Liver (1)

Diseases of the Liver Fe A. Bartolome, M.D. FPASMAP Department of Pathology

Functions of the Liver
processing of dietary amino acids, carbohydrates, lipids and vitamins
removal of microbes and toxins in splanchnic blood
synthesis of plasma proteins
detoxification and excretion into bile of endogenous waste products & pollutant xenobiotics

Patterns of Hepatic Injury Degeneration & Intracellular Accumulation
Degeneration
mild to moderate  hepatocyte swelling  reversible
severe damage  ballooning degeneration  irregularly clumped organelles and large clear spaces
Accumulations in Viable Hepatocytes
iron and copper
triglyceride fat deposits  STEATOSIS
microvesicular – multiple, tiny (e.g. acute fatty liver of pregnancy, alcoholic fatty liver
macrovesicular – single large deposit displacing the nucleus (e.g. obesity, diabetes, alcoholism)

Macrovesicular steatosis Iron stain using the Prussian Blue Reaction (x400). Hemosiderin granules stain as dark blue, coarse granules.

Patterns of Hepatic Injury Necrosis and Apoptosis
Types:
Ischemic coagulative necrosis – “mummified” liver cells with lysed nuclei
Apoptotic cell death – shrunken, pyknotic & intensely eosinophilic cells with fragmented nuclei
Lytic necrosis – outcome of ballooning degeneration  (+) shards of cellular debris
Liquefactive necrosis - abscesses

Necrosis (left lower) is around the centrilobular area. The periportal area is viable.

Ischemia of centrilobular area resulting in coagulative necrosis of hepatic cords. (Preservation of cellular contour with disappearance of nucleus) Some viable hepatocytes with nucleus are seen in the upper middle and upper right areas.

Bridging confluent lytic necrosis in severe chronic viral hepatitis B. Inflamed portal tract ‘bridged’ through area of necrosis with centrilobular area (lower left). The upper right part corresponds to an area of extensive lytic necrosis.

Patterns of Hepatic Injury Necrosis and Apoptosis
Distribution:
Centrilobular – most common; immediately around terminal hepatic vein
Mid-zonal and periportal – rare
Degree of involvement:
Focal or spotty – limited to scattered cells within hepatic lobules
Interface hepatitis – between periportal parenchyma & inflamed portal tracts
Bridging necrosis – span adjacent lobules
Submassive necrosis – entire lobules
Massive – most of the liver

Interface hepatitis

Patterns of Hepatic Injury Inflammation
Hepatitis
Influx of acute and chronic inflammatory cells
Regeneration
Occurs in all but the most fulminant hepatic diseases
Features:
Mitosis
Thickening of hepatic cords
Disorganization of parenchymal structure

Patterns of Hepatic Injury Fibrosis
Consequence of inflammation or direct toxic insult to liver
Irreversible
May eventually subdivide liver into nodules of proliferating hepatocytes surrounded by scar tissue  CIRRHOSIS

Hepatic Failure
Most severe clinical consequence of liver disease
May be:
result of sudden and massive hepatic destruction
end-point of progressive chronic liver disease
80% - 90% loss of hepatic functional capacity

Hepatic Failure
Morphologic alterations causing liver failure:
Massive hepatic necrosis
Mechanisms:
(i) direct damage to hepatocytes
(ii) immune-mediated hepatocyte destruction
a. drug or toxin-induced
b. infection – viral hepatitis except hep. C
Chronic liver disease – most common cause
Hepatic dysfunction without over necrosis – e.g. Reye’s syndrome, tetracycline toxicity, acute fatty liver of pregnancy

Hepatic Failure
Clinical Features:
Jaundice
Hypoalbuminemia  peripheral edema
Hyperammonemia  cerebral dysfunction
Fetor hepaticus  “musty” or “sweet & sour” body odor due to mercaptan formation by action of GI bacteria on methionine (sulfur-containing)
Impaired estrogen metabolism  hyperestrogenemia
(a) palmar erythema – 2 o to local vasodilatation
(b) spider angiomas – central, pulsing, dilated arteriole from which small vessels radiate
(c) hypogonadism & gynecomastia in males

Hepatic Failure
Clinical Features:
Multi-organ system failure
respiratory failure with pneumonia, sepsis + renal failure  cause of death
Coagulopathy
impaired synthesis of factors II, VII, IX and X  (+) bleeding tendency

Hepatic Failure
Complications:
Hepatic encephalopathy
associated with increased blood ammonia levels
reversible if underlying hepatic condition can be corrected
features:
(a) change in consciousness
(b) fluctuating neurologic signs – rigidity, hyperreflexia, asterixis

Hepatic Failure
Complications:
Hepatorenal syndrome
renal failure in patients with chronic liver disease
main renal functional abnormalities:
(a) sodium retention
(b) impaired free water excretion
(c) decreased renal perfusion
(d) decreased GFR

Hepatic Failure
Complications:
Hepatorenal syndrome
decreased urine output with rising BUN & creatinine
ability to concentrate urine retained  hyperosmolar urine without proteins; abnormal sediments; dec. Na +

Cirrhosis
Most common cause is alcoholic liver disease
Key features:
The parenchymal injury & consequent fibrosis are diffuse .
The nodularity is part of the diagnosis  reflects balance between regeneration and scarring.
Vascular architecture is re-organized by the parenchymal damage and scarring  formation of abnormal interconnections

