine, light stools, pruritis, jaundice, and tender hepatomegaly
  • Patients with HCV and children under 3 yo are commonly anicteric (lack jaundice)
  • When jaundice appears, symptoms generally decrease, the transaminases are at their peak, and the WBC count returns to normal
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24
Q

recovery phase

A

The recovery phase of viral hepatitis is marked by:
Continued malaise and weakness in the patient for a few months
Slow normalization of the laboratory abnormalities over the ensuing weeks to months (depending on the severity of the hepatitis)

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25
Q

Acute liver failure or fulminant hepatitis

A

occurs most commonly with HBV and HDV (in the U.S. with HAV and HBV)
-A disasterous complication marked by a drop in transaminases (very little functional tissue left) and a prolonged prothrombin time

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26
Q

chronic hepatitis

A

Persistence of abnormalities beyond 6 months is generally considered to be the definition of chronic hepatitis (see below)
May occur with infection with HBV, HCV (most commonly) and HDV

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27
Q

Clinical features of individual viruses

A

HBV has the greatest association for progression to hepatocellular carcinoma (followed closely by HCV)
HAV is the most common and HEV is the least common type of hepatitis in the U.S.
In children, HAV is commonly encountered in day care centers
HBV is the only DNA virus; the others are RNA viruses
HAV and HEV are transmitted by fecal-oral, water, and food-borne routes

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28
Q

Clinical features of individual viruses 2

A

HBV, HCV, and HDV are transmitted by parental inoculation and by direct contact
HAV is most likely to present with fever and jaundice, while HCV is least likely to present with these findings
Both HAV and HEV have no carrier state or chronic state
HCV is the mildest hepatitis type
-However, it is the most common to progress to a chronic carrier state and chronic hepatitis
-It is the most frequent cause of post-transfusion hepatitis

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29
Q

HDV

A

HDV is a defective RNA virus and requires HBV surface antigen in order to replicate in a hepatocyte

  • Immunization against HBV automatically protects against HDV infection as well
  • The transmission of both HBV and HDV at the same time is called coinfection and subsequent infection of a chronic carrier of HBV with HDV (a superinfection) results in disease ~30- 50 days later
  • Simultaneous HBV/HDV infections → 1 of 3 outcomes:
  • Acute severe hepatitis
  • Mild HBV hepatitis leading to fulminant disease
  • Leads to chronic progressive disease (80%) often culminating in cirrhosis
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30
Q

Laboratory findings

A

Include a mixed type of hyperbilirubinemia
-CB fraction of 20-50% (rarely exceeding 10mg/dL)
Markedly elevated transaminases (ALT>AST, 500-5000 U/L)
Mildly elevated cholestasis enzymes (AP & GGT, <2.5 X normal)
Hypoglycemia from impaired gluconeogenesis and peripheral atypical lymphocytosis are observed
Prothrombin time is prolonged
The urine is usually positive for both BR and urobilinogen (higher than normal)
+ Serologic tests for the major viruses

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31
Q

Histopathology

A

In most respects, is similar in all 5 major types
Focal ballooning degeneration (hepatocyte swelling) and apoptosis are characteristic
-The latter is responsible for the acidophilic bodies (Councilman bodies) commonly seen in liver biopsies
Also see
-Lymphocytic infiltrate (cytotoxic T cells), hypertrophy/hyperplasia of Küpffer cells, acinar disarray, portal tract inflammation
Fatty change is not a feature of acute viral hepatitis except in in chronic hepatitis due to HCV

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32
Q

chronic hepatitis path

A

Bridging necrosis (and fibrosis)

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33
Q

HBV path

A

Liver parenchyma showing hepatocytes with diffuse granular cytoplasm, so-called ground glass hepatocytes.
Immunoperoxidase stain for HBsAg from the same case, showing cytoplasmic inclusions of viral particles

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34
Q

Chronic viral hepatitis

A

Defined as symptomatic, biochemical, or serologic evidence of continuing or replapsing hepatic disease for > 6 months with histologically documented inflammation and necrosis
-Note that there are causes of chronic hepatitis other than viruses
May occur in HBV (10%) or HCV (40-60 %) infection

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35
Q

Chronic viral hepatitis 2

A

The majority of patients with viral hepatitis are men who may or may not be symptomatic (fatigue, malaise, fever, jaundice) and who may present for the first time years later with ascites and terminal liver failure
There is significant discordance between morphological subtypes and the prognosis
-Mild lesions can to progress to severe ones and vice versa
-The mildest type of chronic hepatitis is characterized by lymphocytic infiltration limited to the portal tracts with chronic “transaminitis” (elevated serum transaminases)

