GIT Pathology Flashcards
Name four tasks of the liver
The liver has enormous functional reserve, and regen- eration occurs in all but the most fulminant of hepatic diseases. True or false
True or false
Surgical removal of 60 percent of the liver in abnormal person is followed by what? In which people will there be almost perfect restoration if the patient can survive the metabolic insult of the liver failure?
The functional reserve and the regenerative capac- ity of the liver mask to some extent the clinical impact of early liver damage. However, with progression of diffuse disease or disruption of the circulation or bile flow, the consequences of deranged liver function become severe and even life-threatening.
True or false
Name three major clinical consequences of liver diseases and give examples under each
Name the major clinical syndromes of liver disease. What is the gold standard for diagnosis of liver disease
What are the serum measurements to check for hepatocyte integrity and which levels( increase or decrease) show liver disease? What are the serum measurements for checking biliary excretory function? What are the serum measurements for checking hepatocyte function
task of maintaining the body’s metabolic homeostasis. This task includes the processing of dietary amino acids, car- bohydrates, lipids, and vitamins; synthesis of serum proteins; and detoxification and excretion into bile of endogenous waste products and xenobiotics. Surgical removal of 60% of the liver in a normal person is followed by minimal and transient hepatic impairment, with restoration of most of its mass by regen- eration within 4 to 6 weeks. In persons who have sustained massive hepatic necrosis, almost perfect restoration may occur if the patient can survive the metabolic insult of liver failure.
1.Characteristic Signs of Severe Hepatic Dysfunction
Jaundice and cholestasis Hypoalbuminemia
Hyperammonemia Hypoglycemia
Palmar erythema
Spider angiomas Hypogonadism
Gynecomastia
Weight loss
Muscle wasting
2.Portal Hypertension Associated with Cirrhosis
Ascites with or without spontaneous bacterial peritonitis
Splenomegaly
Esophageal varices
Hemorrhoids
Caput medusae—abdominal skin
3.Complications of Hepatic Failure Coagulopathy Hepatic encephalopathy Hepatorenal syndrome Portopulmonary hypertension Hepatopulmonary syndrome
The major clinical syndromes of liver disease are hepatic failure, cirrhosis, portal hypertension, and cholestasis. .with liver biopsy representing the gold standard for diagnosis.
Hepatocyte integrity:
Cytosolic hepatocellular enzymes† (an increase shows liver disease);
Serum aspartate aminotransferase (AST)
Serum alanine aminotransferase (ALT) Serum lactate dehydrogenase (LDH)
2.Biliary excretory function:
Substances secreted in bile†(increase shows liver disease);
Serum bilirubin
Total: unconjugated plus conjugated Direct: conjugated only
Delta: covalently linked to albumin
Urine bilirubin
Serum bile acids
Plasma membrane enzymes† (from damage to
bile canaliculi)(increase show liver disease);
Serum alkaline phosphatase
Serum γ-glutamyl transpeptidase Serum 5′-nucleotidase
3.Hepatocyte function:
Proteins secreted into the blood ;
Serum albumin‡(decrease shows liver disease)
Prothrombin time†(increase shows liver disease)(factors V,VII, X,
prothrombin, fibrinogen)
Hepatocyte metabolism;
Serum ammonia†
Aminopyrine breath test (hepatic demethylation)
Galactose elimination (intravenous injection)
*The most commonly performed tests are in italics. †An elevation indicates liver disease.
‡A decrease indicates liver disease.
What is the most severe clinical consequence of liver disease? How does it develop And when does it develop? Less commonly,this clinical consequence is a result of what? How much hepatic function must be lost before this clinical consequence occurs? In many cases, the balance is tipped toward decompensation by intercurrent conditions or events that place demands on the liver,name some of these conditions or events. The patterns of injury that cause liver failure fall into three categories name them and what causes them and the clinical features or signs .what is subacute failure? What is the histological correlate of acute liver failure? What is the most common route to hepatic failure and is the end point of what? Classify the processes that initiate and drive chronic damage to the liver. Chronic damage to the liver often ends in what? Which pattern of injury that leads to hepatic failure is less common ? What happens in this kind of pattern and which setting is this kind of pattern seen?
What are the clinical manifestations of haptic failure from chronic liver disease and state what causes them. State some signs and symptoms of chronic liver disease each spider angioma is of what characteristic? Acute liver failure may manifest as what? Why is hepatic failure life threatening?(explain three reasons)
Hepatic Failure
The most severe clinical consequence of liver disease is hepatic failure. It generally develops as the end point of progressive damage to the liver, either through insidious piecemeal destruction of hepatocytes or by repetitive waves of symptomatic parenchymal damage. Less com- monly, hepatic failure is the result of sudden, massive destruction. Whatever the sequence, 80% to 90% of hepatic function must be lost before hepatic failure ensues. These include systemic infections, electrolyte dis- turbances, major surgery, heart failure, and gastrointestinal bleeding.
The patterns of injury that cause liver failure fall into three categories:
• Acute liver failure with massive hepatic necrosis.Most often caused by drugs or viral hepatitis, acute liver failure denotes clinical hepatic insufficiency that progresses from onset of symptoms to hepatic encephalopathy within 2 to 3 weeks. A course extending as long as 3 months is called subacute failure. The histologic correlate of acute liver failure is massive hepatic necrosis, whatever the underlying cause. It is an uncommon but life- threatening condition that often necessitates liver transplantation.
• Chronic liver disease. This is the most common route to hepatic failure and is the end point of relentless chronic liver damage. While all structural components of the liver are involved in end-stage chronic liver disease, the processes that initiate and drive chronic damage to the liver can usually be classified as either primarily hepatocytic (or parenchymal), biliary, or vascular. Regard- less of the initiating factors, chronic damage to the liver often ends in cirrhosis, as described later.
• Hepaticdysfunctionwithoutovertnecrosis.Lesscommonly than the forms described above, hepatocytes may be viable but unable to perform their normal metabolic function. Settings where this is seen most often are mito- chondrial injury in Reye syndrome, acute fatty liver of pregnancy, and some drug- or toxin-mediated injuries.
Clinical Features
The clinical manifestations of hepatic failure from chronic liver disease are much the same regardless of the cause of the disease. Jaundice is an almost invariable finding. Impaired hepatic synthesis and secretion of albumin lead to hypoalbuminemia, which predisposes to peripheral edema. Hyperammonemia is attributable to defective hepatic urea cycle function. Signs and symptoms of chronic disease include palmar erythema (a reflection of local vasodilatation) and spider angiomas of the skin. Each angioma is a central, pulsating, dilated arteriole from which small vessels radiate. There may also be impaired estrogen metabolism and consequent hyperestrogenemia, which leads to hypo- gonadism and gynecomastia in men. Acute liver failure may manifest as jaundice or encephalopathy, but notably absent on physical examination are the other stigmata of chronic liver disease.