Pathogenesis:
Progressive fibrosis & re-organization of vascular micro-architecture of liver
Collagen deposition (types I & III) in the lobule Loss of fenestration of sinusoidal endothelial cells New vascular channels in the septae Create delicate or broad septal tracts Impaired hepatocellular protein secretion (albumin, clotting factors, lipoproteins) Shunting of blood around the parenchyma

Main characteristics
Bridging fibrous septae
link portal tracts with one another & portal tracts with terminal hepatic vein
Parenchymal nodules
contain proliferating hepatocytes encircled by fibrosis
micronodules - < 3 mm diameter
macronodules - > 3 mm to several cm
Disruption of architecture of entire liver

Complications associated with cirrhosis:
Hepatic failure
Multiple coagulation defects
Hypoalbuminemia due to decreased albumin synthesis  pitting edema and ascites
Increased serum ammonia due to defective urea cycle

Portal hypertension
Ascites
Congestive splenomegaly
Esophageal varices
Hemorrhoids, periumbilical collateral circulation

Cirrhosis
Hepatorenal syndrome due to decreased renal blood flow
Hyperestrinism in males
Gynecomastia
Spider angiomas
Female distribution of hair

Criteria for Diagnosis: liver biopsy or at least three of the following:
Hyperglobulinemia, esp. with hypoalbuminemia
Low protein (<2.5 g/dL) ascites
Evidence of hypersplenism (usu. Thrombocytopenia, often with leukopenia)
Evidence of portal hypertension (e.g. varices)
Characteristic “corkscrew” hepatic arterioles on celiac arteriography
Shunting of blood

Bridging fibrous septae Nodules

Alcoholic Liver Disease
Hepatic Steatosis
Alcoholic fatty liver
Moderate alcohol intake  microvesicular
Chronic alcohol intake  macrovesicular
Enlarged, soft, yellow, greasy liver
Completely reversible

Alcoholic Hepatitis
Characteristics:
Hepatocyte swelling & necrosis  ballooning due to accumulation of fat, water & proteins
Mallory bodies – eosinophilic cytoplasmic inclusions in degenerating hepatocytes
Neutrophilic reaction – accumulate around degenerating hepatocytes (“satellitosis”)
Fibrosis – (+) activation of sinusoidal stellate cells & portal tract fibroblasts

Histological features of alcoholic hepatitis. (A) Low- power view demonstrating the cardinal features of steatosis, fibrosis, inflammation, and hepatocellular injury.

Histological features of alcoholic hepatitis. (B) (Black arrows) Mallory bodies are irregular eosinophilic cytoplasmic structures with a rope-like appearance. (Open arrow) Ballooning degeneration of hepatocytes.

Histological features of alcoholic hepatitis. (c) (Open arrow) Pericellular fibrosis, also termed 'chicken-wire' fibrosis surrounds individual degenerate hepatocytes; (Black arrow) Perivenular fibrosis extends from the central vein.

Histological features of alcoholic hepatitis. (d) The unit lesion (also termed satellitosis) comprises a degenerating hepatocyte with (arrow) a surrounding cuff of neutrophils. Marked steatosis is also evident.

Alcoholic cirrhosis
Final, irreversible; 10 – 15% of alcoholics
Micronodular with scattered larger nodules  “ hobnail ” appearance of liver surface
Broad expanses of tough, pale scar tissue due to ischemic necrosis & fibrous obliteration of nodules  Laennec cirrhosis

Short-term ingestion of up to 80 gm of alcohol (~8 beers) over one to several days  FATTY LIVER
Daily intake of 160 gms or more for 10-20 years  SEVERE INJURY

Alcohol Effects
Alcohol through action of alcohol DH & acetaldehyde DH  excess NADH + H +  increased lipid biosynthesis
Impaired assembly & secretion of lipoproteins + increased peripheral fat catabolism  fatty liver
Impaired hepatic methionine catabolism  dec. intrahepatic glutathione (GSH) levels  inc. sensitivity to oxidative injury

Alcohol Effects
Induction of cytochrome P 450
(a) CYP2E1  inc. alcohol catabolism in ER & inc. conversion of other drugs to toxic metabolites
(b) production of reactive O 2 species  damage membrane  hepatocellular dysfunction
Impaired microtubular and mitochondrial function
Alcohol  acetaldehyde  (+) lipid peroxidation  disrupt cytoskeletal and membrane function

Alcohol Effects
Become a major caloric source  displace other nutrients  (+) malnutrition and vitamin deficiencies
Lead to chronic gastritis, intestinal mucosal damage and pancreatitis  impaired digestive function
Induce release of bacterial endotoxin into portal circulation from gut  (+) liver inflammation
Induce release of endothelins from sinusoidal endothelial cells  (+) vasoconstriction & contraction of stellate cells  dec. hepatic sinusoidal perfusion  regional hypoxia

Gynecomastia due to alcoholic cirrhosis A 32 year old male patient with normal secondary sex characteristics, no testicular mass, no hystory of drug ingestion, no other endocrine abnormalities and a normal neurological examination. Nevertheless, he had a history of more than 15 years of large amounts of alcohol intake and a liver biopsy confirm alcoholic cirrhosis (Laennec's Cirrhosis).

