Diseases of the liver and pancreas

Chronic Viral Hepatitis

• 
  Symptomatic, biochemical, or serologic evidence of continuing or relapsing hepatic disease for > 6 months, optimally with histologically documented inflammation and necrosis, is taken to mean chronic hepatitis
  
• 
  Classified according to the extent of inflammation:
  

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  Chronic persistent hepatitis - inflammation confined to portal tracts.
  
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  Chronic active hepatitis - portal tract inflammation spills into the parenchyma and surrounds regions of necrotic hepatocytes.
  
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  Chronic lobular hepatitis - persistent inflammation is confined to the lobule
  

Morphology of chronic hepatitis

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  Ranges from exceedingly mild to severe, to eventual cirrhosis.
  

Mildest form:

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  An inflammatory infiltrate limited to portal tracts
  
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  Liver architecture usually well preserved
  

Progressive disease:

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  Histologic hallmark is piecemeal necrosis
  

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  Chronic inflammatory infiltrate spills out from portal tracts into adjacent parenchyma
  
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  Associated necrosis of hepatocytes in the limiting plate
  

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  Bridging necrosis may connect adjacent portal-portal, central-central, and portal-central zones.
  
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  Although piecemeal and bridging necrosis do not imply inevitable progression of disease, continued loss of hepatocytes results in fibrous septum formation, which, accompanied by hepatocyte regeneration, results in cirrhosis.
  

Piecemeal Necrosis – Chronic Active Hepatitis Features of Acute and Chronic Hepatitis






Exam from picture:

Piecemeal necrosis = chronic hepatitis
Autoimmune Hepatitis

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  Is a chronic hepatitis of unknown etiology, which has clinical and histologic features virtually indistinguishable from chronic viral hepatitis
  
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  May run an indolent or a severe and progressive course
  
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  Responds dramatically to immunosuppressive therapy.
  
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  Salient features include:
  
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  Female predominance (70%), particularly young and perimenopausal women.
  
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  Absence of viral serologic markers.
  
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  Elevated serum IgG levels
  
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  High serum titers of autoantibodies in 80% of cases, including antinuclear (ANA), anti—smooth muscle (SMA), antimitochondrial (AMA), and anti—liver and kidney microsome (LKM) antibodies.
  

• 
  Because there is often a positive lupus erythematosus (LE) test, autoimmune hepatitis was formerly called “lupoid” hepatitis.
  

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  •An increased frequency of HLA B8 or DRw3.
  

Fulminant Hepatitis

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  Hepatic insufficiency progressing from onset of symptoms>hepatic encephalopathy within 2-3wks
  

Drug-Induced and Toxin-Induced Liver Disease

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  Liver is the major drug-metabolizing and drug-detoxifying organ
  
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  Therefore is subject to potential damage from pharmaceutical and environmental chemicals
  
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  Injury may result from :
  
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  Direct toxicity
  
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  Hepatic conversion of a xenobiotic to an active toxin
  
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  Via immune mechanisms, usually when the drug or a metabolite acts as a hapten to convert a cellular protein into an immunogen.
  

Drug reactions may be classified as

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  Intrinsic (predictable) reactions:
  

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  Occur in anyone who accumulates a sufficient dose
  
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  Examples: Acetaminophen, Tetracycline, Anti-neoplastic agents, Amanita phalloides toxin, CCl4
  

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  Idiosyncratic (Unpredictable) reactions:
  

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  Depend on idiosyncrasies of the host
  

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  Host’s propensity to mount an immune response to the antigenic stimulus
  
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  Rate at which the host metabolizes the agent
  

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  Examples: Sulfonamides, Methyldopa, Allopurinol
  

• 
  Injury may be
  
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  Immediate
  
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  Develop in weeks/ months - manifesting only after liver is damaged severely
  
• 
  Injury may take the form of
  
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  Hepatocyte necrosis
  
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  Cholestasis
  
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  Insidious onset of liver dysfunction
  
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  Drug-induced chronic hepatitis is clinically and histologically indistinguishable from chronic viral hepatitis
  
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  Diagnosis of drug-induced liver disease may be made based on a temporal association of liver damage with drug administration
  
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  Exposure to a toxin or therapeutic agent should be included in the differential diagnosis of any form of liver disease.
  

