Liver Disease -

Liver Disease -

Liver Disease Lecture 6 Introduction The liver has a central and critical biochemical role in the metabolism, digestion, detoxification, and elimination of substances from the body. All blood from the intestinal tract initially passes through the liver, where products derived from digestion of food are processed, transformed, and (in some cases) stored. These include amino acids, carbohydrates, fatty acids, cholesterol, lipids, vitamins, and minerals. Most major plasma proteins (with the exception of immunoglobulins [Igs] and the von Willebrand factor) are mainly or exclusively synthesized in the liver.

2 Introduction The liver responds to multiple hormonal and neural stimuli to regulate blood glucose concentrations. it stores dietary glucose as glycogen for later use. The major site for gluconeogenesis. Central in lipid metabolism; it extracts and processes dietary lipids, and it is the principal site of cholesterol, triglyceride, and lipoprotein synthesis. 3 The synthesis of bile acids from cholesterol,

with secretion of these compounds into the bile, which facilitates the absorption of dietary fat and fat-soluble vitamins. Introduction The liver is also the primary site of metabolism of both endogenous substances and exogenous compounds (eg, drugs and toxins). This process, known as biotransformation, converts lipophilic substances to hydrophilic ones for subsequent elimination. The liver is a major site of catabolism of hormones, and thus participates in regulation of plasma hormone concentrations. The liver is also involved in hormone synthesis, producing such hormones as insulin-like growth factor 1, angiotensinogen, hepcidin, prohormone 25-OH vitamin D.

Many of these hepatic functions can be assessed by laboratory procedures to gain insight into the integrity of the liver. 4 Introduction 5 As a large organ, the liver shares with many other organs the ability to perform its functions with extensive reserve capacity. In many cases, individuals with liver disease maintain normal function despite extensive liver damage. In such cases, liver disease may be recognized only by using tests that detect injury.

Most commonly, this is accomplished by measuring plasma activities of enzymes found within liver cells, which are released in somewhat specific patterns with different forms of injury. Introduction Chronic liver injury often involves fibrosis in the liver; markers of the fibrotic process might be indicators of the degree of injury. Chronic damage is often due to chronic inflammation; cytokines alter the pattern of liver protein production, which allows detection of inflammation. Some proteins are produced in increased amounts with liver regeneration and neoplasia; such markers may be useful in

detecting liver cell proliferation. 6 CLINICAL MANIFESTATIONS OF LIVER DISEASE Various characteristics indicate the presence of liver disease, including: Fibrosis, Jaundice, Portal hypertension, an increase in the blood pressure within a system of veins called the portal venous system Veins coming from the stomach, intestine, spleen, and pancreas merge into the portal vein, which then branches into smaller vessels and travels through the liver. If the vessels in the liver are blocked due to liver damage, blood cannot

flow properly through the liver. As a result, high pressure in the portal system develops. This may lead to the development of large, swollen veins (varices) within the esophagus, stomach, rectum, or umbilical area (belly button). Varices can rupture and bleed, resulting in potentially life-threatening complications. 7 CLINICAL MANIFESTATIONS OF LIVER DISEASE The portal-venous system. HV, Hepatic vein; IMV, inferior mesenteric vein; IVC, inferior vena cava; LGV, left gastric vein;

LRV, left renal vein; PV, portal vein; RRV, right renal vein; SMV, superior mesenteric vein; SV, splenic vein. 8 CLINICAL MANIFESTATIONS OF LIVER DISEASE Abnormal renal function, Portal hypertension is a common factor in all cases of Hepatorenal Syndrome that develop in chronic liver disease, but HRS may also occur in acute liver failure. Altered drug metabolism,