Cause of death:
Hepatic coma
Massive gastrointestinal hemorrhage
Intercurrent infection
Hepatorenal syndrome following alcoholic hepatitis
Hepatocellular carcinoma

Portal Hypertension
Causes:
A. Pre-hepatic
Obstructive thrombosis
Narrowing of portal vein prior to ramification within the liver
B. Intrahepatic
Cirrhosis – most common
Schistosomiasis
Massive fatty change
Diffuse fibrosing granulomatous disease (TB)
Diseases affecting portal microcirculation

Portal Hypertension
Causes:
C. Post-hepatic
Severe right-sided heart failure
Constrictive pericarditis
Hepatic vein outflow obstruction

Portal Hypertension
Clinical consequences:
Ascites
collection of fluid in peritoneal cavity
clinically detectable: at least 500 ml.
contents: < 3 gm/dL of protein (albumin), glucose, Na + , K + , mesothelial cells, mononuclear wbc

Portal Hypertension
Ascites
Pathogenesis:
Sinusoidal HPN  drive fluid into space of Disse  removed by lymphatics
Percolation of hepatic lymph into peritoneal cavity  hepatic lymph flow in cirrhosis = 20 L/day
Intestinal fluid leakage
Renal retention of Na + & H 2 O due to 2 O hyperaldosteronism  activation of RAAS

Portal Hypertension
Porto-systemic Shunts
Inc. portal system pressure Development of by-passes Systemic & portal circulation share common capillary beds Veins around & within rectum Cardio-esophageal junction Periumbilical & abdominal wall hemorrhoids Esophageal varices Caput medusae

Photograph shows a caput medusae accentuated by a large amount of ascites in a patient being prepared for liver transplantation. An extensive plexus of veins is seen emanating from the umbilical region and radiating across the anterior abdominal wall.

Portal Hypertension
Splenomegaly
secondary to long-standing congestion
lead to hypersplenism

Jaundice and Cholestasis JAUNDICE
retention of bilirubin
functions of bile:
Emulsification of fat
Elimination of systemic waste products
Rate of bilirubin production = rate of hepatic uptake, conjugation and biliary excretion

Crigler-Najjar Syndrome
Hereditary glucuronyl transferase deficiency
Rare familial autosomal recessive disease
Due to marked deficiency (type II) or absence (type I) of glucuronyl transferase
Type I should always be ruled out when persistent unconjugated bilirubin levels of 20 mg/dL are seen after 1 week of age without obvious hemolysis and especially after breast-milk jaundice has been ruled out.

Gilbert’s Disease
Chronic, benign, intermittent, familial (AD), non-hemolytic unconjugated hyperbilirubinemia with evanescent increases of B1
Due to defective transport and conjugation of B1
Jaundice accentuated by pregnancy, fever, exercise, and various drugs including alcohol and birth control pills

Dubin-Johnson Syndrome
Sprinz-Nelson Syndrome
Due to defective transport of bilirubin-glucuronide through hepatocytes into canaliculi
Characterized by mild, recurrent jaundice
Hepatomegaly and RUQ pain may be present
Jaundice may be produced by estrogens, birth control pills, or last trimester of pregnancy
May resemble mild viral hepatitis

Differential Diagnosis of Hereditary Jaundice with Normal Liver Chemistries & No Signs or Symptoms of Liver Disease Unconjugated Hyperbilirubinemia Crigler-Najjar Syndrome Gilbert’s Type I Type II Incidence Inheritance mode Serum bilirubin usual total (mg/dL) Defect Age at onset of jaundice <7% of pop’n Very rare Uncommon AD AR AD <3; < 6 >20 <20 Mostly B1; inc. All indirect All indirect with fasting Hepatic UDP-glucuronyl transferase activity Decreased Absent Marked dec. Adolescence Infancy Childhood, adolescence

Differential Diagnosis of Hereditary Jaundice with Normal Liver Chemistries & No Signs or Symptoms of Liver Disease Unconjugated Hyperbilirubinemia Crigler-Najjar Syndrome Gilbert’s Type I Type II Usual clinical features Liver biopsy Treatment Appear in early Jaundice, Asymptomatic adulthood; kernicterus in jaundice, often 1 st re- infants, kernicterus cognized w/ young adults rare fasting Normal Normal Normal Not needed Liver transplant Phenobarbital

Differential Diagnosis of Hereditary Jaundice with Normal Liver Chemistries & No Signs or Symptoms of Liver Disease Conjugated Hyperbilirubinemia Dubin-Johnson Rotor’s Syndrome Incidence Inheritance mode Serum bilirubin usual total (mg/dL) Defect Urine total coproporphyrin Age at onset of jaundice Usual clinical features Oral cholecystogram Liver biopsy Treatment Uncommon AR 2-7; < 25 Direct ~ 60% Impaired biliary excretion Normal Childhood, adolescence Asymptomatic jaundice in young adults GB not visualized Charac. pigment Not needed Rare AR 2-7; < 20 Direct ~ 60% Impaired biliary excretion Increased Adolescence, early adulthood Asymptomatic jaundice Normal No pigment None

Comparison of Jaundice (Cholestatic & Hepatocelllular) *Serum bilirubin > 10 mg/dL is rarely seen with CBD stone and usually indicates carcinoma. Hepatocellular Cholestasis Infiltration Disease example Acute viral hep. CBD stone Metastatic tumor Serum bilirubin (mg/dL) 4 – 8 6 – 20* Usually <4, often normal AST, ALT (U/mL) Markedly inc., often 500-1,000 May be sl. Inc., < 200 May be slightly inc., < 100 Serum ALP 1-2x normal 3-5x normal 2-4x normal PT Inc. in severe disease Inc. in chronic cases Normal Response to parenteral vit. K No Yes