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36
Q

Discordance between morphological subtypes and the prognosis

A

In the worst cases, the disease progresses to frank cirrhosis (see below) and to liver failure or to hepatocellular carcinoma
Etiology (virus type) rather than the histologic pattern is the single most important factor determining the probability of developing progressive chronic hepatitis

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37
Q

Fulminant hepatitis

A

Occurs when hepatic insufficiency progresses from onset of symptoms to encephalopathy in 2-3 weeks (traditional definition says within 8 weeks)
Fulminant viral hepatitis is the cause of 12% of cases of fulminant hepatic failure in the U.S. (HAV and HBV)
Can be induced by hepatitis viruses A,B,C,D, and E
Reactivation of chronic hepatitis B or acute herpesvirus infection are sometimes the cause
Drug and other chemical toxicity make up 52% of fulminant hepatic failure
-Particularly, acetominophen (10-15 g), isoniazid, antidepressants (MAOIs), halothane, methyldopa

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38
Q

Circulatory Disorders

A

In most cases, clinically significant liver compromise does not occur
Can be classified as to whether blood flow into, through, or from the liver is impaired
Impaired blood flow THROUGH the liver

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39
Q

Acute hepatic congestion

A

Most commonly due to right heart failure
Liver is enlarged
Results in “nutmeg liver”
-Has a mottled appearance

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40
Q

Chronic passive congestion

A

Is most commonly a result of chronic right heart failure
Other causes include hepatic vein thrombosis, constrictive pericarditis, and tricuspid stenosis
Bridging fibrosis between terminal hepatic veins (THVs) over time may produce “cardiac sclerosis” (cirrhosis)

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41
Q

left sided heart failure or shock

A

may lead to hepatic hypoperfusion and hypoxia

Results in centrilobular (ischemic) necrosis

42
Q

Hepatic vein thrombosis (Budd-Chiari syndrome)

A

Associated with a hypercoagulable state most commonly secondary to polycythemia vera
-Also due to paroxysmal nocturnal hemoglobinuria, oral contraceptives, and intra-abdominal cancers

Prompt surgical treatment is required
Mortality ranges form 50-90%
Veno-occlusive disease (sinusoidal obstruction syndrome):
-Associated with pyrrolizidine alkaloids, graft-vs-host reactions in bone marrow transplant patients, and hypervitaminosis A

43
Q

Impaired flow INTO the liver

A

Hepatic artery compromise

  • Liver infarction due to occlusion of the hepatic artery is rare owing to the double blood supply to the liver
  • However, hepatic artery thrombosis in a transplanted liver is likely to result in infarction
  • Portal vein obstruction and thrombosis
44
Q

Alcohol-related Diseases

A

Currently, 67% of the population 18 yo and older drink alcohol
>14 million Americans meet the criteria for alcohol (ethanol [EtOH]) abuse and/or dependence
-Higher in men (11%) than women (4%)

Classified as :

  1. Fatty liver disease (most common; reversible)
  2. alcoholic hepatitis (reversible, if person stops drinking)
  3. cirrhosis (irreversible)
45
Q

Alcohol Abuse

A

Alcohol abuse causes 200,000 deaths annually
-Many are DUI related
~ 25 % of people with alcoholism have no liver disease, 30 % have fatty liver, 20 % have alcoholic hepatitis, and 25 % have cirrhosis
Risk factors for developing the above changes:
-The duration and magnitude of alcohol ingestion (regardless of kind, i.e., beer, wine, distilled spirits)
*A daily intake of > 80g EtOH by ♂s and > 40g by ♀s for 10-20 years will likely result in cirrhosis
*80 g of EtOH is present in a ½ pint of whiskey (80 proof or 40% EtOH), eight 12 oz. cans of beer (3.6% EtOH [wimpy beer]), or a liter of wine (12.5% EtOH)

46
Q

Risk factors for alcohol related disease

A

Sex of the patient (females > males)
-Women are more susceptible to liver damage than men, develop liver disease at an earlier age, and have a higher mortality rate in acute injury
*Due to decreased gastric metabolism of EtOH (?) and differences in body mass (?)
*♀ have lower gastric alcohol dehydrogenase activity so have higher blood levels than men when drinking the equivalent amount of EtOH
Nutritional status
-Protein-energy malnutrition (PEM) is commonly present in people with alcoholism
-EtOH contains 7 kcal/g
*However, it contains no vitamins, minerals, proteins, or fats (so has “empty” calories)
*Since many people with alcoholism consume 30-50% of their calories as EtOH, the etiology of PEM is understandable
Presence of coexisting HCV
Certain genetic factors (IMPORTANT)
-Genetic susceptibility has been established in families
-Susceptibility to damage may relate to different types of enzymes used in the metabolism of alcohol