This is reflected in delayed metabolism. Only patients with evidence of liver failure, such as encephalopathy, coagulopathy, or ascites, need alterations in dosing. 9 CLINICAL MANIFESTATIONS OF LIVER DISEASE 10 CLINICAL MANIFESTATIONS OF LIVER DISEASE Nutritional and metabolic abnormalities, alterations in glucose metabolism hypokalemia caused by secondary

hyperaldosteronism hypoalbuminemia is frequently present because of decreased production and sinusoidal leakage of albumin in patients with portal hypertension in patients with chronic cholestasis, impaired delivery of bile salts to the duodenum may result in malabsorption of lipids and fatsoluble vitamins, leading to deficiencies in vitamins A, D, E, and K 11 CLINICAL MANIFESTATIONS OF LIVER DISEASE Disordered hemostasis, The liver manufactures most of the soluble clotting factors (the major exceptions being factor VIII and von Willebrand factor) and a

number of inhibitors of clotting (proteins C and S, antithrombin III). The liver also clears activated clotting factors from the circulation. Bile acids are necessary for vitamin K absorption and are needed to produce the active forms of several clotting factors, as well as proteins C and S 12 CLINICAL MANIFESTATIONS OF LIVER DISEASE Release of enzymes into various body fluids Enzymes are found at different locations within cells. AST and ALT are cytosolic enzymes. As such, they can be released with cell injury and appear in

plasma relatively rapidly. In contrast, ALP and GGT are membrane-bound glycoprotein enzymes. The most important location of both enzymes is on the canalicular membrane of hepatocytes. 13 Cell injury, the simplest mechanism, appears to allow leakage of cytoplasmic enzymes from cells GGT and ALP into the circulation is less well understood. GGT and ALP into the circulation is less well understood. DISEASES OF THE LIVER The liver has a limited number of ways of

responding to injury. Acute injury to the liver may be asymptomatic, but often presents as jaundice. The major acute liver disorders are acute hepatitis and cholestasis. Chronic liver injury generally takes the clinical form of chronic hepatitis; its long-term complications include cirrhosis and HCC. 14 DISEASES OF THE LIVER Mechanisms and Patterns of Injury Cell death occurs by necrosis (death of cell) or apoptosis (programmed cell death) or both.

The target cell determines the pattern of injury, with hepatocyte injury leading to hepatocellular disease and biliary cell injury leading to cholestasis. All cellular injury induces fibrosis as an adaptive or healing response, with the duration of injury and genetic factors determining whether cirrhosis and ultimately carcinoma occur. 15 DISEASES OF THE LIVER Mechanisms and Patterns of Injury 16

DISEASES OF THE LIVER Mechanisms and Patterns of Injury Cellular necrosis occurs as the result of an injurious environment has been referred to as murder. It is characterized by cellular swelling with loss of membrane integrity. Toxic injury from compounds such as carbon tetrachloride, aspirin, and acetaminophen occurs for the most part by necrosis. Apoptosis occurs as the result of accelerated programmed death in which the cell participates in its own demise and thus commits suicide. It is characterized by cell shrinkage, with nuclear

chromatin condensation and fragmentation forming apoptotic bodies. Most forms of hepatitis are associated with apoptosis. Both typically leads to leakage of cytoplasmic enzymes. 17 DISEASES OF THE LIVER Mechanisms and Patterns of Injury Laboratory tests are helpful in distinguishing between: The pattern of injury (hepatocellular vs cholestatic), the aminotransferase enzymes and ALP are used The chronicity of injury (acute vs chronic), plasma albumin determines the chronicity

the severity of injury (mild vs severe) the PT or factor V concentration determines the severity 18 Classically, liver fibrosis has been assessed using liver biopsy, but in recent years several noninvasive methods of assessment of liver fibrosis have been described and evaluated. Although liver biopsy yields incomparable information about the nature, severity, and chronicity of liver disease, noninvasive tests may provide more accurate assessment of liver fibrosis, and in particular, disease severity and prognosis. DISEASES OF THE LIVER

Disorders of Bilirubin Metabolism 19 DISEASES OF THE LIVER Acute Hepatitis Acute hepatitis refers to an acute injury directed against the hepatocytes. The injury may be mediated: Directly, which occurs with certain drugs, such as acetaminophen or with ischemia, a typical rapid rise in cytosolic enzymes, such as AST, ALT, and lactate dehydrogenase (LDH), is followed by a rapid fall, with rates of decline similar to known halflives of the enzymes.