Liver Function Tests: Normal Values & Changes Tests Normal Values Hepatocellular Jaundice Uncomplicated Obstructive Jaundice Bilirubin Direct Indirect 0.1-0.3 mg/dL 0.2-0.7 mg/dL Increased Increased Increased Increased Urine bilirubin None Increased Increased Serum albumin/ total protein Alb, 3.5-5.5 g/dL Tot, 6.5-8.4 g/dL Albumin decreased Unchanged Alk phos 30-115 IU/L Increased (+) Increased (++++) Prothrombin time INR of 1.0-1.4; 10% inc. after vit K in 24 hrs No response to parenteral vit. K; prolonged Prolonged but responds to parenteral vit. K ALT, AST ALT: 5-35 IU/L AST: 5-40 IU/L Inc. in hepatocellular damage, viral hepatitis Minimally increased

Cholestasis
retention of bilirubin and other solutes eliminated in bile
Causes:
Hepatocellular dysfunction
Intrahepatic
Blockage of intrahepatic bile ducts
Drugs (oral contraceptives, anabolic steroids)
Extrahepatic
Blockage of CBD
Gallstone, primary sclerosing cholangitis, extrahepatic biliary atresia, CA of head of pancreas

Cholestasis
Extrahepatic Biliary Atresia
Cause of jaundice in the newborn
Inflammatory destruction of all or part of the extrahepatic bile ducts
Bile duct proliferation in the triads
Common indication for liver transplantation in a child

Cholestasis
Primary Sclerosing Pericholangitis
Obliterative fibrosis of intrahepatic and extrahepatic bile ducts
Male dominant
Associated with ulcerative colitis
Jaundice, cirrhosis + increased incidence of cholangiocarcinoma

“ Onion-skinning” around bile duct

Cholestasis
Features:
Jaundice with pruritus – deposition of bile acids and bile salts in skin
Malabsorption – bile salts do not enter S.I.
Skin xanthomas – due to hyperlipidemia & impaired excretion of cholesterol
Inc. serum alk. phos. – released due to detergent action of retained bile salts on hepatocyte membrane
Deficiency of fat soluble vitamins (A, D or K)

Skin xanthomas

Cholestasis
Morphology:
Accumulation of bile pigment within the hepatic parenchyma  distention of bile ducts and ductules
Bile stasis  induce proliferation of duct epithelial cells  ductal proliferation
Portal tract edema & periductal neutrophilic infiltrates
Prolonged cholestasis  focal detergent dissolution of hepatocytes  bile lakes with cellular debris & pigments
Portal tract fibrosis

Infectious Disorders
Viral hepatitis
Miliary tuberculosis
Malaria
Staphylococcal bacteremia  2 0 to TSS
Salmonellosis  typhoid fever
Candida
Parasitic & helminthic infection

Viral Hepatitis
Hepatotropic viruses
Hepatitis viruses
Epstein-Barr virus
Cytomegalovirus
Yellow fever
Children & immunocompromised  rubella, adenovirus, herpesvirus, enterovirus, CMV

Hepatitis Viruses
Small, non-enveloped, ssRNA
Picornavirus genus Hepatovirus
Serology:
Hepatitis A

Hepadnaviridae
present in all physiologic and pathologic body fluids  blood & body fluids the primary vehicle for transmission
Incubation period: 4 – 26 weeks
MOT:
Transfusion
Blood products
Dialysis
Needle stick accidents among health care workers
IV drug abuse
Sexual contact
Vertical transmission – lead to carrier state for life
Hepatitis B

Protein sequences encoded by HBV genome
HBcAg – nucleocapsid “core” protein; remains in hepatocytes for assembly of complete virion
HBeAg – secreted into blood
HBsAg – envelope glycoprotein
DNA polymerase – with reverse transcriptase activity
HBx protein – necessary for virus replication  acts as transcriptional activator of viral genes; play a role in development of HCC in HBV-infected patients
Hepatitis B

Spectrum of illness
Acute infection with resolution
Chronic hepatitis  cirrhosis  HCC or carrier
Fulminant hepatitis with massive liver necrosis
Backdrop of hepatitis D infection
Hepatitis B

Carrier state – (+) HBsAg in serum for 6 months or longer after initial detection
Serology:
Hepatitis B

Hepatitis B: Common Serologic Patterns HBsAg HBsAb HBeAg HBeAb HBcAb (TOTAL) HBcAb-IgM Interpretation + -- -- -- -- -- Late incubation or early acute HBV + -- + -- -- -- Early acute HBV; highly infectious + -- + -- + + Acute HBV -- -- -- -- + + Serologic window -- -- -- + + + Convalescence + -- + + + -- Chronic infection (chronic carrier) -- + -- -- -- -- Old previous HBV with recovery and immunity OR vaccination OR passive transfer of antibody

Hepatitis B: Serologic Tests of Candidate for HBV Vaccine Test HBsAg HBsAb HBcAb Interpretation Follow-up + -- -- Acute HBV infection Repeat serology for resolution or chronicity -- -- + Acute HBV or carrier Previous HBV infection; vaccinate -- + + Immune; previous HBV infection or vaccination None + -- + Previous HBV infection; may not be immune Vaccinate -- -- -- Not immune Vaccinate