Hepatic failure is life-threatening for several rea- sons. The accumulation of toxic metabolites may have widespread effects and patients are highly susceptible to failure of multiple organ systems. Thus, respiratory failure with pneumonia and sepsis can give rise to renal failure and thus claim the lives of many individuals with hepatic failure. A coagulopathy develops, attributable to impaired hepatic synthesis of blood clotting factors. The resultant bleeding tendency may lead to massive gastrointestinal hemorrhage as well as bleeding elsewhere. Intestinal absorption of blood places a metabolic load on the liver that worsens the severity of hepatic failure.
Jaundice results from what? Name two functions of hepatic bile formation. When does jaundice occur and state the amount of serum bilirubin in jaundice and the serum bilirubin in a normal adult. What is cholestasis?
What is bilirubin ? Most of the daily production is derived from what?
What is an important cause of jaundice in hematologic disorders? Where is bilirubin formed? Which bilirubin binds to serum albumin? State the hepatocellular processing of bilirubin sequence. Most bilirubin glucuronides are deconjugated by what and degraded to what? Where are The urobilinogens and the residue of intact pigment largely excreted? Approximately 20% of the urobilinogens are reab- sorbed in the ileum and colon, returned to the liver, and promptly reexcreted into bile. True or false
Cholestasis results from what and may manifest as what? State one other presenting symptom. Why will skin xanthomas appear? What is a charac teristic lab finding in cholestasis? And where is this enzyme present? Why must hepatic origin of this enzyme be verified? Reduced bile flow also causes what? Cholestasis is caused by what diseases can’t be treated surgically?
Jaundice and Cholestasis
Jaundice results from the retention of bile. Hepatic bile formation serves two major functions. First, bile constitutes the primary pathway for the elimination of bilirubin, excess cholesterol, and xenobiotics that are insufficiently water- soluble to be excreted in the urine. Second, secreted bile salts and phospholipid molecules promote emulsification of dietary fat in the lumen of the gut. Bile formation is a complex process and is readily disrupted by a variety of hepatic insults. Thus, jaundice, a yellow discoloration of skin and sclerae (icterus), occurs when systemic retention of bilirubin produces serum levels above 2.0 mg/dL (the normal level in adults is below 1.2 mg/dL). Cholestasis is defined as systemic retention of not only bilirubin but also other solutes eliminated in bile (particularly bile salts and cholesterol).
Bilirubin and Bile Acids
Bilirubin is the end product of heme degradation .Most of the daily production (0.2 to 0.3 g) is derived from breakdown of senescent red cells within mononuclear phagocytes, with the remainder derived primarily from the turnover of hepatic hemoproteins. Excessive destruction of erythroid progenitors in the bone marrow due to intramed- ullary apoptosis (ineffective erythropoiesis) is an important cause of jaundice in hematologic disorders.Whatever the source, heme oxygenase oxidizes heme to biliverdin, which is then reduced to bilirubin by biliverdin reductase. Bilirubin thus formed outside the liver in cells of the mononuclear phagocyte system (including the spleen) is released and bound to serum albumin. Hepato- cellular processing of bilirubin involves the following sequence:
1. Carrier-mediated uptake at the sinusoidal membrane
2. Cytosolic protein binding and delivery to the endoplas-
mic reticulum
3. Conjugation with one or two molecules of glucuronic
acid by bilirubin uridine diphosphate–glucuronosyl-
transferase
4. Excretion of the water-soluble, nontoxic bilirubin glu- curonides into bile. Most bilirubin glucuronides are
deconjugated by gut bacterial β-glucuronidases and degraded to colorless urobilinogens. The urobilinogens and the residue of intact pigment are largely excreted in feces. Conjugated and unconju- gated bile acids also are reabsorbed in the ileum and returned to the liver by the enterohepatic circulation.
Cholestasis, which results from impaired bile flow due to hepatocellular dysfunction or intrahepatic or extrahe- patic biliary obstruction, also may manifest as jaundice. However, sometimes pruritus is the presenting symptom, the pathogenesis of which remains obscure. Skin xanthomas (focal accumulations of cholesterol) sometimes appear, the result of hyperlipidemia and impaired excretion of choles- terol. A characteristic laboratory finding is elevated serum alka- line phosphatase, an enzyme present in bile duct epithelium and in the canalicular membrane of hepatocytes. A differ- ent alkaline phosphatase isozyme normally is expressed in many other tissues such as bone, and so hepatic origin must be verified. Reduced bile flow also causes intestinal malabsorption including inadequate absorption of the fat- soluble vitamins A, D, and K.
Extrahepatic biliary obstruction frequently is amenable to surgical correction. By contrast, cholestasis caused by diseases of the intrahepatic biliary tree or hepatocellular secretory failure (collectively termed intrahepatic cholestasis) cannot be treated surgically (short of transplantation), and the patient’s condition may be worsened by an operative procedure. Thus, there is some urgency in identifying the cause of jaundice and cholestasis.
What is the pathogenesis of jaundice? :
When will jaundice occur? More than one mechanism may operate to cause jaundice, especially in hepa- titis, when both unconjugated and conjugated bilirubin may be produced in excess true or false
In severe disease bilirubin levels may reach what amount? What are the most common causes of jaundice?
What is neonatal jaundice and how does it occur? Jaundice also may result from inborn errors of metabolism, including which two syndromes? Define what they are and their primary causes
State the two main causes of jaundice and give three examples under each
In summary when does jaundice occur? What are the two most common causes involving accumulation of conjugated bilirubin? What is the most common cause of jaundice involving the accumulation of unconjugated bilirubin? What is cholestasis?
What enzyme is usually elevated In cholestasis?
PATHOGENESIS
In the normal adult, the rate of systemic bilirubin production is equal to the rates of hepatic uptake, conjugation, and biliary excretion. Jaundice occurs when the equilibrium between bilirubin production and clearance is disrupted;. In severe disease, bilirubin levels may reach 30 to 40 mg/dL.
Of these various causes of jaundice, the most common are hepatitis, obstruction to the flow of bile and hemolytic anemia Because the hepatic machinery for conjugating and excreting bilirubin does not fully mature until about 2 weeks of age, almost every newborn develops transient and mild unconjugated hyperbilirubinemia, termed neonatal jaundice or physio- logic jaundice of the newborn.
Jaundice also may result from inborn errors of metabolism, including
• Gilbert syndrome, a relatively common (7% of the population), benign, somewhat heterogeneous inherited condition manifesting as mild, fluctuating unconjugated hyperbilirubinemia. The primary cause is decreased hepatic levels of glucuronosyltransferase attributed to a mutation in the encoding gene; polymorphisms in the gene may play a role in the variable expression of this disease. The hyperbilirubinemia is not associated with any morbidity.
• Dubin-Johnson syndrome results from an autosomal recessive defect in the transport protein responsible for hepatocellular excretion of bilirubin glucuronides across the canalicular membrane. Affected persons exhibit con- jugated hyperbilirubinemia. Other than having a darkly pigmented liver (from polymerized epinephrine metabo- lites, not bilirubin) and hepatomegaly, patients are other- wise without functional problems.