Indirectly, which occurs with immunologically mediated injury from most of the hepatitis viruses and most drugs, including ethanol. 20 With immunologic injury, a gradual rise in cytosolic enzymes occurs, followed by a plateau phase and gradual resolution of enzyme elevation DISEASES OF THE LIVER Acute Hepatitis Although jaundice is a key clinical finding in acute hepatitis, it is often absent. An increase in AST & ALT enzymes has sensitivity and specificity greater than 90%

for acute hepatitis: AST activity to greater than 200 U/L or ALT activity to greater than 300 U/L ALP usually is mildly elevated: typically is < 3 times the upper reference limit in 90% of cases of acute hepatitis. 21 DISEASES OF THE LIVER Acute Hepatitis Increased plasma concentration of bilirubin, when present, typically is predominantly due to direct reacting bilirubin; indirect bilirubin is higher than direct bilirubin

in approximately 15% of cases. The distribution of direct bilirubin percentage is identical in acute hepatitis and bile duct obstruction, making the relative amount of direct bilirubin inconsequential in the differential between hepatitis and obstruction. 22 DISEASES OF THE LIVER Acute Hepatitis Liver synthetic function usually is well preserved in most forms of acute hepatitis. The outcome of acute hepatitis is variable. In most cases, complete recovery occurs, and

liver regeneration leads to normal structure and function. With some viruses, failure to clear infection leads to development of chronic hepatitis. In a small percentage of cases, massive destruction of the liver leads to acute (fulminant) hepatic failure, which is associated with high mortality unless liver transplantation is performed. 23 DISEASES OF THE LIVER Acute Hepatitis 24

DISEASES OF THE LIVER Acute Hepatitis: Toxic Hepatitis Toxic hepatitis refers to direct damage of hepatocytes by a toxin or toxic metabolite. Toxic reactions are usually predictable and are directly related to the dose of the agent ingested. In North America and Europe, the most common cause of toxic hepatitis (and the most common cause of acute liver failure) is acetaminophen, a widely used nonprescription pain reliever. The metabolism of acetaminophen is affected by: Dose, Induction of metabolic enzymes, and Concentrations of glutathione. 25

DISEASES OF THE LIVER Acute Hepatitis: Toxic Hepatitis When a large dose of acetaminophen is ingested (average lethal dose as a single ingestion is 15 g), The metabolic pathways are overcome, glutathione is depleted, and toxic intermediates accumulate, causing liver damage. When metabolic enzymes are induced (such as by ethanol) or glutathione is depleted (which occurs in alcoholism and with starvation), toxicity can occur with relatively small doses of acetaminophen (total doses of 24 g).

Toxicity can also occur with excessive cumulative doses of acetaminophen; such accidental overdoses appear to be responsible for approximately one-half of cases of toxicity. 26 DISEASES OF THE LIVER Acute Hepatitis: Toxic Hepatitis Non-toxic Non-toxic 27 NAPBQI (N-acetyl-p-benzoquinone imine)

DISEASES OF THE LIVER Acute Hepatitis: Toxic Hepatitis Diagnosis is often based on: History and increased acetaminophen concentrations; In patients who present later, and for whom a history cannot be obtained, measurement of acetaminophen-protein adducts allows diagnosis. The first laboratory abnormality to appear is: An increase in PT, 4 seconds above the control value in most cases

followed by increased activity of cytosolic enzymes, with AST tending to be higher than ALT. 28 Peak activities (typically >100 times the upper reference intervals) usually occur by 24 to 48 hours, followed by rapid clearance at rates approximating the known half-lives of the enzymes. DISEASES OF THE LIVER Acute Hepatitis: Toxic Hepatitis Prognosis is related most closely to the prolonged increase in PT; Persistent elevation of PT 4 days after

ingestion is associated with a poor prognosis. Other markers of risk include development of acute renal failure and the presence of lactic acidosis, particularly if the pH is less than 7.30. 29 DISEASES OF THE LIVER Acute Hepatitis: Ischemic Hepatitis (Shock Liver) Hepatic hypoperfusion (ischemic hepatitis) is one of the most common causes of elevated cytosolic enzymes; in hospital patients, it is

the cause of most cases of acute hepatitis. Ischemic hepatitis may follow any cause of shock; The most common causes are septic and cardiogenic shock Not all patients with shock develop ischemic hepatitis; 30 in one recent study, only 13.8% of those with septic shock did, but mortality was significantly higher in such patients. DISEASES OF THE LIVER