47
Q

Alcohol related diseases other than those involving the liver

A

CNS abnormalities (e.g., Wernickes encephalopathy, Korsakoff’s psychosis; cancer (squamous cell cancer in the oropharynx, esophagus, or vocal cords); pancreatitis, thiamine and folate deficiency; peripheral neuropathy; fetal-alcohol syndrome; and congestive cardiomyopathy

48
Q

Alcohol metabolism

A

alcohol →alcohol dehydrogenase → acetaldehyde + NADH + H+ →aldehyde dehydrogenase→ acetate + NADH + H+ → acetyl-CoA
Alcohol dehydrogenase metabolizes alcohol in the cytosol, while acetaldehyde dehydrogenase metabolizes acetaldehyde (toxic to cells) in the mitochondria
Acetaldehyde is the major toxic product responsible for most of the damage that occurs in the liver (see below)
- Asian people may have a defect in the latter enzyme, which leads to a buildup of acetaldehyde in the blood (they get sick faster)
-This is similar to the effect of Antabuse (disulfiram) which inhibits the enzyme
Other individuals have an enzyme that metabolizes alcohol faster

49
Q

Cirrhosis

A

Refers to the presence of IRREVERSIBLE DIFFUSE FIBROSIS in the liver with or without the formation of regenerative nodules
Fibrous tissue is formed in response to inflammation or direct toxic insult to the liver
-With continuing fibrosis, the liver is subdivided into nodules of regenerating hepatocytes surrounded by scar tissue (cirrhotic state)
Cirrhosis may begin with a micronodular pattern (< 3 mm nodules) and end with a predominantly macronodular pattern (>3 mm nodules) with a mixed pattern in between
Alcoholic cirrhosis tends to have a micronodular pattern

50
Q

alcoholic cirrhosis

A

The characteristic diffuse nodularity of the surface reflects the interplay between nodular regeneration and scarring. The greenish tint of some nodules is due to bile stasis. A hepatocellular carcinoma is present as a budding mass at the lower edge of the right lobe (arrow, lower left of figure).

51
Q

cirrhosis

A

Alcoholic liver disease is the most common cause of cirrhosis (~ 65%) in the United States
-Followed by macronodular (postnecrotic) cirrhosis secondary to chronic active viral hepatitis (HBV, HCV, HDV; 10-30%)
Other causes include Wilson’s disease, -antitrypsin deficiency
The most common cause of death is rupture of esophageal varices (a complication of portal hypertension)
Complications associated with cirrhosis, in general, relate to the development of hepatocellular failure, portal hyper-tension, and progression to hepatocellular carcinoma

52
Q

Hepatocellular Failure

A

Most severe consequence of liver disease
80-90% of hepatic functional capacity must be affected before hepatic failure occurs
-Balance may tipped toward failure by intercurrent disease that places a demand on the liver (e.g., GI bleeding, infection, electrolyte disturbance, severe stress [surgery or heart failure])
May be seen in the setting of fulminant hepatic failure (FHF) related to drug use (e.g., acetaminophen) and viral infections most commonly (e.g., HBV) and chronic liver disease (e.g., cirrhosis)
FHF, by definition, is acute liver failure (massive hepatic necrosis) associated with hepatic encephalopathy occurring within a few weeks of symptoms of hepatic dysfunction
-The major difference between FHF and chronic liver disease as a cause of hepatocellular failure is the short duration of onset in FHF and the absence of portal hypertension (which may be a feature of chronic liver disease)
Chronic liver disease is the endpoint for chronic hepatitis ending in cirrhosis
Hepatic dysfunction without necrosis
-Hepatocytes are unable to perform normal metabolic functions
*Observed in Reye’s syndrome, tetracycline toxicity, and acute fatty liver of pregnancy

53
Q

Hepatocellular Failure 2

A

Multiple coagulation defects are commonly present in hepatocellular failure owing to inability of hepatocytes to synthesize coagulation factors
-The prothrombin test is the best monitor of these deficiencies and is not corrected by intramuscular injection of vitamin K
Hypoalbuminemia from decreased albumin synthesis reduces plasma oncotic pressure (predisposing to pitting edema and ascites)
Severely impaired liver function renders patients highly susceptible to failure of multiple organ systems

54
Q

Hepatic encephalopathy

A

Is a reversible metabolic disorder associated with diffuse slowing of brain waves on an electroencephalogram and clinical evidence of encephalopathy
Clinical findings in early stages of encephalopathy consist of alterations in the mental status examination, somnolence, disordered sleep rhythms, and asterixis (inability to sustain posture, flapping tremor)
As encephalopathy progresses, the patient becomes less arouseable, asterixis worsens, incontinence occurs, and eventually coma and death take place

55
Q

Functional renal failure (hepatorenal syndrome)