Main causes of jaundice
1.Predominantly Unconjugated Hyperbilirubinemia
a. Excess Production of Bilirubin
Hemolytic anemias
Resorption of blood from internal hemorrhage (e.g., alimentary tract
bleeding, hematomas)
Ineffective erythropoiesis syndromes (e.g., pernicious anemia,
thalassemia)
b.Reduced Hepatic Uptake
Drug interference with membrane carrier systems
Diffuse hepatocellular disease (e.g., viral or drug-induced hepatitis,
cirrhosis)
c. Impaired Bilirubin Conjugation
Physiologic jaundice of the newborn
2.Predominantly Conjugated Hyperbilirubinemia
a. Decreased Hepatocellular Excretion
Deficiency in canalicular membrane transporters Drug-induced canalicular membrane dysfunction (e.g., oral
contraceptives, cyclosporine)
Hepatocellular damage or toxicity (e.g., viral or drug-induced hepatitis,
total parenteral nutrition, systemic b.infection)
Impaired Intra- or Extrahepatic Bile Flow
Inflammatory destruction of intrahepatic bile ducts (e.g., primary biliary cirrhosis, primary sclerosing cholangitis, graft-versus-host disease, liver transplantation); gall stones, carcinoma of the pancreas
SUMMARY
Jaundice and Cholestasis
• Jaundice occurs when retention of bilirubin leads to serum levels above 2.0 mg/dL.
• Hepatitis and intra- or extrahepatic obstruction of bile flow are the most common causes of jaundice involving the accumulation of conjugated bilirubin.
• Hemolytic anemias are the most common cause of jaundice involving the accumulation of unconjugated bilirubin.
• Cholestasis is the impairment of bile flow resulting in the retention of bilirubin, bile acids, and cholesterol.
• Serum alkaline phosphatase usually is elevated in chole- static conditions.
Which two ways can hepatic encephalopathy develop? Patients w hepatic encephalopathy show a spectrum of what dysfunctions?
Name some associated fluctuating neurologic signs. Name the characteristic sign in hepatic encephalopathy. What minor morphological changes are seen in the brain? What two factors are important in the start of hepatic encephalopathy
In an acute setting,what may cause encephalopathy ? In a chronic setting what may cause it? What are the major causes of cirrhosis? What is cirrhosis?
What are the main characteristics of cirrhosis? Hepatocytes in parenchymal nodules derive from which two sources? What is cryptogenic cirrhosis?
Hepatic Encephalopathy
Hepatic encephalopathy may develop rapidly in acute liver failure or insidiously with gradually evolving chronic liver failure from cirrhosis. In either setting, patients with hepatic encephalopathy show a spectrum of brain dysfunc- tion ranging from subtle behavioral abnormalities to marked confusion and stupor, to deep coma and death. These changes may progress over hours or days as, for example, in fulminant hepatic failure or gradually in a person with marginal hepatic function from chronic liver disease. Associated fluctuating neurologic signs include rigidity, hyperreflexia, nonspecific electroen- cephalographic changes, and, rarely, seizures. Particularly characteristic is asterixis (also called flapping tremor), which is a pattern of nonrhythmic, rapid extension- flexion movements of the head and extremities, best seen when the arms are held in extension with dorsiflexed wrists.
In most instances there are only minor morphologic changes in the brain, such as edema and an astrocytic reac- tion. Two factors seem to be important in the genesis of this disorder:
• Severe loss of hepatocellular function
• Shunting of blood from portal to systemic circulation
around the chronically diseased liver
In the acute setting, an elevation in blood ammonia, which impairs neuronal function and promotes general- ized brain edema, seems to be key. In the chronic setting, deranged neurotransmitter production, particularly in monoaminergic, opioidergic, γ-aminobutyric acid (GABA)- ergic, and endocannabanoid systems, leads to neuronal dysfunction.
Cirrhosis
Its major causes include chronic viral infections, alcoholic or nonalcoholic steatohepatitis (NASH), autoim- mune diseases affecting hepatocytes and/or bile ducts, and iron overload. Cirrhosis is defined as a diffuse process char- acterized by fibrosis and the conversion of normal liver architec- ture into structurally abnormal nodules. Its main characteristics by definition are not focal but rather involve most (if not all) of the diseased liver and include
• Fibrous septa in the form of delicate bands or broad scars around multiple adjacent lobules. Long-standing fibro- sis generally is irreversible so long as disease persists or if disease-associated vascular shunts are widespread, although regression is possible if the underlying cause of liver disease is reversed.
• Parenchymal nodules, ranging in size from very small (less than 3 mm in diameter—micronodules) to large (over 1 cm—macronodules), encircled by these fibrous bands. Hepatocytes in these nodules derive from two sources: (1) preexistent, long-lived hepatocytes that, by the time cirrhosis is established, display features of rep- licative senescence; and (2) newly formed hepatocytes capable of replication that are derived from stem/pro- genitor cells found adjacent to the canals of Hering and small bile ductules—the hepatobiliary stem cell niche. These stem/progenitor cells also give rise to the ductular reactions found at the periphery of most cirrhotic nodules, where parenchyma meets stromal scar, and are accom- panied by proliferating endothelial cells, myofibroblasts, and inflammatory cells.
After all known causes have been excluded, about 10% of cases remain, referred to as cryptogenic cirrhosis, although in recent years most of these are recognized as probable “burned-out” NASH.
State the three processes central to the pathogenesis of cirrhosis. What is common to all forms of cirrhosis? In the normal liver what is present only in the liver capsule, in portal tracts, and around central veins? What is the space of Disse ? What’s the difference between a normal liver and a cirrhosis liver?
What is the major source of excess collagen in cirrhosis and where do they lie? What is the normal function of this major source? During development of fibrosis what happens to this source?
What stimulates the process that happens to this source during fibrosis and the production of excess collagen?
Where do the things that do the stimulation come from? During the course of chronic liver disease, fibrosis is a dynamic process that involves what? How do Vascular injuries and changes play significant roles in remodeling of the liver into a cirrhotic state? What are the major vascular lesions that contribute to defects in liver function? The causes of liver cell injury that give rise to cirrhosis are varied and depend on the etiology (viral, alcoholic, drugs). True or false
Regenerating liver cells form what ?
What signs may develop in cirrhosis? If overt hepatic failure develops in cirrhosis what will usually precipitate it ? Most cases of ultimately fatal cirrhosis involve some mechanisms,name them.
In summary what are the three main characteristics of cirrhosis?
What are the most frequent causes of cirrhosis? Name some less frequent causes? The main complications of cirrhosis are related to what three conditions?
PATHOGENESIS
Three processes are central to the pathogenesis of cirrhosis: death of hepatocytes, extracellular matrix deposition, and vascular reorganization.