Most common chronic blood-borne infection  accounts for 50% of all patients with chronic liver disease in the US
Flaviviridae family, genus Hepacivirus
HCV RNA polymerase with poor fidelity  inherently unstable  (+) genomic instability & antigenic variability within one individual  evade IFN-mediated anti-viral response  repeated bouts of hepatic damage
Hepatitis C

Persistent infection and chronic hepatitis are the hallmarks of HCV infection
MOT: 1. inoculations
2. blood transfusions
3. hemodialysis
4. sexual transmission
5. perinatal
Hepatitis C

Hepatitis C
potential outcomes:
Stable cirrhosis Death

Hepatitis C
serology:

Hepatitis D
hepatitis delta virus
replication defective  cause infection only when encapsulated by HBsAg
co-infection vs. superinfection

Hepatitis D

Comparison of Types of HDV Infections Coinfection Superinfection HBV infection Acute Chronic HDV infection Acute Acute to chronic Chronicity rate < 5% > 75% Serology HBsAg HBcAb-IgM Anti-HDV-total Anti-HDV-IgM HDAg + + Negative or low Transient + Transient + Usu. persistent Negative + Transient Usu. persistent Liver HDAg Transient + Usu. persistent

Hepatitis G
Flavivirus similar to HCV
MOT:
Contaminated blood or blood products
Sexual contact
75% cleared from plasma; 25% chronic
Site of replication: mononuclear cells  not hepatotropic  no increase in serum transaminases
No pathologic effect
Commonly co-infects patients with HIV  protects against HIV disease

Hepatitis
Clinicopathologic Syndromes:
Acute asymptomatic infection with recovery
Minimal serum transaminase elevation
Common in HCV-infected patients
Acute symptomatic infection with recovery
4 phases:
(a) Incubation period
(b) Pre-icteric phase – non-specific S/Sx
(c) Icteric phase – conjugated hyperbilirubinemia
(d) Convalescence

Hepatitis
Chronic hepatitis
Asymptomatic, biochemical or serologic evidence of continuing or relapsing hepatic disease for more than 6 months, with histologically documented inflammation and necrosis

Hepatitis
Fulminant hepatic failure
Hepatic insufficiency progresses from onset of symptoms to hepatic encephalopathy within 2 – 3 wks
Extrahepatic complications
(a) coagulopathy & bleeding
(b) cardiac instability
(c) renal failure
(d) ARDS
(e) electrolyte & acid imbalance
(f) sepsis

Hepatitis
Morphology:
Acute Hepatitis
Ballooning degeneration  ground- glass hepatocytes
Periportal necrosis with inflammatory infiltrates
Lobular disarray
2 patterns of hepatocyte death:
cytolysis 2 0 to rupture of cell membrane
apoptosis due to anti-viral cytotoxic T cells
severe acute hepatitis  (+) bridging necrosis

Also known as acidophilic bodies, apoptotic bodies, or Councilman bodies (arrows), these intensely eosinophilic dead hepatocytes are engulfed by Kupffer cells and digested.

Hepatitis
Morphology:
Chronic Hepatitis
periportal lymphoid aggregates
Periportal necrosis & fibrosis
Bridging necrosis & fibrosis
Hallmark of irreversible liver damage is deposition of fibrous tissue

Metabolic Disorders
Non-alcoholic Fatty Liver Disease
(NAFL)
Occurs in patients who are not heavy drinkers
Strong association with obesity, dyslipidemia and insulin resistance, and overt type 2 DM
Presents only with elevated serum aminotransferases and/or GGT
(+) accumulation of triglycerides within hepatocytes
Progress to non-alcoholic steatohepatitis (NASH)  CIRRHOSIS

Metabolic Disorders
Hemochromatosis
Excessive accumulation of body iron  deposit in parenchymal organs (e.g. liver and pancreas)
May be secondary to a genetic defect (increased absorption) OR a consequence of parenteral administration of iron
Over 1/3 of iron accumulated stored in the liver
Increased risk of hepatocellular carcinoma

Metabolic Disorders
Hemochromatosis
Hereditary hemochromatosis
Mutations involving hereditary hemochromatosis gene HFE
Unrestricted re-absorption of iron in the small intestines
Secondary or acquired  hemosiderosis
Causes: multiple blood transfusions, alcohol abuse

Metabolic Disorders
Hemochromatosis
Features:
Fully developed cases with micronodular cirrhosis (all patients), type I DM, and skin pigmentation
Destruction of exocrine pancreas  malabsorption
Males predominate due to delayed iron accumulation in women

Metabolic Disorders
Hemochromatosis
Morphology:
Hemosiderin deposition in liver, pancreas, myocardium, pituitary gland, adrenal gland, thyroid & parathyroid glands, joints, and skin  stain with Prussian blue
Liver cirrhosis
Pancreatic fibrosis

Metabolic Disorders
Hemochromatosis
Classic clinical triad:
Pigment cirrhosis with hepatomegaly
Skin pigmentation – increased melanin production
Diabetes mellitus – destruction of β -islet cells
Death due to cirrhosis or cardiac disease
Risk for development of hepatocellular CA 200-fold greater