Drug-Induced and Toxin-Induced Liver Disease

Table exam:

Centrilobular necrosis  CCl4

Diffuse or massive necrosis  halothane

Hepatitis acute and chronic  isoniazid, oxyphenisation

Cholestasis  CONTRACEPTIVES
Hepatic or portal vein thrombosis: estrogens, including oral contraceptives: TEST  hepatocellular carcinoma
Reye’s Syndrome

• 
  Is a rare disease characterized by fatty change in the liver and encephalopathy that in its most severe forms may be fatal.
  
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  Primarily affects children < 9 years (most < 4 years of age)
  
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  Typically, Reye’s syndrome develops 3 to 5 days after a viral illness, heralded by vomiting and accompanied by irritability or lethargy and hepatomegaly.
  
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  75% of the patients progress no further and recover with no residual effects
  
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  Remaining 25% have more serious illness
  

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  Progressively deeper levels of coma
  
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  Elevated levels of serum bilirubin, aminotransferases
  

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  Survivors may be left with permanent neurologic impairments
  

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  Death results from progressive deterioration of the mental state with delirium, convulsions, and coma.
  

• 
  Therapy for Reye’s syndrome is entirely symptomatic and supportive.
  

Alcoholic Liver Disease

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  Alcohol abuse constitutes the major form of liver disease
  

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  More than 10 million Americans are alcoholics
  
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  Alcohol abuse causes 200,000 deaths annually
  
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  It is the fifth leading cause of death
  
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  25-30% of hospitalized patients have problems related to alcohol abuse
  

• 
  Three distinctive, albeit overlapping, forms of liver disease collectively referred to as alcoholic liver disease:
  

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  Hepatic steatosis
  
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  Alcoholic hepatitis
  
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  Cirrhosis
  

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  These conditions may exist independently of each other and do not necessarily represent a continuum of changes
  

Hepatic Steatosis (Fatty Liver)

Moderate intake of alcohol:

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  Small (microvesicular) lipid droplets accumulate in hepatocytes.
  

Chronic intake of alcohol:

GROSS:

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  Liver often enlarged: upto 4 - 6 kg
  
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  Is soft, yellow and greasy
  

MICROSCOPIC:

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  Lipid accumulates creating large clear macrovesicular spaces, compressing and displacing the nucleus to the periphery of the hepatocyte.
  

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  Initially centrilobular
  
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  In severe cases involves the entire lobule
  

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  Fibrous tissue develops around the central veins and extends into the adjacent sinusoids.
  
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  Up to the time that fibrosis appears, the fatty change is completely reversible if there is further abstention from alcohol.
  

Fatty Liver

Alcoholic Hepatitis

Alcoholic hepatitis exhibits the following:

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  Liver cell necrosis – Single or scattered foci of cells undergo swelling (ballooning) and necrosis, more frequently in the centrilobular regions
  
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  Mallory bodies – Scattered hepatocytes containing eosinophilic cytoplasmic inclusions (tangled skeins of cytokeratin intermediate filaments and other proteins)
  
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  These may also be seen in:
  
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  Primary biliary cirrhosis
  
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  Wilson’s disease
  
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  Chronic cholestatic syndromes
  
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  Focal nodular hyperplasia
  
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  Hepatocellular carcinoma
  
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  Neutrophilic reaction:
  
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  Neutrophils accumulate around degenerating liver cells, particularly those having Mallory bodies
  
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  Lymphocytes and macrophages also enter portal tracts and spill into the lobule
  
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  Fibrosis:
  
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  Almost always present
  
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  Sinusoidal and perivenular fibrosis
  
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  Occasionally periportal fibrosis may predominate
  
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  Particularly with repeated bouts of heavy alcohol intake
  
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  Fat may be present or entirely absent
  
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  Deranged iron processing leads to a modest accumulation of hemosiderin in hepatocytes and Kupffer cells
  

Alcoholic Hepatitis

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  cluster of neutrophils marks the site Mallory Body
  

of a necrotic hepatocyte

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  Eosinophilic Mallory body (arrow)
  

Alcoholic Cirrhosis

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  Final and irreversible form of alcoholic liver disease
  
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  Usually evolves slowly and insidiously
  

GROSS:

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  Initially cirrhotic liver is yellow-tan, fatty, enlarged, usually weighing > 2 kg
  
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  Over the span of years, transformed into a brown, shrunken, nonfatty organ, sometimes < 1 kg in wt
  

MICROSCOPIC:

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  Cirrhosis may develop within 1 to 2 years in the setting of alcoholic hepatitis
  
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  Initially developing fibrous septae are delicate
  
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  Regenerative activity of the entrapped parenchymal acini generates “micronodules”
  
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  With time, the nodularity becomes more prominent; scattered nodules may become quite large, and occasionally nodules > 2 cm in diameter may develop – “macronodules”
  
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  As fibrous septae dissect and surround nodules, the liver becomes more fibrotic, loses fat, and shrinks progressively in size.
  