Changes in the connective tissue and extracellular matrix (ECM) are common to all forms of cirrhosis. In the normal liver, ECM consisting of interstitial collagens (fibril-forming collagen types I, III, V, and XI) is present only in the liver capsule, in portal tracts, and around central veins. The hepa- tocytes have no true basement membrane; instead, a delicate framework containing type IV collagen and other proteins lies in the space between sinusoidal endothelial cells and hepato- cytes (the space of Disse). By contrast, in cirrhosis, types I and III collagen and other ECM components are deposited in the space of Disse
The major source of excess collagen in cirrhosis are the perisinusoidal stellate cells (formerly known as Ito cells), which lie in the space of Disse. Although they normally function as storage cells for vitamin A, during the develop- ment of fibrosis they activate and transform into myofi- broblasts. The stimuli for the activation of stellate cells and production of collagen are believed to include reactive oxygen species, growth factors, and cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and lym- photoxins, which can be produced by damaged hepatocytes or by stimulated Kupffer cells and sinusoidal endothelial cells. Activated stellate cells themselves produce growth factors, cytokines, and chemokines that cause their further prolifera- tion and collagen synthesis—in particular, transforming growth factor-β (TGF-β). Portal fibroblasts probably also participate in some forms of cirrhosis. During the course of chronic liver disease, fibrosis is a dynamic process that involves the synthesis, deposition, and resorption of ECM components, modulated by changing balances between metalloproteases and tissue inhibitors of metalloproteases .Thus, even in late-stage disease, if the disease process is halted or eliminated, significant remodeling and even restoration of liver function (cirrhotic regression) is possible.
Vascular injuries and changes also play significant roles in remodeling of the liver into a cirrhotic state. Inflammation and thrombosis of portal veins, hepatic arteries, and/or central veins may lead to alternating zones of parenchymal hypoperfusion, with resulting parenchymal atrophy, and hyperperfusion, with overcompensating regeneration. The major vascular lesions that contribute to defects in liver func- tion are loss of sinusoidal endothelial cell fenestrations (Fig. 15–2) and the development of portal vein–hepatic vein and hepatic artery–portal vein vascular shunts. While normal sinusoids have fenestrated endothelial cells that allow free exchange of solutes between plasma and hepatocytes, loss of fenestrations and increased basement membrane formation convert thin-walled sinusoids into higher pressure, fast-flowing vascular channels without such solute exchange. In particular, the movement of proteins (e.g., albumin, clot- ting factors, lipoproteins) between hepatocytes and the plasma is markedly impaired. These functional changes are aggravated by the loss of microvilli from the hepatocyte surface, further diminishing its transport capacity. Vascular shunts mentioned earlier lead to abnormal vascular pressures in the liver and contribute to hepatic dysfunction and portal hypertension.
As described earlier, the normal liver cells are replaced by parenchymal nodules derived from long-lived surviving hepa- tocytes and new cells generated from stem cells. The regen- erating liver cells form spherical nodules confined by fibrous septa.
Clinical Features
All forms of cirrhosis may be clinically silent. When symp- toms appear, they typically are nonspecific and include anorexia, weight loss, weakness, and, in advanced disease, frank debilitation. Incipient or overt hepatic failure may develop, usually precipitated by imposition of a metabolic load on the liver, as from systemic infection or a gastroin- testinal hemorrhage. Most cases of ultimately fatal cirrhosis involve one of the following mechanisms:
• Progressive liver failure
• A complication related to portal hypertension
• The development of hepatocellular carcinoma
SUMMARY
Cirrhosis
• The three main characteristics of cirrhosis are (1) involve- ment of most or all of the liver, (2) bridging fibrous septa, and (3) parenchymal nodules containing a mix of senes- cent and replicating (often stem/progenitor cell-derived) hepatocytes.
• Cirrhosis usually is an end-stage process that may have multiple causes. The most frequent are chronic hepatitis B and C and alcoholic and nonalcoholic steatohepatitis. Less frequent causes are autoimmune and biliary diseases and metabolic conditions such as hemochromatosis.
• The main complications of cirrhosis are related to decreased liver function, portal hypertension, and increased risk for development of hepatocellular carcinoma.
Portal Hypertension
Increased resistance to portal blood flow may develop from prehepatic, intrahepatic, and posthepatic causes (described later). The dominant intrahepatic cause is cirrhosis, accounting for most cases of portal hypertension. Far less frequent are instances of noncirrhotic portal hypertension, such as from schistosomiasis, massive fatty change, diffuse granuloma- tous diseases (e.g., sarcoidosis, miliary tuberculosis), and diseases affecting the portal microcirculation, exemplified by nodular regenerative hyperplasia.
Portal hypertension in cirrhosis results from increased resistance to portal flow at the level of the sinusoids and compression of central veins by perivenular fibrosis and expanded parenchymal nodules. Anastomoses between the arterial and portal systems in the fibrous bands also contribute to portal hypertension by imposing arterial pressure on the normally low-pressure portal venous system. Another major factor in the causation of portal hypertension is an increase in portal venous blood flow resulting from a hyperdynamic circulation. This is caused by arterial vasodilation in the splanchnic circulation, result- ing primarily from increased production of nitric oxide (NO) in the vascular bed. This occurs in response to reduced clearance of bacterial DNA absorbed from the gut that bypasses the Kupffer cells due to intrahepatic shunting of blood from portal to systemic circulation. Bacterial DNA causes increased production of NO. The major clinical con- sequences are discussed next (Fig. 15–3).
Ascites
Ascites refers to the collection of excess fluid in the perito- neal cavity. It usually becomes clinically detectable when at least 500 mL have accumulated, but many liters may.
collect, causing massive abdominal distention. Ascites gen- erally is a serous fluid containing as much as 3 g/dL of protein (largely albumin). More importantly, the serum to ascites albumin gradient is ≥1.1 g/dL. The fluid may contain a scant number of mesothelial cells and mononu- clear leukocytes. Influx of neutrophils suggests secondary infection, whereas presence of red cells points to possible disseminated intraabdominal cancer. With long-standing ascites, seepage of peritoneal fluid through transdiaphrag- matic lymphatics may produce hydrothorax, more often on the right side.
PATHOGENESIS
The pathogenesis of ascites is complex, involving one or more of the following mechanisms:
• Increased movement of intravascular fluid into the extra-
vascular space of Disse, caused by sinusoidal hypertension
and hypoalbuminemia.
• Leakage of fluid from the hepatic interstitium into the
peritoneal cavity. Normal thoracic duct lymph flow is 800 to 1000 mL/day. With cirrhosis, hepatic lymphatic flow may approach 20 L/day, exceeding thoracic duct capacity. Hepatic lymph is rich in proteins and low in triglycerides, as reflected in the protein-rich ascitic fluid.