Acute Hepatitis: Ischemic Hepatitis (Shock Liver) Another study found that cardiac dysfunction, especially right heart failure, appeared necessary to cause the clinical picture of ischemic hepatitis. Bilirubin elevations typically are minimal, and they usually peak several days after enzyme activity reaches its greatest point. Laboratory findings are similar to those seen in toxic hepatitis, and acute renal failure is a common complicating factor. Prognosis is primarily related to the underlying cause of hypotension; individuals with prolonged elevation of bilirubin appear to have a poor prognosis. 31

DISEASES OF THE LIVER Acute Hepatitis: Other Causes of Acute Hepatitis Alcoholic hepatitis Alcoholic hepatitis is often suspected by the combination of mild elevations in enzymes (peak AST typically <300 U/L), AST/ALT ratio >2, and leukocytosis. 32 DISEASES OF THE LIVER Acute Hepatitis: Other Causes of Acute Hepatitis Drugs

Drugs can cause liver injury through a number of mechanisms, but the most common is immunemediated injury to hepatocytes. Criteria used to recognize drug-induced liver injury include: A temporal relationship between drug exposure and onset of hepatitis, Exclusion of other known causes of hepatitis, The presence of extrahepatic hypersensitivity especially skin rash, arthralgia, renal injury, and eosinophilia 33 The development of liver injury on rechallenge, Previously published reports of similar reactions. DISEASES OF THE LIVER

Acute Hepatitis: Other Causes of Acute Hepatitis 34 Although usually associated with prescription drugs, complementary and alternative products are becoming increasingly recognized as causes of acute hepatitis and in a US study, these products were responsible for 9% of all cases. Although drug reactions typically develop soon after that start of treatment, several months may elapse between the time of initial exposure and development of acute hepatitis. Approximately 60% of cases cause severe acute hepatitis with jaundice. Serious reactions are more common in individuals who

are continued on the medication. In 15% to 30% of cases, liver injury persists and becomes chronic after cessation of the drug. DISEASES OF THE LIVER Acute Hepatitis: Other Causes of Acute Hepatitis Some of the disorders that usually produce chronic may occasionally present in an acute fashion. Auto-immune hepatitis (AIH) has an acute component in up to 40% of cases. Clinically, it differs from other forms of acute hepatitis because it is characterized by: decreased albumin, increased globulins, and a more prolonged increase in aminotransferases.

Acute AIH is diagnosed by the absence of other causes of acute hepatitis and the presence of autoimmune markers. 35 DISEASES OF THE LIVER Approach to the Patient With Acute Hepatitis Once a diagnosis of acute hepatitis has been established, additional laboratory testing is usually required to determine the cause. Although the incidence of acute viral hepatitis has decreased, serologic studies should be performed to rule out infectious causes. A typical panel of tests should include:

IgM anti-HAV, HBsAg, IgM anti-HBc, anti-HCV, and HCV RNA (or HCV core antigen, if available). 36 Marked elevations (>100 times the upper reference intervals) in AST or ALT, particularly if AST is higher than ALT, should suggest the possibility of toxic or ischemic liver injury. DISEASES OF THE LIVER Approach to the Patient With Acute Hepatitis Minimal increases (<8 times the reference interval) in AST, with AST greater than ALT, in a patient with jaundice and leukocytosis indicate likely alcoholic

hepatitis. Imaging studies of the biliary tract are appropriate to rule out obstruction in those who present with sudden onset of symptoms, especially if accompanied by: right upper quadrant pain and tenderness, laboratory evidence of pancreatitis, or a history of gallstones. The presence of increased plasma globulin and decreased albumin concentrations suggest the possibility of AIH, while the presence of hemolytic anemia and acute renal failure, should suggest the possibility of Wilson disease. 37 DISEASES OF THE LIVER Acute Hepatitis