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  Parenchymal islands are engulfed by ever wider bands of fibrous tissue, and the liver is converted into a mixed micronodular and macronodular pattern
  

Alcoholic Cirrhosis - Micro-nodular Cirrhosis

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  Micro- and macro-nodules entrapped in fibrous tissue
  
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  Fatty change also present
  

GROSS:

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  Further ischemic necrosis + fibrous obliteration of nodules > broad expanses of tough, pale scar tissue, leaving residual parenchymal nodules that protrude like “hobnails” from the surface of the liver - “Laennec’s cirrhosis”
  

MICROSCOPIC:

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  Septae contain scattered lymphocytes
  
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  Some reactive bile duct proliferation
  
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  Bile stasis often develops
  
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  Mallory bodies rarely evident at this stage.
  

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  Thus, end-stage alcoholic cirrhosis comes to resemble, both macroscopically and microscopically, postnecrotic cirrhosis.
  

Alcoholic Liver Disease

Clinical Course

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  Short-term ingestion of up to 80 gm of ethanol per day (8 beers or 7 ounces of 80 proof liquor) = mild, reversible hepatic changes, such as fatty liver.
  
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  Daily ingestion of >160 gm of ethanol for 10 - 20 years is associated more consistently with severe injury
  
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  Chronic intake of 80 – 160 gm/day = borderline risk for severe injury
  
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  Only 10 to 15% of alcoholics, however, develop cirrhosis.
  
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  Susceptibility to alcoholic hepatic injury: Women > men
  

Hepatic steatosis :

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  Asymptomatic
  
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  May become evident as mild elevation of serum bilirubin and alkaline phosphatase
  
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  Severe hepatic compromise (e.g., malaise, anorexia, hepatic failure and death) is unusual
  
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  Alcohol withdrawal and the provision of an adequate diet are sufficient treatment.
  

Alcoholic hepatitis:

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  Tends to appear relatively acutely, usually following a bout of heavy drinking.
  
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  Asymptomatic to fulminant hepatic failure
  
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  Between these two extremes are the nonspecific symptoms
  
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  Malaise, anorexia, weight loss, upper abdominal discomfort, tender hepatomegaly
  
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  Hyperbilirubinemia, elevated alkaline phosphatase
  
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  Fever and neutrophilic leukocytosis frequently occur
  
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  Outlook - unpredictable
  
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  Each bout of hepatitis incurs about a 10 to 20% risk of death
  
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  Cirrhosis appears in 30% of patients within a few years if there are repeated bouts
  
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  With proper nutrition and total cessation of alcohol consumption, alcoholic hepatitis may slowly clear.
  
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  In some patients, however, the hepatitis persists despite abstinence and progresses to cirrhosis.
  

Alcoholic cirrhosis:

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  First signs of cirrhosis relate to complications of portal hypertension, sometimes as life-threatening variceal hemorrhage.
  
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  Alternatively- malaise, weakness, weight loss, and loss of appetite precede the appearance of jaundice, ascites, and peripheral edema (impaired albumin synthesis)
  
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  The stigmata of cirrhosis (e.g., grossly distended abdomen, wasted extremities, caput medusae) may be dramatically evident
  

Laboratory findings reflect the developing hepatic compromise

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  Elevated serum transaminase levels
  
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  Hyperbilirubinemia
  
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  Variable elevation of serum alkaline phosphatase
  
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  Hypoproteinemia
  
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  Anemia.
  