• Renal retention of sodium and water due to secondary hyperaldosteronism (Chapter 3), despite a total body sodium mass greater than normal
Portosystemic Shunt
With the rise in portal venous pressure, shunts develop wherever the systemic and portal circulations share capil- lary beds. Principal sites are veins around and within the rectum (manifest as hemorrhoids), the cardioesophageal junction (producing esophagogastric varices), the retro- peritoneum, and the falciform ligament of the liver (involv- ing periumbilical and abdominal wall collaterals). Although hemorrhoidal bleeding may occur, it is rarely massive or life-threatening. Much more important are the esophagogas- tric varices that appear in about 65% of persons with advanced cirrhosis of the liver, causing massive hemateme- sis and death in some instances (Chapter 14). Rarely, abdominal wall collaterals appear as dilated subcutaneous veins extending outward from the umbilicus (caput medusae).
Splenomegaly
Long-standing congestion may cause congestive spleno- megaly. The degree of enlargement varies widely (usually 1000 g or less) and is not necessarily correlated with other features of portal hypertension. Massive splenomegaly may secondarily induce a variety of hematologic abnor- malities attributable to hypersplenism
Hepatorenal Syndrome
Hepatorenal syndrome generally appears only with severe liver disease and is marked by the development of renal failure without primary abnormalities of the kidneys themselves. Excluded by this definition are con- comitant toxic damage to both the liver and the kidney, as may occur in carbon tetrachloride and mushroom poison- ing and the copper toxicity of Wilson disease. Also excluded are instances of advanced hepatic failure in which circula- tory collapse leads to acute tubular necrosis and renal failure. Kidney function promptly improves if hepatic failure is reversed. Although the exact cause is unknown, evidence points to splanchnic vasodilatation and systemic vasoconstriction, leading to a severe reduction in renal blood flow, particularly to the cortex.
The syndrome is heralded by a drop in urine output and rising blood urea nitrogen and creatinine values. The ability to concentrate urine is retained, producing a hyperosmolar urine devoid of proteins and abnormal sediment that is surprisingly low in sodium (unlike renal tubular necrosis). Renal dialysis or other treatments are at best bridges to the only cure, liver transplantation; however, transplantation recipients with hepatorenal syn- drome have a high mortality in the months after the operation.
Portopulmonary Hypertension and
Hepatopulmonary Syndrome
Pulmonary dysfunction in chronic liver disease is common and may be life-threatening. Causes of liver injury also may damage the lungs (e.g., α1-antitrypsin deficiency leading to both cirrhosis and emphysema). Ascites, pressing upward on the diaphragm, and pleural effusions associated with portal hypertension can compromise lung capacity. Finally, changes in pulmonary blood flow occurring secondary to hepatic failure may lead to portopulmonary hypertension or hepatopulmonary syndrome.
Portopulmonary hypertension is defined as pulmonary arterial hypertension associated with liver disease or portal hypertension. Although the mechanisms underlying this condition remain obscure, they seem to involve portal hypertension of any cause (cirrhotic or non-cirrhotic) and excessive pulmonary vasoconstriction and vascular remod- eling, which eventually lead to right-sided heart failure; the most common clinical manifestations are dyspnea on exertion and clubbing of the fingers, followed by palpitations and chest pain.
Hepatopulmonary syndrome is associated with abnor- mal intrapulmonary vascular dilatation in combination with increased pulmonary blood flow. Shunting of blood through such dilatations leads to ventilation-perfusion mismatch and reduced oxygen diffusion, thus giving rise to severe arterial hypoxemia with dyspnea and cyanosis. Oxygen supplementation can alleviate these problems early on, though the most severe intrapulmonary vascular dilatation or formation of arteriovenous malformations causes right- to-left shunting that is only partially correctable. Platypnea (easier breathing while lying down as compared to when sitting or standing) and orthodeoxia (fall of arterial blood oxygen with upright posture) are pathognomonic of hepa- topulmonary syndrome.
DRUG- OR TOXIN-INDUCED LIVER DISEASE
As the major drug metabolizing and detoxifying organ in the body, the liver is subject to injury from an enormous array of therapeutic and environmental chemicals. Injury may result from direct toxicity, through hepatic conversion of a xenobiotic to an active toxin, or by immune mecha- nisms, such as by a drug or a metabolite acting as a hapten to convert a cellular protein into an immunogen.
A diagnosis of drug- or toxin-induced liver disease may be made on the basis of a temporal association of liver damage with drug or toxin exposure and, it is hoped, recovery on removal of the compound(s), combined with exclusion of other potential causes. Exposure to a toxin or therapeutic agent should always be included in the differential diagnosis of any form of liver disease. By far the most impor- tant agent that produces toxic liver injury is alcohol; its characteristic histologic (but not clinical) features are shared with nonalcoholic fatty liver disease (NAFLD) and therefore it is discussed in that section.
Drug-induced liver disease is a common condition that may manifest as a mild reaction or, much more seriously, as acute liver failure or chronic liver disease. A large number of drugs and chemicals can produce liver injury (Table 15–4). It is important to keep in mind that com- pounds other than those normally thought of as drugs or medicines may be to blame; often careful, persistent history taking will uncover exposure to other potential toxins such as herbal remedies, dietary supplements, topical applica- tions (e.g., ointments, perfumes, shampoo), and environ- mental exposures (e.g., cleaning solvents, pesticides, fertilizers).
Principles of drug and toxic injury are discussed in Chapter 7. Here it suffices to note that drug reactions may be classified as predictable or unpredictable (idiosyncratic). Predictable drug or toxin reactions affect all people in a dose-dependent fashion. Unpredictable reactions depend on individual host variations, particularly the propensity to mount an immune response to drug-related antigen or the rate at which the agent is metabolized. Both classes of injury may be immediate or take weeks to months to develop.
A classic predictable hepatotoxin is acetaminophen, now the most common cause of acute liver failure neces- sitating transplantation in the United States. The toxic agent is not acetaminophen itself but rather toxic metabo- lites produced by the cytochrome P-450 system in acinus zone 3 hepatocytes (Fig. 15–4). As these cells die, the zone 2 hepatocytes take over this metabolic function, in turn becoming injured. In severe overdoses the zone of injury extends to the periportal hepatocytes, resulting in fulmi- nant hepatic failure (Fig. 15–5, A and B). While intentional suicidal overdoses are common, so are accidental over- doses. This is because the cytotoxicity is dependent on the activity of the cytochrome P-450 system, which may be upregulated by other agents taken in combination with acetaminophen, such as alcohol (beware acetaminophen as a hangover prophylactic) or codeine in acetaminophen compound tablets.
Examples of drugs that can cause idiosyncratic reactions are chlorpromazine (an agent that causes cholestasis in individuals who metabolize it slowly), halothane (which can cause a fatal immune-mediated hepatitis in some persons exposed to this anesthetic on several occasions), and other drugs such as sulfonamides, α-methyldopa, and allopurinol. Often, idiosyncratic drug or toxin reactions involve a variable combination of direct cytotoxicity and immune-mediated hepatocyte or bile duct destruction. Examples of hepatotoxins are given in each disease-specific category described later.
SUMMARY
Drug- or Toxin-Induced Liver Disease
• Drug- and toxin-induced liver disease may be predictable (intrinsic) or unpredictable (idiosyncratic).