38 DISEASES OF THE LIVER Chronic Hepatitis Chronic hepatitis is defined as chronic inflammation of the liver that persists for at least 6 months, or signs and symptoms of chronic liver disease in the presence of elevated cytosolic enzymes. It is characterized by ongoing inflammatory damage to hepatocytes, which are often accompanied by hepatocyte regeneration and scarring. Formerly, chronic hepatitis was subdivided into three forms (chronic persistent, chronic lobular,

and chronic active) based on histologic characteristics. 39 DISEASES OF THE LIVER Chronic Hepatitis Chronic persistent inflammatory activity confined to portal areas. Chronic lobular inflammatory activity and necrosis scattered throughout the lobule -- good prognosis. Chronic active inflammation that spilled into the adjacent lobule associated with necrosis and fibrosis, which progress to

cirrhosis and liver failure 40 It was recognized that individuals often had each of these diseases at different points in time, and often in different areas of the liver in the same biopsy. Current classifications describe the cause and evaluate the severity of inflammatory injury (termed grade) and the extent of fibrosis (termed stage). 41 DISEASES OF THE LIVER Chronic Hepatitis

42 DISEASES OF THE LIVER Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis 43 Nonalcoholic fatty liver disease is now a major cause of chronic liver disease and is increasing in prevalence. Ludwig and colleagues first described patients who had histologic features identical to those of alcoholic hepatitis (including hepatocyte ballooning, presence of Mallory hyaline, and

neutrophil infiltration), but who had no history of heavy alcohol intake (< 20 g/day) and did not have AST values higher than ALT values. They introduced the term NASH to describe this entity, which was more common in women than in men, and was usually associated with diabetes and/or obesity. DISEASES OF THE LIVER Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis Black arrowhead: Mallory's hyaline bodies (pink filamentous structures).

Black arrow: ballooned hepatocytes. White arrow: hepatocytes containing fat globules. White arrowhead: displaced nucleus 44 DISEASES OF THE LIVER Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis 45

DISEASES OF THE LIVER Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis It is now recognized that NAFLD is associated strongly with the presence of the metabolic syndrome; almost half of individuals who meet the criteria for metabolic syndrome have NAFLD, and as many as 20% to 30% of the population in North America and Europe has NAFLD, making it far and away the most common form of liver disease and an extremely common condition in the population in the developed world.

Approximately 10% of those with NAFLD have the more severe form, NASH. The frequency in obese or diabetic individuals is much higher, with NAFLD in 60% to 75% and NASH in 20% to 25%. 46 47 DISEASES OF THE LIVER Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis The frequency of cirrhosis in NASH is not well established, but it has been suggested that

NASH may be a major cause of cryptogenic cirrhosis, that is, cirrhosis for which no underlying cause can be determined. Because weight loss develops with chronic illness, fat may disappear from the liver, leaving only fibrosis. 48 DISEASES OF THE LIVER Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis Current evidence suggests that accumulation of fat in NAFLD is a consequence of insulin resistance.

A variety of mechanisms may lead to insulin resistance, including genetic predisposition, increased concentrations of free fatty acids, and the presence of cytokines such as TNF-. Because TNF- is produced at a rate that correlates with body fat mass, and is critical to development of insulin resistance in obesity, it may be a key factor in the development of NAFLD. However, the pathogenesis is more complicated because a variety of other factors lead to increased fat accumulation in the liver, but they have not been associated with the development of NASH, including: 49 increased carbohydrate intake, certain drugs, and

IRS1 is no longer phosphorylated on its tyrosine residues but on serine residues, resulting in nonfunctional, inhibitory proteins. TNF-; also influences increased gene expressions of TNF-; but decreases GLUT4 expressions, resulting in lower levels of GLUT4 proteins. Glucose uptake is reduced, leading to hyperglycemia and hyperinsulinemia.