Metabolic Disorders
Wilson’s Disease (Hepatolenticular degeneration)
Copper accumulation particularly in liver, brain, and eye (demonstrated by rhodamine stain for copper)
Due to mutation of Wilson’s disease gene ( ATP7B ) on chr. 13  decreased synthesis of ceruloplasmin  defective biliary excretion of copper

Metabolic Disorders
Wilson’s Disease
Morphology:
Fatty change  acute hepatitis  chronic hepatitis  cirrhosis
Massive liver necrosis a rare manifestation
Brain – atrophy or cavitation of basal ganglia, particularly in putamen (movement disorder)
Eye lesions – Kayser-Fleischer rings in Descemet’s membrane

Metabolic Disorders
Wilson’s Disease
Diagnosis:
Decreased serum ceruloplasmin
Increased hepatic copper content (>250 ug/gram dry weight)
Increased urinary copper excretion
Treatment: copper chelation therapy with D-penicillamine

Metabolic Disorders
Α 1-Antitrypsin deficiency
Autosomal dominant  normal genotype is PiMM  most common abnormal allele is Z
PiZZ variant with decreased AAT in serum  cause liver damage
Mutant protein cannot be secreted into blood

Metabolic Disorders
Α 1-Antitrypsin deficiency
Clinical Findings:
Children
Neonatal hepatitis with intrahepatic cholestasis
Most common cause of cirrhosis in children
Increased risk for hepatocellular carcinoma
Young adults with panacinar emphysema

Circulatory Disorders
Pre-hepatic Obstruction to Blood Flow
Obstruction of blood flow to the liver (i.e., hepatic artery and portal vein)
Hepatic artery thrombosis with infarction
Causes: liver transplant rejection or vasculitis due to polyarteritis nodosa
Portal vein thrombosis
Causes: pylephlebitis (inflammation of portal vein, usually due to acute AP), polycythemia vera, hepatocellular CA (invasion of portal vein)

Intrahepatic Obstruction to Blood Flow
Obstruction to sinusoidal blood flow
Causes:
cirrhosis
centrilobular hemorrhagic necrosis
peliosis hepatis
sickle cell disease

Centrilobular hemorrhagic necrosis
Most often due to left-sided HF and right-sided HF
LHF  decreased cardiac output  hypoperfusion of liver  ischemic necrosis of hepatocytes around central vein
RHF  back-up of systemic venous blood into central veins and sinusoids

Centrilobular hemorrhagic necrosis
Enlarged liver with mottled red appearance (“nutmeg” liver)  congestion of central veins and sinusoids)

Peliosis hepatis
Sinusoidal dilatation due to blood
Causes: anabolic steroids; Bartonella henselae

Post-hepatic Obstruction to Blood Flow
Obstruction of blood flow out of the liver (e.g., hepatic vein)
Causes:
Hepatic vein thrombosis (Budd-Chiari syndrome)
Veno-occlusive disease

Budd-Chiari Syndrome
Thrombosis of the major hepatic vein causing extreme blood retention in the liver
Causes:
Polycythemia vera – most common
Oral contraceptive pills
Hepatocellular carcinoma invasion of hepatic vein

Budd-Chiari Syndrome
Clinical:
Enlarged, painful liver
Portal hypertension, ascites, splenomegaly
High mortality rate
Laboratory: increased transaminases, increased PT

Liver Abscess
common in developing countries
usually pyogenic  multiple, small abscesses ( E. coli, P. vulgaris, Enterobacter aerogenes, anaerobes )
parasitic – usually solitary  amebic & echinococcal

Liver Abscess
Reach liver via:
Portal vein
Arterial supply
Ascending infection in biliary tract  ascending cholangitis
Direct invasion from nearby source
Penetrating injury
Clinical: RUQ pain, fever, tender hepatomegaly

Liver Abscess
Abnormalities of liver function tests:
Dec. serum albumin (50%); inc. serum globulin
Inc. serum ALP (75%)
Inc. serum bilirubin (20-25%)  >10 mg/dL usually indicates pyogenic rather than amebic origin  poorer prognosis because of greater tissue destruction
Inc. wbc (70%)
Anemia (60%)
Laboratory findings due to complications: R pleural effusion (20%), subphrenic abscess, pneumonia, empyema, bronchopleural fistula

Amebic liver abscess Amebic liver abscess with perforation of abscess through abdominal wall

Pyogenic liver abscess

Drug & Toxin-Induced Hepatic Disease
Mechanism of injury:
Direct toxicity
Hepatic conversion of a xenobiotic to an actual toxin
Immune mechanisms  drug or metabolite acts as hapten
Types of injury:
Hepatocyte necrosis
Cholestasis
Insidious liver dysfunction
Reye syndrome – children given ASA; extensive accumulation of fat droplets within hepatocytes (microvesicular steatosis)

Reye syndrome
Usually in children < 4 years of age
Often follows a chickenpox or influenza infection
Mitochondrial damage (? virus, salicylates)
Disruption of urea cycle  increased serum ammonia
Defective beta-oxidation of fatty acids

Reye syndrome
Microvesicular steatosis (? Salicylate effect)
Clinical findings:
Encephalopathy
Hepatomegaly  liver failure
Laboratory findings:
Transaminasemia
Normal to slight inc. total bilirubin
Increased serum ammonia