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  In some instances, liver biopsy may be indicated because in ~ 10 to 20% of cases of presumed alcoholic cirrhosis, another disease process is found on biopsy
  

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  In the end-stage alcoholic, the immediate causes of death are :
  

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  Hepatic coma
  
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  Massive gastrointestinal variceal hemorrhage
  
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  Intercurrent infection (to which these patients are predisposed)
  
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  Hepatorenal syndrome following a bout of alcoholic hepatitis
  

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  In ~ 3 to 6% of cases, death is related to the development of hepatocellular carcinoma
  

Non-Alcoholic Steato-Hepatitis

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  Occurs in patients who do not drink alcohol
  
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  Non-specific symptoms of fatigue and malaise
  
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  Risk factors
  

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  Obesity - most important
  
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  Diabetes mellitus – Type II
  
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  Hypertriglyceridemia
  

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  Chief risk – development of cirrhosis
  

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  Microscopically:
  

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  Sinusoidal fibrosis
  
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  Mallory hyaline
  
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  Steatosis
  

Inborn Errors of Metabolism and Pediatric Liver Disease

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  Hemochromatosis
  
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  Wilson’s Disease
  
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  Alpha-1-Antitrypsin Deficiency
  
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  Reye’s Syndrome
  
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  Neonatal Hepatitis
  

Table: exam: q’s

Hereditary hemochromatosis

African iron overload (Bantu siderosis)
Hemochromatosis

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  Definition: Excessive accumulation of body iron, most of which is deposited in the parenchymal cells of various organs, particularly liver and pancreas.
  
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  Primary or idiopathic hemochromatosis:
  
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  Also known as Hereditary Hemochromatosis (HHC)
  
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  Is a homozygous recessive heritable disorder.
  
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  Secondary hemochromatosis: Disorders in which the source of excess iron can be defined
  
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  In normal adults ~ 0.5 gm iron stored in liver, 98% of which is in hepatocytes.
  
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  Hemochromatosis gene is located on the short arm of chromosome 6, close to the HLA gene locus
  
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  Associated HLA haplotypes include A3 in 70% of patients (versus 25% in the normal population) and, to a lesser extent, B7, B14, or Bw35
  
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  Total iron accumulation may exceed 50 gm
  
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  Males predominate (5 to 7:1)
  
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  Symptoms first appear in the fifth to sixth decades of life.
  
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  Clinically fully developed cases exhibit the following features:
  

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  Micronodular cirrhosis–most patients
  
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  Diabetes mellitus–75 to 80%
  
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  Skin pigmentation–75 to 80% of cases.
  

Pathogenesis

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  Symptoms typically develop after 20 gm of storage iron have accumulated.
  
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  Fundamental disease mechanism appears to be direct iron toxicity to host tissues, mediated by the following proposed mechanisms:
  

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  Lipid peroxidation via iron-catalyzed free radical reactions
  
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  Iron stimulation of collagen formation
  
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  Direct interactions of iron with DNA, leading to lethal alterations or predisposing to hepatocellular carcinoma.
  

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  Whatever the actions of iron, it is reversible in cells not fatally injured, and removal of excess iron during therapy promotes recovery of tissue function.
  
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  Iron accumulates as ferritin and hemosiderin in the parenchymal tissues of the body
  
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  Liver
  
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  Pancreas
  
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  Myocardium
  
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  Endocrine glands
  

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  Linings of joints
  
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  No significant deposition in the bone marrow
  

LIVER:

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  Iron appears as golden-yellow hemosiderin granules in the cytoplasm of periportal hepatocytes
  
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  Grossly, liver appears slightly larger than normal, dense, and chocolate brown.
  
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  Microscopically, fibrous septa develop slowly, leading ultimately to a micro-nodular pattern of cirrhosis.
  

PANCREAS:

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  Becomes intensely pigmented,
  
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  Has diffuse interstitial fibrosis
  
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  May exhibit some parenchymal atrophy
  
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  Hemosiderin is deposited in the acinar and the islet cells
  
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  Intensity of iron staining in the pancreatic islets correlates somewhat with the occurrence and severity of the diabetes
  

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  Dark brown color of the liver, pancreas and lymph node
  

Hemosiderin deposition Dark brown deposits of hemosiderin in

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  Fibrous bands – cirrhosis hepatocytes and Kupffer cells
  

HEART:

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  Often enlarged
  
• 
  Hemosiderin granules deposited within the myocardial fibers, inducing a striking brown coloration to the myocardium.
  

SKIN:

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  Usually has increased pigmentation, mainly owing to increased epithelial melanin (seen also with other forms of cirrhosis).
  
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  A distinctive, metallic, slate-gray pigmentation is related to accumulation of hemosiderin in dermal macrophages and fibroblasts.
  

JOINTS:

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  Deposition in joint synovial linings, acute synovitis may develop.
  
• 
  Excessive deposition of calcium pyrophosphate damages the articular cartilage, producing disabling arthritis referred to as pseudogout.
  