• Predictable hepatotoxins affect most individuals in a dose- dependent fashion.
• Unpredictable hepatotoxins affect rare persons in an idio- syncratic way, often involving a combination of direct cyto- toxicity and immune-mediated injury.
• Every pattern of liver injury can be caused by some toxin or drug; therefore, exposures involving these agents must always be considered in the differential diagnosis.
• In addition to prescription and over-the-counter medica- tions, herbal remedies, dietary supplements, topical appli- cations, and environmental exposures may be responsible for hepatotoxicity.
State the morphological patterns and the associated agents for these patterns of injury (cholestasic pattern,cholestatic hepatitis,hepatocellular necrosis,steatosis,steatohepatitis,fibrosis and cirrhosis,granulomas,vascular lesions,neoplasms)
What are the main morphological features of acute hepatitis (gross and microscopic) and of chronic hepatitis
Cholestatic pattern
Morphology: Bland hepatocellular cholestasis, without inflammation Agent:Contraceptive and anabolic steroids; estrogen replacement therapy
Cholestatic hepatitis
Morphology: cholestasis with lobular inflammation and necrosis; may show bile duct destruction
Agents:Numerous antibiotics; phenothiazines
Hepatocellular necrosis
M-Spotty hepatocyte necrosis submassive necrosis, zone 3
Massive necrosis
Agents: Methyldopa, phenytoin Acetaminophen, halothane Isoniazid, phenytoin
Steatosis:
M-macrovesicular
Agent: Ethanol, methotrexate, corticosteroids, total parenteral nutrition
Steatohepatitis
M-macrovesicular,mallory bodies
Agents:Amiodarone and ethanol
Fibrosis and cirrhosis
M-periportal and pericellular fibrosis
Agent: Methotrexate, isoniazid, enalapril
Granulomas:
M-Noncaseating epithelioid granulomas
Agent: Sulfonamides, numerous other agents
Vascular lesions
M-Sinusoidal obstruction syndrome (venoocclusive disease): obliteration of central veins
Budd-Chiari syndrome
Sinusoidal dilatation
Peliosis hepatis: blood-filled cavities, not lined by
endothelial cells
Agent:high -dose chemotherapy, bush teas
Oral contraceptives
Oral contraceptives, numerous other agents Anabolic steroids, tamoxifen
Neoplasms: M-hepatic adenoma Hepatocellular carcinoma Cholangiocarcinoma Angiosarcoma Agent: Oral contraceptives, anabolic steroids Thorotrast Thorotrast Thorotrast, vinyl chloride
Acute Hepatitis
Gross Changes:
Enlarged, reddened liver; greenish if cholestatic
Parenchymal Changes (Microscopic):
Hepatocyte injury: swelling (ballooning degeneration)
Cholestasis: canalicular bile plugs
HCV: mild fatty change of hepatocytes
Hepatocyte necrosis: isolated cells or clusters
Cytolysis (rupture) or apoptosis (shrinkage)
If severe: bridging necrosis (portal-portal, central-central,
portal-central)
Lobular disarray: loss of normal architecture
Regenerative changes: hepatocyte proliferation
Sinusoidal cell reactive changes
Accumulation of phagocytosed cellular debris in Kupffer cells
Influx of mononuclear cells into sinusoids Portal tracts
Inflammation: predominantly mononuclear
Inflammatory spillover into adjacent parenchyma, with hepatocyte
necrosis
Chronic Hepatitis
Changes shared with acute hepatitis
Hepatocyte injury, necrosis, apoptosis, and regeneration
Sinusoidal cell reactive changes
Portal tracts Inflammation
Confined to portal tracts, or
Spillover into adjacent parenchyma, with necrosis of hepatocytes
(“interface hepatitis”), or Bridging inflammation and necrosis
Fibrosis
Portal deposition, or
Portal and periportal deposition, or Formation of bridging fibrous septa
HBV: ground-glass hepatocytes (accumulation of HBsAg)
HCV: bile duct epithelial cell proliferation, lymphoid aggregate
formation
ACUTE AND CHRONIC HEPATITIS
The terminology of acute and chronic hepatitis can be con- fusing, since the term hepatitis is applied to a number of different diseases and different forms of liver injury. For example, hepatitis is a descriptor for specific histopatho- logic patterns of hepatocyte injury associated with inflam- mation and, when chronic, with scarring. Acute and chronic forms of hepatitis are distinguished in part by duration and in part by the pattern of cell injury. Viral hepatitides are also classified on the basis of the causative hepatotropic virus such as hepatitis types A, B, C, D, and E. Because all forms of hepatitis, including those due to the hepatitis viruses as well as autoimmune and drug- and toxin- induced hepatitides, share the same patterns of injury, the general descriptions are presented first, followed by clini- copathologic correlations specific to each cause.
MORPHOLOGY
On gross inspection, liver involved by mild acute hepatitis appears normal or slightly mottled. At the other end of the spectrum, in massive hepatic necrosis the liver may shrink to 500 to 700 g and become transformed into a limp, red organ covered by a wrinkled, baggy capsule. The distribution of liver destruction is extremely capricious: The entire liver may be involved, or only patchy areas affected. On sectioning (Fig. 15–5, A), necrotic areas have a muddy-red, mushy appearance with blotchy bile staining.
If patients survive for more than a week, surviving hepato- cytes begin to regenerate (Chapter 2). If the parenchymal framework is preserved, regeneration is orderly and liver architecture is restored. With more massive destruction, regeneration is disorderly, yielding nodular masses of liver cells separated by granulation tissue and, eventually, scar, particularly in patients with a protracted course of submas- sive necrosis.
The gross appearance of the liver in chronic hepatitis may be normal or include grossly evident focal scarring or, as cir- rhosis develops, may feature widespread nodularity sur- rounded by extensive scarring.
The general microscopic features of acute and chronic hepatitis of all causes are listed in Table 15–5. Unlike most other organ systems in which the distinction between acute and chronic inflammation depends on the predominant type of inflammatory cell—neutrophilic in acute injury, mononuclear in chronic phases—mononuclear infiltrates pre- dominate in all phases of most hepatitic diseases because they all invoke T cell–mediated immunity. Thus, the distinc- tion between acute and chronic hepatitis is based on the pattern of cell injury and severity of inflamma- tion, with acute hepatitis often showing less inflam- mation and more hepatocyte death than chronic hepatitis. Both hepatocyte injury and inflammation, while related, can be highly variable depending on etiology and host factors. The hepatocyte injury takes two forms. The first is swelling (ballooning degeneration), producing cells with empty- appearing pale cytoplasm that subsequently rupture and undergo necrosis (cytolysis). The necrotic cells appear to have dropped out, leaving collapsing sinusoidal collagen reticulin framework behind; scavenger macrophages mark sites of dropout. The second pattern of cell death is apop- tosis, in which hepatocytes shrink, become intensely eosino- philic, and have fragmented nuclei; effector T cells may be present in the immediate vicinity. When located in the paren- chyma away from portal tracts, these features are called lobular hepatitis (Fig. 15–6).