Hepatic Disease Associated with Pregnancy
Pre-eclampsia
Hypertension, proteinuria, dependent pitting edema in the third trimester
HELLP syndrome  hemolytic anemia with schistocytes, elevated liver enzymes, low platelet (due to DIC)
Morphology:
fibrin deposition in periportal sinusoids
hemorrhage into space of Disse
periportal hepatocellular coagulative necrosis

Congested liver of HELLP syndrome

Acute fatty liver of pregnancy (AFLP)
sub-clinical hepatic dysfunction to hepatic failure, coma and death
Abnormality in beta-oxidation of fatty acids
3 rd trimester; with multiple metabolic defects
diagnosis depends on:
high index of suspicion
characteristic microvesicular steatosis demonstrated on frozen tissue sections OR with stain (oil red-O or Sudan black)
Treatment: termination of pregnancy

Acute fatty liver of pregnancy: lobular parenchyma characterized by microvesicular steatosis and a small number of lymphocytes. (H&E)

Intrahepatic cholestasis of pregnancy
Characteristics:
onset of pruritus in 3 rd trimester
darkening of urine with occ. light stools
jaundice – conjugated hyperbilirubinemia
Mechanism: altered hormonal state + biliary secretion defects  cholestasis
Increased incidence of fetal distress, stillbirth and prematurity

Nodules & Tumors Nodular Hyperplasia
non-cirrhotic liver nodules
types:
Focal nodular hyperplasia
spontaneous mass lesion; female preponderance
Morphology:
central stellate scar with large arterial vessels exhibiting fibromuscular hyperplasia  (+) narrowed lumen
Intense lymphocytic infiltration
bile duct proliferation

Focal Nodular Hyperplasia: Subcapsular solid mass with central scar, composed of the normal components of liver lobule

Central portion of nodular hyperplasia showing the interphase between the fibrous scar and the hepatocytic nodules.

Nodules & Tumors Nodular Hyperplasia
Nodular regenerative hyperplasia
(+) development of portal HPN
Associated with conditions affecting intrahepatic blood flow  renal transplant, BM transplant, vasculitic conditions
Morphology: plump hepatocytes surrounded by atrophic cells; no fibrosis

Nodular Regenerative Hyperplasia: non-cirrhotic non-neoplastic nodular transformation of the liver parenchyma.

Nodules & Tumors Benign Neoplasms
Cavernous hemangioma
Most common; blood vessel tumor
Soft nodules < 2 cm diameter immediately beneath the capsule
Clinical significance: mistaken for metastatic tumors  blind percutaneous biopsies not done

Cavernous Hemangioma Normal liver Hemangioma

Nodules & Tumors Benign Neoplasms
Liver cell adenomas
Cell of origin: hepatocytes
Young women on oral contraceptives  regress on discontinuance of use
Clinical significance:
Present as intrahepatic mass  mistaken for HCC
If subcapsular  (+) rupture  intraperitoneal hemorrhage
May harbor HCC – rare
Morphology: cords of hepatocytes with clear cytoplasm (w/ glycogen), absent portal tracts & prominent arterial vessels and draining veins

The hepatic adenoma is composed of cells that closely resemble normal hepatocytes with disorganized hepatocyte cords and does not contain a normal lobular architecture. At the upper right is a well-circumscribed neoplasm that is arising in liver. This is an hepatic adenoma. Normal liver Adenoma

Nodules & Tumors Malignant Tumors
Primary tumors uncommon  often involved in metastatic spread
Hepatoblastoma
rare; most common liver tumor of young children
fatal if not resected
(+) activation of Wnt/ β -catenin signaling pathway  stabilize mutations of β -catenin

Hepatoblastoma Hepatoblastoma found to be invading the inferior vena cava at the time of surgical exploration.

Nodules & Tumors Malignant Tumors
Angiosarcoma
rare; malignant endothelial neoplasm
associated with exposure to vinyl chloride, arsenic or Thorotrast
highly aggressive, metastatic, fatal

Angiosarcoma: Section of liver, showing multiple hemorrhagic tumor deposits.

Nodules & Tumors
Cholangiocarcinoma
malignancy of intrahepatic biliary tract
risk factors:
Primary sclerosing cholangitis
Congenital fibropolycystic diseases of biliary system
Previous exposure to Thorotrast
Chronic liver fluke infection (O. sinensis)
Morphology: resemble sclerosing adenocarcinoma  well-defined glandular & tubular structures separated by dense collagenous stroma

Intrahepatic cholangiocarcinomas are classified as either peripheral or hilar. The hilar variety are located in the hepatic hilum region and appear as discrete masses.

Peripheral cholangiocarcinoma is the most common and develops in the interlobular ducts of the liver, where the interlobular bile duct branches within the portal triads. They may be a single or multiple masses.