TESTES: May be small and atrophic but are not usually significantly pigmented
Clinical Features

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  Hepatomegaly
  
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  Abdominal pain
  
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  Skin pigmentation (particularly in sun-exposed areas)
  
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  Diabetes mellitus. Also called as ‘Bronzed Diabetes’
  
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  Cardiac dysfunction (arrhythmias, cardiomyopathy)
  
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  Atypical arthritis.
  
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  In some patients, the presenting complaint is hypogonadism, for example, amenorrhea in the female and loss of libido and impotence in the male.
  
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  Death may result from cirrhosis or cardiac disease.
  
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  The most common cause of death in established HHC is hepatocellular carcinoma, for which the risk is 200-fold greater than the general population.
  
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  Screening for HHC is accomplished by measuring:
  

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  serum iron
  
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  Total iron binding capacity
  
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  Serum Ferritin levels
  
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  Liver biopsy if indicated.
  

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  Secondary causes of iron overload must be excluded
  

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  history of numerous blood transfusions
  
• 
  grossly excessive iron ingestion
  
• 
  dyserythropoietic syndromes.
  

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  Most important for identification of patients with asymptomatic HHC is screening of family members of probands, which includes HLA typing.
  
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  Treatment: Use of iron chelators
  

Wilson’s Disease

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  Autosomal recessive disorder of copper metabolism
  
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  Accumulation of toxic levels of copper in many tissues and organs, principally the liver, brain, and eye: “hepatolenticular degeneration.”
  
• 
  Genetic defect is on chromosome 13, in linkage with the esterase D locus.
  

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  Initial steps of copper absorption and transport to the liver are normal.
  
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  Absorbed copper, however, fails to enter the circulation in the form of ceruloplasmin, and biliary excretion of copper is markedly diminished.
  
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  Copper thus accumulates progressively in the liver, in excess of the metallothionein-binding capacity causing toxic liver injury.
  
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  Usually by five years of age, nonceruloplasmin-bound copper spills over into the circulation, causing hemolysis and pathologic changes at other sites, such as brain, cornea, kidneys, bones, joints, and parathyroids.
  
• 
  Concomitantly, urinary excretion of copper becomes markedly increased.
  
• 
  Biochemical diagnosis of Wilson’s disease
  

• 
  Decrease in serum ceruloplasmin
  
• 
  Increase in hepatic copper content
  
• 
  Increased urinary excretion of copper
  

Morphology

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  Fatty change
  
• 
  Focal hepatocyte necrosis
  
• 
  With more severe disease,
  
• 
  Acute hepatitis or chronic hepatitis develops, both of which are similar in histologic appearance to viral hepatitis
  
• 
  With progression of chronic hepatitis, cirrhosis develops
  
• 
  A rare manifestation is massive hepatic necrosis.
  
• 
  Histologic changes are not pathognomonic because
  

• 
  Copper accumulates in chronic obstructive cholestasis
  
• 
  Histology cannot reliably distinguish Wilson’s disease from viral-induced and drug-induced hepatitis (and vice versa)
  

• 
  Most helpful is hepatic copper determination, which is characteristically in excess of 250 mg/gm dry weight.
  

Red-brown granular material seen is excessive lysosomal copper in hepatocytes

• 
  Neurologic changes constitute toxic injury to neurons, most marked in the basal ganglia, particularly the putamen, sometimes leading to grossly visible cavitations.
  
• 
  Kayser-Fleischer rings appear in the cornea in almost all patients with neurologic involvement.
  

• 
  Green-to-brown deposits of copper in Desçemet’s membrane (close to the limbus of the cornea)
  
• 
  Are characteristic but not pathognomonic
  

• 
  May be found in other forms of chronic cholestasis
  

Clinical Features

• 
  Presents in childhood or adolescence
  
• 
  Usually with manifestations of liver disease
  

• 
  Jaundice
  
• 
  Hepatomegaly
  
• 
  In the absence of neurologic changes
  
• 
  Reverse is true in 40% of cases
  

• 
  Neurological manifestations:
  

• 
  Parkinson-like movement disorder
  
• 
  Psychiatric disturbance - behavioral disorders to frank psychosis
  

• 
  Ocular changes
  

Treatment:

• 
  Long-term use of copper chelators (e.g., penicillamine)
  
• 
  Liver transplantation - fulminant hepatitis and unmanageable cirrhosis