In severe cases, confluent necrosis of hepatocytes is seen around central veins (Fig. 15–5, B). In these areas there may be cellular debris, collapsed reticulin fibers, congestion/ hemorrhage, and variable inflammation. With increasing severity, central-portal bridging necrosis develops, fol- lowed by, even worse, parenchymal collapse. When the injury is overwhelming, massive hepatic necrosis and fulmi- nant liver failure ensue. In occasional cases, the injury is not severe enough to cause death (or necessitate transplanta- tion), and the liver survives, although with abundant scarring that replaces areas of confluent necrosis. In such cases, some patients rapidly develop posthepatitic cirrhosis.
Portal inflammation in acute hepatitis is minimal or absent; dense mononuclear portal infiltrates of variable promi- nence are the defining lesion of chronic hepatitis (Fig. 15–7). There is often interface hepatitis as well, distin- guished from lobular hepatitis by its location at the interface between hepatocellular parenchyma and portal stroma (or scars, when present). The hallmark of severe chronic liver damage is scarring. At first, only portal tracts exhibit fibrosis, but in some patients, with time, fibrous septa—bands of dense scar—will extend between portal tracts. In the most severe cases, continued scarring and nodule formation leads to the development of cirrhosis (Fig 15–8).
Clinical assessment of chronic hepatitis often requires liver biopsy in addition to clinical and serologic data. Liver biopsy is helpful in confirming the clinical diagnosis, excluding common concomitant conditions (e.g., fatty liver disease, hemochromatosis), assessing histologic features associated with an increased risk of malignancy (e.g., small and large cell change, described later), grading the extent of hepato- cyte injury and inflammation, and staging the pro- gression of scarring. Such grading and staging are useful for assessing prognosis and therapeutic options.
What are the two main types of Cholelithiasis and state what they’re made of
What is the only significant pathway for elimination of excess cholesterol from the body and in what forms is the elimination done?
When will cholesterol crystallize out of solution?
What enhances cholesterol gallstone formation?
How are pigment stones formed?
Gallstones is prevalent in which gender more?
Name the risk factors for gallstones
There are two main types of gallstones: cholesterol stones, containing crystalline choles- terol monohydrate (80% of stones in the West), and pigment stones, made of bilirubin calcium salts.
PATHOGENESIS
Bile formation is the only significant pathway for elimination of excess cholesterol from the body, either as free choles- terol or as bile salts. Cholesterol is rendered water-soluble by aggregation with bile salts and lecithins. When cholesterol concentrations exceed the solubilizing capacity of bile (super- saturation), cholesterol can no longer remain dispersed and crystallizes out of solution. Cholesterol gallstone formation is enhanced by hypomobility of the gallbladder (stasis), which promotes nucleation, and by mucus hypersecre- tion, with consequent trapping of the crystals, thereby enhancing their aggregation into stones.
Formation of pigment stones is more likely in the presence of unconjugated bilirubin in the biliary tree, as occurs in hemolytic anemias and infections of the biliary tract. The precipitates are primarily insoluble calcium bilirubinate salts. Some elaboration on these risk factors follows:
• Age and gender. The prevalence of gallstones increases
throughout life. In the United States, less than 5% to 6% of the population younger than age 40 has stones, in contrast with 25% to 30% of those older than 80 years. The prevalence in women of all ages is about twice as high as in men.
• Ethnic and geographic. Cholesterol gallstone preva- lence approaches 50% to 75% in certain Native American populations—the Pima, Hopi, and Navajos—whereas pigment stones are rare; the prevalence seems to be related to biliary cholesterol hypersecretion.
• Heredity. In addition to ethnicity, a positive family history imparts increased risk, as do a variety of inborn errors of metabolism such as those associated with impaired bile salt synthesis and secretion.
• Environment. Estrogenic influences, including oral con- traceptives and pregnancy, increase hepatic cholesterol uptake and synthesis, leading to excess biliary secretion of cholesterol. Obesity, rapid weight loss, and treatment with the hypocholesterolemic agent clofibrate also are strongly associated with increased biliary cholesterol secretion.
• Acquired disorders. Any condition in which gallbladder motility is reduced predisposes to gallstones, such as preg- nancy, rapid weight loss, and spinal cord injury. In most cases, however, gallbladder hypomotility is present without obvious cause.
What are the risk factors for formation of cholesterol stones and formation of pigment stones
Cholesterol stones arise from where?
Pure cholesterol stones are what colour and what will cause a gray-white to black discoloration? What is the shape and consistency of the stones?
Are cholesterol stones radiolucent or radiopaque?
Where do pigment stones arise and what’s the classification of pigment stones?
Where are each type found?
The stones contain what? What are the differences between the types of pigment stones
What are the symptoms of gallstones?
What causes the pain? Name some severe complications
The larger the calculi,what happens?
Cholesterol Stones Demography: Northern Europeans, North and South Americans, Native Americans, Mexican Americans Advancing age Female sex hormones Female gender Oral contraceptives Pregnancy Obesity and insulin resistance Rapid weight reduction Gallbladder stasis Inborn disorders of bile acid metabolism Dyslipidemia syndromes
Pigment Stones
Demography: Asian more than Western, rural more than urban Chronic hemolysis (e.g., sickle cell anemia, hereditary spherocytosis) Biliary infection
Gastrointestinal disorders: ileal disease (e.g., Crohn disease), ileal
resection or bypass, cystic fibrosis with pancreatic insufficiency
MORPHOLOGY
Cholesterol stones arise exclusively in the gallbladder and consist of 50% to 100% cholesterol. Pure cholesterol stones are pale yellow; increasing proportions of calcium carbonate, phosphates, and bilirubin impart gray-white to black discoloration .They are ovoid and firm; they can occur singly, but most often there are several, with faceted surfaces resulting from their apposition. Most cho- lesterol stones are radiolucent, although as many as 20% may have sufficient calcium carbonate to be radiopaque.
Pigment stones may arise anywhere in the biliary tree and are classified into black and brown stones. In general, black pigment stones are found in sterile gallbladder bile, while brown stones are found in infected intrahepatic or extrahepatic ducts. The stones contain calcium salts of unconjugated bilirubin and lesser amounts of other calcium salts, mucin glycoproteins, and cholesterol. Black stones are usually small in size, fragile to the touch, and numerous . Brown stones tend to be single or few in number and to have a soft, greasy, soaplike consistency that results from the presence of retained fatty acid salts released by the action of bacterial phospholipases on biliary lecithins. Because of calcium carbonates and phosphates, 50% to 75% of black stones are radiopaque. Brown stones, which contain calcium soaps, are radiolucent.