A

Is defined as renal failure with severe liver disease with no intrinsic abnormality demonstrable in the kidneys
The etiology is unknown
-Vasoconstriction of renal vessels (by endothelin-1) with decreased blood flow to the cortex plus preservation of tubular function is a proposed mechanism
The condition improves with reversal of liver failure
The kidneys at autopsy are grossly normal and histologic evidence of tubular necrosis is absent
Patients have oliguria with the usual proportionate increase in the serum blood urea nitrogen and creatinine

56
Q

Hepatocellular failure is associated

A

with an inability to degrade hormones such as estrogens, 17ketosteroids (dehydroepiandrosterone and androstenedione), and aldosterone

  • Hyperestrinism in a male is the result of failure to metabolize estrogens and 17-ketosterolds (which are converted bv aromatases to estrogen in adipose cells)
  • Signs of hyperestrinism are gynecomastia, palmar ervthema, spider angiomas, testicular atrophy (which decreases spermatogenesis), and a female distribution of hair (sparse axillary hair, lack of hair ascending to the umbilicus
57
Q

Inability to degrade hormones

A

Males with hepatocellular failure have reduced free testosterone levels owing to hyperestrinism, which increases the synthesis of sex hormone-binding globulin (SHBG) by the liver
SHBG has a higher affinity for testosterone than for estrogen
-Hence the serum levels of testosterone are lowered
-Low testosterone levels result in sexual impotence
Furthermore, if the patient is an alcoholic, alcohol will decrease testosterone synthesis by interfering with the ability of luteinizing hormone to bind with Leydig’s cells (the site of testosterone synthesis) in the testicles
-Alcohol also directly decreases the release of luteinizing and follicle-stimulating hormones from the anterior pituitary

58
Q

Secondary hyperaldasteronism

A

with retention of salt and water is due not only to faulty metabolism of aldosterone by the liver but also to a reduction in cardiac output with subsequent stimulation of the renin-angiotensin-aldosterone system
-Contributes to pitting edema and ascites owing to retention of salt and water

59
Q

chronic respiratory alkalosis

A

Is a consistent metabolic abnormality in liver failure
The toxic products from impaired hepatic detoxification overstimulate the respiratory center increasing the clearance of C02

Hypoglycemia commonly occurs owing to a decrease in gluconeogenesis and glycogen stores in the liver
Malabsorption may occur as a result of the inability to synthesize primary bile acids or salts

60
Q

Ascites

A

Is a consistent feature of chronic liver failure
Its pathogenesis is multifactorial (see below)
In cirrhosis (the most common cause of ascites), the development of portal hypertension leads to an increase in portal vein hydrostatic pressure and leakage of a transudate into the abdominal cavity
Additional factors that contribute to the production of ascites are:
-Decreased oncotic pressure (hypoalbuminemia)
-An increase in hepatic lymph formation due to intrasinusoidal obstruction (fibrosis) with subsequent leakage from the capsular surface, and
-Secondary hyperaldosteronism

61
Q

Fatty liver (steatosis)

A

Alcohol is singled out as the most common cause of fatty liver (steatosis)
Unlike the other types of alcohol-related liver disease, it may develop after only a single overindulgence of alcohol
The liver becomes diffusely enlarged and has a yellowish-brown appearance
-Individual hepatocytes are enlarged by a single fat droplet that pushes the nucleus to the periphery of the cell (macrovesicular steatosis vs. microvesicular steatosis in which many small fat droplets are present in the cell but do not displace the nucleus)
Initially, the fatty change is primarily in zone III around THV, but with more prolonged alcohol intake it eventually diffuses throughout the liver
In general, fatty livers produce mild elevation of transaminases and cholestasis enzymes, but jaundice is uncommon
The lesion is reversible once alcohol is discontinued

62
Q

Alcoholic Hepatitis

A

most commonly associated with bouts of heavy drinking in excess of 100 g/d for more than one year
Morphology
-Grossly, the liver is enlarged and tender
-Microscopically, there is fatty change, Mallory’s bodies (alcoholic hyaline), a neutrophilic infiltrate (viral hepatitis has a lymphocyte infiltrate), intrahepatic cholestasis in zone III areas, and perivenular fibrosis
Clinically, patients have a low-grade fever, jaundice, and ascites and may even progress to hepatic encephalopathy (see above)

63
Q

Alcoholic hepatitis lab

A

Include a transaminasemia with AST (< 500 U/L) > ALT, elevated cholestasis enzymes (GGT is disproportionately increased owing to enzyme induction by alcohol), and an elevated total bilirubin

64
Q

Alcoholic hepatitis Hematologic abnormalities

A

Consist of a macrocytic anemia (which is either due to direct alcohol effect on the RBC membrane [round target cells] or to folate deficiency [more common]), absolute neutrophilic leukocytosis, and abnormal coagulation tests (prolonged prothrombin time)