50 IR: insulin receptor; Y: tyrosine; S: serine; IRS1: insulin receptor substrate 1; PI3K: phosphoinositide kinase 3; PIP2: phosphatidylinositol 4,5-bisphosphate; TNF-: tumour necrosis factor; ; FFA: free fatty acid; IKK: a type of serine kinase; ROS: reactive oxygen species; PPAR: peroxisome proliferator activatorreceptor; ; GLUT4: glucose transporter 4. DISEASES OF THE LIVER Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis A clinical approach to the identification of patients with NASH typically involves:

A compatible clinical history and the presence of steatosis on imaging studies, Exclusion of other causes of liver injury, and May include liver biopsy to confirm the diagnosis and determine the extent of injury (but not if patients improve clinically with weight loss and exercise). Although increased activities of liver enzymes are often used to distinguish NASH from other forms of NAFLD, the degree of necroinflammatory damage is not related to elevations in AST or ALT activity, and the likelihood of significant liver damage is similar in those with normal or elevated ALT. 51 DISEASES OF THE LIVER

Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis 52 The search for laboratory tests capable of identifying the minority of patients with NASH among the large numbers of individuals with NAFLD have highlighted cytokeratin 18 (CK18) and N-terminal procollagen III propeptide (PIIINP) as potential serum markers of NASH. Greater progress has been made in the identification and validation of blood tests for liver fibrosis in NAFLD with a variety of indirect and direct tests being validated for this purpose,

including the NAFLD Fibrosis Score, BARD (calculated from body mass index, AST/ALT ratio and diabetes), and the Enhanced Liver Fibrosis (ELF) test. NAFLD Fibrosis Score 53 BARD score 54 DISEASES OF THE LIVER Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis

Of these, both the NAFLD Fibrosis Score and ELF tests have been shown to predict longterm outcomes in NAFLD. It remains to be seen if these tests either alone or in conjunction with other tests will be capable of accurately stratifying patients with NAFLD into: those with NASH and those with fibrosis. 55 DISEASES OF THE LIVER Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis

To date, major treatments for NAFLD have been aimed at lowering body weight and fat content. Loss of weight is often associated with decreased ALT values; in one study, a 1% decrease in weight was associated with an 8% decrease in ALT activity. 56 The association of NAFLD with insulin resistance has suggested treatment with antidiabetic medications, particularly those that increase insulin responsiveness; studies have not been conclusive as to the benefits of

such treatment. DISEASES OF THE LIVER Chronic Hepatitis: Autoimmune Hepatitis (AIH) AIH represents a rapidly progressive form of chronic hepatitis, with up to 40% 6-month mortality in untreated individuals; Associated with the presence of autoimmune markers. It is relatively uncommon, An annual incidence of 1.9 cases per 100,000 population in the United States, but it is responsible for 3% to 6% of all liver transplantations; The disease recurs in approximately 30% of patients after transplantation.

Forms of AIH have been found in individuals of all ages, with no racial or ethnic preference. It has been associated with specific HLA haplotypes, notably DR3 and DR4, as is true for many other autoimmune diseases. 57 DISEASES OF THE LIVER Chronic Hepatitis: Autoimmune Hepatitis AIH is associated with the presence of liver and nonliver autoantibodies in plasma. These are helpful in diagnosis but are not likely to be the cause of liver injury.

The most important antibodies for diagnosis include: Antinuclear antibody (ANA), Antismooth muscle (or anti-actin) antibody (ASMA), Anti-liverkidney microsomal antigen type 1, and Antisoluble liver antigen (SLA), which is insensitive but highly specific. 58 DISEASES OF THE LIVER Chronic Hepatitis: Autoimmune Hepatitis A variety of other autoantibodies are found frequently in AIH, some of which are found in

other disorders. Tests for these autoimmune markers: initially used cell or tissue preparations studied by indirect immunofluorescence, but these have largely been replaced by assays that detect antibodies to purified proteins. 59 DISEASES OF THE LIVER Chronic Hepatitis: Autoimmune Hepatitis Criteria for the diagnosis of AIH were developed by an international group and subsequently revised; a simplified scoring system has also been developed.