70% to 80% of individuals with gallstones remain asymp- tomatic throughout life, with the risk of symptoms dimin- ishing over time. In the unfortunate minority, however, the symptoms are striking. There is usually pain, often excru- ciating, which typically localizes to the right upper quad- rant or epigastric region and can be constant or, less commonly, spasmodic. Such “biliary” pain is caused by gallbladder or biliary tree obstruction, or by inflammation of the gallbladder itself. More severe complications include empyema, perforation, fistulas, inflammation of the biliary tree, and obstructive cholestasis or pancreatitis. The larger the calculi, the less likely they are to enter the cystic or common ducts to produce obstruction; it is the very small stones, or “gravel,” that are more dangerous. Occasionally a large stone may erode directly into an adjacent loop of small bowel, generating intestinal obstruction (gallstone ileus).
What is cholecystitis ?
What does the gallbladder look like in acute cholecystitis?
In severe cases what is seen?
What is seen in the gallbladder lumen?
What is empyema of the gallbladder?
In mild cases what is seen on the gallbladder wall? What is gangrenous cholecystitis? On histologic exam what is seen? In the absence of superimposed acute cholecystitis, what are the only signs of inflammation?
Cholecystitis
Inflammation of the gallbladder may be acute, chronic, or acute superimposed on chronic, and almost always occurs in association with gallstones.
In acute cholecystitis, the gallbladder usually is enlarged and tense, and it assumes a bright red or blotchy, violaceous color, the latter imparted by subserosal hemorrhages. The serosa frequently is covered by a fibrinous, or in severe cases, fibrinopurulent exudate. In 90% of cases, stones are present, often obstructing the neck of the gallbladder or the cystic duct. The gallbladder lumen is filled with cloudy or turbid bile that may contain fibrin, blood, and frank pus. When the contained exudate is mostly pus, the condition is referred to as empyema of the gallbladder. In mild cases the gallbladder wall is thickened, edematous, and hyperemic. In more severe cases the gallbladder is transformed into a green-black necrotic organ—a condition termed gangre- nous cholecystitis. On histologic examination, the inflam- matory reactions are not distinctive and consist of the usual patterns of acute inflammation (i.e., edema, leukocytic infil- tration, vascular congestion, frank abscess formation, or gan- grenous necrosis).
The morphologic changes in chronic cholecystitis are extremely variable and sometimes subtle. The mere presence of stones within the gallbladder, even in the absence of acute inflammation, often is taken as sufficient justification for the diagnosis. The gallbladder may be contracted, of normal size, or enlarged. Mucosal ulcerations are infrequent; the submu- cosa and subserosa often are thickened from fibrosis. In the absence of superimposed acute cholecystitis, mural lympho- cytes are the only signs of inflammation.
What is acute calculous cholecystitis? What precipitates it?
It is the most common major complication of what condition?
What are the manifestations of this condition with obstruction obstruction?
Acute calculous cholecystitis is initially the result of what?
What causes the inflammation?
What events occur in the absence of bacterial infection
What insults predispose someone to acute acalculous cholecystitis
How will chronic cholecystitis develop?
Acute Calculous Cholecystitis
Acute inflammation of a gallbladder that contains stones is termed acute calculous cholecystitis and is precipitated by obstruction of the gallbladder neck or cystic duct. It is the most common major complication of gallstones and the most common reason for emergency cholecystectomy. Manifestations of obstruction may appear with remarkable suddenness and constitute a surgical emergency. In some cases, however, symptoms may be mild and resolve without medical intervention.
Acute calculous cholecystitis is initially the result of chemical irritation and inflammation of the gallbladder wall in the setting of obstruction to bile outflow. The action of phospholipases derived from the mucosa hydrolyzes biliary lecithin to lysolecithin, which is toxic to the mucosa. The normally protective glycoprotein mucous layer is dis- rupted, exposing the mucosal epithelium to the direct detergent action of bile salts. Prostaglandins released within the wall of the distended gallbladder contribute to mucosal and mural inflammation. Distention and increased intraluminal pressure also may compromise blood flow to the mucosa. These events occur in the absence of bacterial infection; only later may bacterial contamina- tion develop.
Acute Acalculous Cholecystitis
Between 5% and 12% of gallbladders removed for acute cholecystitis contain no gallstones. Most cases occur in seri- ously ill patients. Some of the most common predisposing insults are
• Major, nonbiliary surgery
• Severe trauma (e.g., from motor vehicle crashes)
• Severe burns
• Sepsis
Other contributing factors include dehydration, gallblad- der stasis and sludging, vascular compromise, and, ulti- mately, bacterial contamination.
Chronic Cholecystitis
Chronic cholecystitis may be the sequel to repeated bouts of acute cholecystitis, but in most instances it develops without any history of acute attacks. Like acute cholecysti- tis it is almost always associated with gallstones. However, gallstones do not seem to have a direct role in the initiation of inflammation or the development of pain, because chronic acalculous cholecystitis causes symptoms and mor- phologic alterations similar to those seen in the calculous form. Rather, supersaturation of bile predisposes the patient to both chronic inflammation and, in most instances, stone formation. Microorganisms, usually E. coli and enterococci, can be cultured from the bile in only about one third of cases. Unlike acute calculous cholecystitis, stone obstruction of gallbladder outflow in chronic chole- cystitis is not a requisite. Most gallbladders removed at elective surgery for gallstones show features of chronic cholecystitis, making it likely that biliary symptoms emerge after long-term coexistence of gallstones and low-grade inflammation.
Clinical Features
Acute calculous cholecystitis presents with biliary pain that lasts for more than 6 hours. The pain is severe, usually steady, upper abdominal in location, and often radiates to the right shoulder. Fever, nausea, leukocytosis, and prostration are classic; the presence of conjugated hyperbilirubinemia suggests obstruction of the common bile duct. The right subcostal region is markedly tender and rigid as a result of spasm of the abdominal muscles; occasionally a tender, distended gallbladder can be pal- pated. Mild attacks usually subside spontaneously over 1 to 10 days; however, recurrence is common. Approximately 25% of symptomatic patients are sufficiently ill to require surgical intervention.
Symptoms arising from acute acalculous cholecystitis usually are obscured by the generally severe clinical condi- tion of the patient. The diagnosis therefore rests on keeping this possibility in mind.
Chronic cholecystitis does not have the striking manifesta- tions of the acute forms and is usually characterized by recurrent attacks of steady epigastric or right upper quad- rant pain. Nausea, vomiting, and intolerance for fatty foods are frequent accompaniments.
The diagnosis of acute cholecystitis usually is based on the detection of gallstones by ultrasonography, typically accompanied by evidence of a thickened gallbladder wall. Chronic cholecystitis, on the other hand, is a pathologic diagnosis based on the examination of the resected gall- bladder. Attention to this disorder is important because of the potential for the following serious complications:
• Bacterial superinfection with cholangitis or sepsis
• Gallbladder perforation and local abscess formation
• Gallbladder rupture with diffuse peritonitis
• Biliary enteric (cholecystenteric) fistula, with drainage of
bile into adjacent organs, entry of air and bacteria into the biliary tree, and potentially gallstone-induced intes- tinal obstruction (ileus)
• Aggravation of preexisting medical illness, with cardiac, pulmonary, renal, or liver decompensation