Approximately 20% die of hepatic failure, and 30% of those who survive develop alcoholic cirrhosis
Alcoholic hepatitis is reversible if the patient totally abstains from alcohol

65
Q

Autoimmune (lupoid) hepatitis

A

Is a chronic active hepatitis type most commonly seen in young and perimenopausal women (female predominance [78%])
Viral serological markers are absent
IgG and gammaglobulin levels are >1.5 times normal
Autoimmune hepatitis has an insidious onset and usually presents with jaundice (80%), hepatosplenomegaly (50-80%), diarrhea (30%), and signs of other autoimmune disorders (e.g., autoimmune hemolytic anemia, Hashimoto’s thyroiditis)
Autoimmune hepatitis has no direct relationship to systemic lupus erythematosus (SLE) other than a positive antinuclear antibody (ANA) test (50-80%) and a positive LE prep (15%; neutrophil with phagocytosed altered DNA)
Additional laboratory abnormalities include a positive anti-smooth muscle antibody (75%) and positive anti-liver/kidney/microsome autoantibodies
Responds to immunosuppressive therapy
However, in a significant number of patients, the disease progresses to cirrhosis (40%)

66
Q

Portal hypertension

A 
Portal hypertension (PH) is secondary to obstruction to normal blood flow
It may be the result of prehepatic obstruction (e.g., portal vein thrombosis), intrahepatic obstruction (e.g., cirrhosis, the most common cause), or posthepatic obstruction (e.g., Budd-Chiari syndrome, venoocclusive disease)
PH results in retrograde blood flow owing to increased intrasinusoidal pressure hampering blood flow into the liver
67
Q

Cholestasis

A

Is obstruction to the flow of bile
May be intra- or extra-hepatic in origin
One of the most important consequences of cholestasis is the exclusion of bile from the intestine
In order of decreasing percentage, bile contains salts, electrolytes, phospholipids, proteins, cholesterol, and conjugated bilirubin
The primary bile acids (cholic and chenodeoxycholic acid) are synthesized from cholesterol (CH)
-Approximately 50% of CH is eliminated from the body each day by its conversion to primary bile acids

68
Q

Intrahepatic cholestasis causes

A

hereditary hyperbilirubinemias (e.g., Dubin-Johnson syndrome),
biliary atresia drug use (e.g., oral contraceptives), viral hepatitis (early cholestatic phase)
neonatal cholestasis,
alcoholic hepatitis,
primary biliary cirrhosis

69
Q

Extrahepatic cholestasis

A

Is more common than intrahepatic cholestasis
May be caused by:
-Choledocholithiasis (the most common cause)
-Carcinoma of the head of the pancreas (second most common cause)
-Carcinoma of the bile ducts, inflammatory strictures, biliary atresia, primary sclerosing cholangitis, and parasitic diseases
Grossly, the liver is enlarged and has a diffuse greenish discoloration

70
Q

Cholestatic liver disease clinical & lab

A

Clinically, patients have complaints of jaundice and pruritis (which often precedes jaundice and is due to bile salt deposition in the skin)
Physical examination
-Frequently reveals skin xanthomas and xanthelasmas from increased cholesterol deposition in macrophages
-Clay colored stools are noted on rectal examination, and the urine is a dark orange color
Laboratory abnormalities
-Consist of a mild to moderate transaminasemia, markedly increased cholestasis enzymes (5-20 times normal) and high serum cholesterol levels

71
Q

Primary sclerosing cholangitis

A

Is a patchy obliterative inflammatory fibrosis of the large bile ducts that leads to strictures and cholestasis
Is associated with inflammatory bowel disease (most commonly ulcerative colitis) in 50-70% of cases
It is more common in males than females
The walls of the intra-and extrahepatic ducts are markedly thickened (concentric fibrosis) and the lumens are narrowed, producing areas of stricture altering with bead-like dilatations
An obstructive enzyme pattern often predates signs and symptoms of the disease (e.g., jaundice, pruritis) in 85% of cases
Secondary biliary cirrhosis and liver failure usually occur in 10-12 years
Cholangiocarcinoma may also occur

72
Q

Primary biliary cirrhosis (PBC)

A

PBC is a progressive disease characterized by autoimmune destruction of small interlobular bile ducts and bile duct radicals in the portal triads

  • It has a 10/1 female to male ratio and frequents middle age (40-50 yo)
  • Is often associated with other autoimmune diseases such as Sjogren’s syndrome, rheumatoid arthritis, CREST syndrome, Hashimoto’s thyroiditis, and renal tubular acidosis
  • The pathogenesis involves the production of antimitochondrial antibodies to epithelial antigens in bile duct epithelium
  • It progresses through four stages:
  • The fourth stage is characterized by cirrhosis and absence of bile ducts in the above-mentioned areas of inflammation
73
Q