Nodules & Tumors
Hepatocellular Carcinoma
male preponderance; 20 – 40 y/o
Risk factors:
Viral infection – chronic HBV & HCV infection  no cirrhosis
Chronic alcoholism – (+) cirrhosis
Food contaminants – aflatoxin from Aspergillus flavus  bind covalently with cellular DNA  (+) p53 mutation
>85% occur in countries with high rates of chronic HBV and HCV infections

Morphology:
Gross
Unifocal large mass
Multifocal
Diffusely infiltrative

Morphology:
Microscopic:
Well differentiated  trabecular pattern or acinar, pseudoglandular pattern
Poorly differentiated  pleiomorphic with anaplastic giant cells
bile

Clinical features:
upper abdominal pain or fullness
malaise, fatigue, weight loss
hepatomegaly with irregularity or nodularity
Laboratory:
increased tumor markers – serum AFP and serum CEA  not conclusive  false (+) in non-neoplastic conditions (e.g. cirrhosis, chronic hepatitis, massive liver necrosis, fetal neural defects such as anencephaly)

Liver Function Tests
ALBUMIN
Main constituent of total protein
Normal: 3.5 – 5.0 g/dL
Decreased in:
Chronic liver disease (e.g., cirrhosis)
Nephrotic syndrome
Poor nutritional state or states of protein catabolism
Not a useful marker of synthetic liver function

ALANINE TRANSAMINASE (ALT)
Serum Glutamic Pyruvate Transaminase (SGPT) or alanine aminotransaminase
Present in hepatocytes; cytosolic enzyme
Normal: 5 – 35 IU/L
Dramatic increase in: acute liver damage such as viral hepatitis or paracetamol overdose
Elevations measured in multiples of the upper limit of normal (ULN)

ASPARTATE TRANSAMINASE (AST)
Serum Glutamic Oxaloacetic Transaminase (SGOT) or aspartate aminotransaminase
Mitochondrial
Also associated with liver parenchymal cells
Dramatic increase in: acute liver damage
Also present in rbc, cardiac & skeletal muscles

Aminotransferases are most helpful in differentiating hepatocellular injury from cholestasis --
Persistent high serum levels > 400 U/L favor generalized hepatocellular injury (e.g. acute hepatitis)
Values < 400 U/L favor cholestasis and may also be seen in mild hepatocellular injuries from viruses, drugs, alcohol, cirrhosis and primary or metastatic neoplasms

ALKALINE PHOSPHATASE
Enzyme in the cells lining the biliary ducts of the liver
Normal: 40 – 200 IU/L (15-20 y/o); 35 – 125 IU/L (20-100 y/o)
Elevation > 4x the normal  cholestasis of either intrahepatic or extrahepatic cause
Dramatic increase in: large bile duct obstruction, intrahepatic cholestasis or infiltrative diseases of the liver
Also present in bone and placental tissue  higher in growing children

TOTAL BILIRUBIN (N = 0.3-1.0 mg/dL or 5-17  mol)
Causes of elevated levels:
Prehepatic – increased bilirubin production (e.g. hemolytic anemias, internal hemorrhage)
Hepatic – deficiencies in bilirubin metabolism (e.g. dec. uptake, impaired conjugation, dec. secretion of bilirubin)
Posthepatic – obstruction of bile ducts, either within the liver or outside the liver
Diagnosis narrowed down by looking at levels of direct bilirubin

DIRECT BILIRUBIN (N = 0 – 0.3 mg/dL or 5  mol)
If direct bilirubin is normal  problem is excess unconjugated bilirubin  location of problem is upstream of bilirubin excretion  suspect hemolysis, viral hepatitis or cirrhosis
If direct bilirubin is elevated  liver conjugating normally but unable to excrete  suspect bile duct obstruction by gallstones or cancer

DIRECT BILIRUBIN (N = 0 – 0.3 mg/dL or 5  mol)
If indirect fraction > 85% of the total  hemolysis or another cause of unconjugated hyper-bilirubinemia
Elevated B2 in the absence of other liver chemistry test abnormalities  hereditary disorder of hepatic secretion of bilirubin into the canaliculus (e.g. Dubin Johnson or Rotor’s)

GAMMA GLUTAMYL TRANSPEPTIDASE (GGT)
Like ALP, can be found in canalicular membranes
More sensitive marker for cholestatic damage than ALP
May be elevated with even minor, sub-clinical levels of liver dysfunction
Elevated in alcohol toxicity (acute and chronic)

Other Tests Commonly Requested
5’ Nucleotidase (5’ NTD)
Specific for cholestasis or damage to the intra- or extrahepatic biliary system
Used as substitute for GGT for ascertaining whether an elevated ALP is of biliary or extra-biliary origin

Coagulation Tests (e.g. INR)
International Normalized Ratio
Measures the speed of a particular pathway of coagulation, comparing it to the normal
If increased  blood is taking longer to clot
Will only be increased if the liver is so damaged that synthesis of vitamin K-dependent coagulation factors has been impaired
Not a sensitive measure of liver function

Serum Glucose (BG, Glu)
Liver’s ability to produce glucose is usually the last function to be lost in the setting of fulminant liver damage
Lactate Dehydrogenase (LDH)
Found in many body tissues, including the liver
Elevated levels may indicate liver damage

Patterns of Liver Chemistry Test Abnormalities Pattern Bilirubin Alkaline phosphatase Amino- transferase Albumin Prothrombin time Hemolysis Inc. (usu. B1) Normal Normal Normal Normal Acute hepatocellular +/- inc. (B1 and B2) Normal or < 3x normal Usu. >400 (ALT>AST) Normal Normal Chronic hepatocellular +/- inc. (B1 and B2) Normal or < 3x normal Usu. <300 U/L May be dec. Often prolonged; doesn’t correct with vit. K Cholestasis Usually inc. (B1 and B2) > 4x normal Usually < 300 U/L Usually normal Normal; corrects with vit. K if prolonged Infiltrative Usually normal > 4x normal; inc. GGT < 300 U/L Usually normal Normal

Liver (1)

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