Primary biliary cirrhosis (PBC) clinical

A

Pruritus without jaundice is the earliest sign of the disease
The cholestasis enzymes are also markedly elevated
Antimitochondrial antibodies are present in the serum (90% of cases) and increased IgM levels (95%), both of which are markers for the disease and often prompt a liver biopsy
Anti-smooth muscle antibodies and rheumatoid factor are also increased in 65% and 70% of cases, respectively
Cholestatic jaundice is a late finding and correlates with the decrease in the number of bile ducts in the liver that are available to deliver bile to the intestine
Serum CH levels are markedly elevated and commonly produce xanthelasmas and skin eruptions
Malabsorption from decreased bile acids complicates the nutritional status of the patient
Renal tubular acidosis with potassium wasting offers a difficult metabolic problem to manage
Cirrhosis, portal hypertension, and liver failure invariable occur within 5-10 years of symptoms
Liver transplantation offers further longevity to those with end-stage disease

74
Q

Secondary Biliary Cirrhosis

A

Occurs in response to chronic obstruction of the bile ducts
May occur in cystic fibrosis (focal biliary cirrhosis) owing to inspissated* bile blocking the bile ducts, common bile duct stones or strictures, and parasitic diseases involving the bile ducts

*made or having become thickened in consistency (blocked with inspissated bile)

75
Q

Nonalcoholic fatty liver disease (NAFL)

A

A condition resembling alcohol-induced liver disease but occurs in patients who are not (or claim not) to be heavy drinkers
Men and women are equally affected
Strong associations with obesity, dyslipidemia, hyperinsulinemia, and insulin resistance and overt Type 2 diabetes
Patients are largely asymptomatic with abnormal biochemical laboratory tests
Biopsy shows steatosis
-Steatohepatitis (nonalcoholic steatohepatitis or NASH) with multifocal inflammation is an intermediate form of liver damage
May account for up to 70% of chronic hepatitis of “unknown” cause

76
Q

Iron Overload Disorders

A

Excess hemosiderin in the liver may be inherited (hemochromatosis) or secondarily acquired (hemosiderosis)
Hereditary Hemochromatosis
-Is an autosomal recessive disease with an HLA-A3 inheritance pattern (70%)
*Is the most common genetic disease (1/200) in the United States
-People who are homozygous for the disease have an increase in a membrane iron-binding protein on the mucosal cells of the small intestine
-Leads to excessive absorption of iron
-The male-to female ratio is 10/1
-The deposition of iron is predominantly parenchymal rather than in fixed macrophages (a late manifestation of the disease)

77
Q

Hereditary Hemochromatosis Clinical manifestations

A

Occurs more commonly in men and postmenopausal women
Women of reproductive age rarely demonstrate signs or symptoms owing to the loss of blood during menses and childbearing
Symptoms include fatigue, joint pain (patients develop degenerative arthritis), abdominal discomfort (hepatomegaly) impotence in males and secondary amenorrhea in women (hypothalamic and gonadal involvement), and cardiac arrhythmias
Signs consist of skin hyperpigmentation (stimulation of melanocytes by iron and iron itself are responsible), hepatosplenomegaly (micronodular cirrhosis in 100% with portal hypertension), signs of hypothyroidism, malabsorption (pancreatic exocrine deficiency), diabetes mellitus (a late finding of “bronze diabetes” [hyperpigmentation plus diabetes]), and cardiomegaly (restrictive cardiomyopathy)
Hepatocellular carcinoma may occur in 30% of cases

78
Q

Hereditary Hemochromatosis Laboratory

A

Are those of iron overload, mainly an increase in serum iron, percent saturation, and ferritin and a decrease in total iron-binding capacity (increased iron stores decrease liver synthesis of transferrin)
Percent saturation > 62% in males or > 50% in females plus a serum ferritin greater than twice normal (often > 500 g/L) are typical
Direct DNA testing for two abnormal gene loci on chromosome 6 is recommended in patients so affected and as a screen for family members
The confirmatory test is a liver biopsy with quantitation of iron
Phlebotomy is the mainstay of treatment
Hepatocellular carcinoma is the leading cause of death in hemochromatosis

79
Q

Secondary Hemochromatosis (Hemosiderosis)

A

Is an acquired iron overload disease
Occurs with hemolytic anemias associated with ineffective erythropoiesis which is treated with multiple transfusions (usually > 100); drinking well water containing excess iron; and eating food cooked in iron pots (e.g., among the Bantus in Africa [a genetic susceptibility exists])
Iron deposits primarily in fixed macrophages in the liver, bone marrow, and spleen, but it can enter parenchymal cells as well as later in the disease
Particularly common in alcoholic liver disease
-Represents alcohol-induced redistribution of iron (total body iron is not significantly increased)

80
Q

Wilson’s disease (Hepatolenticular Degeneration)

A

Is an autosomal recessive disease characterized by a defect in copper excretion into bile and accumulation of toxic levels of copper in the liver, eye, and brain
A gene defect in a copper-transporting ATPase occurs on chromosome 13
The excess free copper is stored in the liver
-There it produces acute hepatitis that progresses to chronic active hepatitis and postnecrotic cirrhosis
Ceruloplasmin (a copper-binding protein)is an excellent screen for the disease
-Chronic liver disease reduces the synthesis of ceruloplasmin
Unbound free copper spills over into the plasma and deposits in other organs such as Descemet’s membrane in the eye (forming a Kayser-Fleischer ring) and the lenticular nuclei in the brain
-The combination of low ceruloplasmin level plus Kayser-Fleischer ring in the eye is diagnostic for Wilson’s disease
-Degeneration of the lenticular nuclei produces signs of spasticity, dysarthria, and tremors

81
Q

Wilson’s disease 2

A

In Wilson’s disease, the total copper concentration is decreased, owing to decreased ceruloplasmin, the free copper level is increased, as is urinary excretion and the copper content of the liver
The confirmatory test is a liver biopsy with quantitation of copper
Treatment with penicillamine, a copper-chelating agent, improves symptoms but does not reverse cirrhosis

82
Q

-Antitrypsin (AAT) Deficiency

A

Is an autosomal recessive disease characterized by either abnormally low AAT levels in the plasma or defective secretion of AAT secondary to abnormal protein folding in the ER

AAT is a protease inhibitor that is predominantly synthesized in the liver

83
Q

-Antitrypsin (AAT) 2

A 
In general, liver disease is more likely to develop when AAT cannot be secreted from the hepatocytes
Pulmonary disease (panacinar emphysema) is more likely to occur with low concentrations of functional AAT in the serum that are unrelated to a defect in secretion by the liver 
Liver transplantation is the only option for AAT deficiency-induced cirrhosis
All family members should be phenotyped to identify candidates for liver or pulmonary disease
84
Q

Other accumulations

A 
Lysomomal Storage Diseases 
Hypertriglyceridemia
Glycogen storage diseases 
Lipofuscin 
Amyloidosis
85
Q

Focal Nodular Hyperplasia and Nodular Regenerative Hyperplasia

A

These are NEITHER NEOPLASMS NOR VARIANTS OF CIRRHOSIS
Focal nodular hvperplasia presents as a spontaneous mass lesion
-It has a 2/1 female-to-male ratio and no identifiable cause
-Grossly, there is a central stellate scar with wagon-wheel radiation to the periphery
-Bile ducts actively proliferate in the fibrous tissue
-It has no malignant potential and rarely causes intraperitoneal hemorrhage
Nodular regenerative hyperplasia
-Associated with the development of portal hypertension and its attendant clinical manifestations

86
Q

Benign Tumors

A 
Cavernous Hemangiomas 
Liver cell (hepatic) Adenomas
87
Q

Cavernous Hemangiomas

A

Are the most common overall benign tumor of the liver
Occur directly beneath the capsule and should not be mistaken for metastatic tumors
blind percutaneous biopsies should not be performed on them (they will bleed)
They rarely are of clinical importance
Imaging studies confirm the diagnosis

88
Q

Liver cell (hepatic) Adenomas

A

Usually occur in women of childbearing age
They are highly vascular tumors and are associated with:
-The use of oral contraceptives
-Anabolic steroids, and
-Rarely, von Gierke’s glycogen storage disease
They have a tendency to rupture during pregnancy (20% mortality)
Imaging studies confirm the diagnosis
They rarely transform into a hepatocellular carcinoma (notable exception is von Gierke’s disease)

89
Q

Malignant Tumors

A

Metastatic tumors constitute the most common form of cancer of the liver
Common metastatic tumors come from:
-Primary carcinomas located in the lung (most common cause)
-Gastrointestinal tract (second most common cause [esophagus, stomach, pancreas, and colon]), and breast
-Malignant lymphomas and malignant melanomas also frequently metastasize to the liver
Carcinoembryonic antigen (CEA) is used as a marker for recurrence of colorectal and pancreatic cancers
The CT scan is the most accurate imaging technique for detecting metastases

90
Q

Hepatocellular Carcinoma (HCC)

A

Is the most common primary cancer of the liver
Is five times more common in men than in women
Peaks around 60 years of age
>85% of HCC occurs in countries with high rates of chronic HBV infection

91
Q

HCC causes

A

In general, cirrhosis is the most common cause (75-90%)
-Specifically, postnecrotic cirrhosis secondary to HBV (aflatoxins [produced by the fungus Aspergillus flavus]
Other causes
-Chronic alcoholism
-HBV is followed closely by pigment cirrhosis (hemochromatosis) and HCV
-Less common causes include oral contraceptive use, smoking, AAT deficiency, and von Gierke’s disease

92
Q

HCC grossly

A

Grossly, there is invariably a background of cirrhosis with unifocal or multifocal nodular masses representing HCC
Microscopically, there is prominent vessel invasion (portal and hepatic veins) and the presence of bile in neoplastic cells (a reliable finding)

93
Q

HCC clinical features

A

Patients present with fever (liver cell necrosis), abdominal pain, weight loss, and an abdominal mass
Clinical deterioration in a known cirrhotic, increasing abdominal girth (ascites), bloody ascitic fluid, and a sudden rise in serum GGT and AP are highly predictive of HCC
Additional laboratory abnormalities include an increase in α-fetoprotein (75-90%; usually > 500 ng/mL) and an increase in AAT
Ectopic hormone relationships consist of secondary polycythemia (due to erythropoietin production by the tumor) and hypoglycemia related to production of an insulin-like factor

94
Q

HCC clinical features 2

A

CT scanning and angiography (of the hypervascular mass) are the best diagnostic combination for detection of HCC
HCC spreads directly in the liver first and then to regional lymph nodes and the lungs
Vaccination against HBV should decrease the incidence of HCC
Patients survive an average of 6 months after the diagnosis is confirmed

95
Q

Gallstones

A

Gallstones (calculi) and cholecystitis are the most frequent diseases involving the gallbladder

Occur in 10-20% of adult men and 20-40% of adult women

Calculi most commonly precipitate in the gallbladder but may also develop in the common bile duct (CBD)

Cholesterol (80%) and pigment (bilirubin calcium salts) stones (20%) are the two main types

96
Q

gallbladder clinical findings

A

Include: biliary “colic” in the right upper quadrant (distention of the wall due to impaction of a stone in the cystic duct or CBD) and abdominal distention with bloating 30 minutes after eating (particularly fatty foods)
Complications associated with stone formation consist of:
-Obstruction (e.g., in the cystic duct or CBD)
-Acute cholecystitis (stone impacted in cystic duct)
-Biliary fistula (which produces gallstone ileus)
-Chronic cholecystitis
-Acute pancreatitis, and
-A predisposition to gallbladder cancer
Ultrasonography is the gold standard test for the diagnosis of stones and duct dilatation

97
Q

Acute cholecystitis

A

Is a female-dominant disease
Is most commonly the result of an impacted stone (90%) in the cystic duct
-The obstructed duct blocks the efflux of bile, resulting in secondary chemical irritation of the mucosa, which in turn predisposes to bacterial invasion as a secondary event in 80% of cases
In addition, the inflammation surrounding the impacted stone obstructs blood vessels (producing distal ischemia)

98
Q

Acute cholecystitis also contributes to

A

mucosal damage and the potential for bacterial infection
-Escherichia coli is the most common microbial pathogen
Rarely, acalculous ( no stones) cholecystitis can result from primary infection with Salmonella typhi and staphylococci, in the setting of systemic vasculitis, severe atherosclerotic ischemic disease, and acquired immunodeficiency syndrome with biliary tract infection
-Early diagnosis is crucial to prevent a fatal outcome

99
Q

Acute cholecystitis gross & microscopically

A

Gross appearance
-The gallbladder is enlarged, congested, and covered with a fibrohemorrhagic exudate
-The wall of the gallbladder is thickened, edematous, and focally hemorrhagic
Microscopically, there are collections of neutrophils in the wall and the mucosa is replaced or covered by a thick exudate
complications

100
Q

Acute cholecystitis complications

A

Empyema (accumulation of pus in the gallbladder), gangrenous necrosis, and perforation are potential

101
Q

Acute cholecystitis clinical features

A

Patients develop an acute onset of a constant, dull, aching right upper quadrant pain (the pain is not colicky, so “biliary colic” is a misnomer) that occurs within 15-30 minutes of eating
The pain frequently radiates to the right scapula or right shoulder
Shaking chills and fever are commonly present
Right upper quadrant tenderness on palpation after deep inspiration is known as Murphy’s sign
Jaundice may occur and should alert the clinician to the possibility of a stone in the CBD

102
Q

Acute cholecystitis labs

A

Elevated cholestasis markers (AP and GGT) in some cases, and
An absolute neutrophilic leukocytosis with a shift to the left
An elevated serum amylase suggests associated pancreatitis

The natural history of acute cholecystitis depends on whether or not the obstruction is relieved, with 90% resolving over 3-7 days
May require cholecystectomy

Pathology (16 decks)

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