The simplified criteria include: 60 Exclusion of viral hepatitis, Increased plasma IgG concentration, Positive autoantibodies, and Compatible histologic features. It is controversial whether AIH should be further divided into subtypes; the international group that classified diagnostic criteria does not recommend use of subtypes, but many authorities recognize

three different forms (types 1, 2, and 3). DISEASES OF THE LIVER Chronic Hepatitis: Autoimmune Hepatitis Although differences in epidemiology may be evident among the different subtypes, there do not seem to be differences in clinical course or response to treatment. Immunosuppressive treatment using prednisone, alone or in combination with azathioprine, is effective in inducing clinical remission of disease in approximately 80% of cases; other immunosuppressants are now being used to reduce dependence on corticosteroids. Because inherited differences in the activity of thiopurine methyltransferase affect approximately 10% of the population, it has been recommended that

pretreatment determination of enzyme activity should be used to reduce the likelihood of toxicity. 61 DISEASES OF THE LIVER Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic HepatitisHemochromatosis Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism that results in excessive iron absorption and accumulation in tissues, specifically in the parenchymal cells of the liver, heart, pancreas, and other organs. HH is caused by mutations that affect any of the proteins that control the entry of iron into the circulation. These proteins include:

62 Hepcidin, HFE, transferrin receptor 2 (Tfr2), hemojuvelin (HJV) These proteins all sense iron accumulation that hepcidin acts to correct The protein ferroportin (Fpn), which is a cellular transporter of iron down-regulated by hepcidin. 63 DISEASES OF THE LIVER 64 Chronic Hepatitis: Inherited Liver Disease

Presenting as Chronic HepatitisHemochromatosis Hepcidin is believed to be the major regulator of dietary iron absorption and cellular iron release. It exerts its regulatory function by counteracting the function of Fpn, the major cellular iron exporter in the membrane of macrophages, hepatocytes, and the basolateral site of enterocytes. Hepcidin induces the internalization and degradation of Fpn, which results in: Increased intracellular iron stores, Decreased dietary iron absorption, and Decreased circulating iron concentrations. DISEASES OF THE LIVER

65 Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic HepatitisHemochromatosis Patients with most forms of HH are unable to appropriately upregulate hepcidin synthesis in response to increased iron stores. Most cases of hemochromatosis are caused by alterations in the genes that regulate hepcidin

synthesis, including HFE, Tjr2, and Hjv. Deficiency of hepcidin activity in macrophages and enterocytes leads to unrestricted Fpnmediated iron export into the circulation. Hepcidin secretion is part of the innate immune response induced by inflammation and infection that serves to restrict available iron for use by invading pathogens. DISEASES OF THE LIVER Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic HepatitisHemochromatosis Under conditions of low Tf saturation with Fe, the HFE remains largely bound to TfR1 in the PM, and is in a competitive

equilibrium with Fe-bound Tf, as they bind to overlapping sites on TfR1. Monoferric Tf-Fe will be the predominant species under these conditions, and TfR2 will be directed into a lysosomaldegradative pathway. 66 DISEASES OF THE LIVER Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic HepatitisHemochromatosis Under conditions of high Tf saturation with Fe, where the diferric form wil

predominate, Tf-Fe will outcompete HFE for binding to TfR1, leading to the increased dissociation of HFE/TfR1 complexes and an increased proportion of HFE/TfR2 complexes. These latter complexes are thought to activate a signaling cascade to upregulate transcription and expression of hepcidin. Additionally, under conditions of increased Tf saturation with Fe, Tf-Fe will be increasingly bound to TfR2, which will direct the protein away from the lysosomal-degradative route and effectively increase its PM expression. 67

DISEASES OF THE LIVER 68 Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic HepatitisHemochromatosis Hepcidin has a central role in maintenance of iron homeostasis. Hepcidin synthesis is regulated at the transcriptional level by multiple stimuli.

Hepcidin transcription is increased in cases of: Intracellular and extracellular iron concentrations, as does inflammation, While Hepcidin transcription is decreased in: Cases of increased erythropoietic activity In turn, hepcidin regulates plasma iron concentrations by controlling ferroportin concentrations on iron-exporting cells. DISEASES OF THE LIVER Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic HepatitisHemochromatosis 69

DISEASES OF THE LIVER Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic HepatitisHemochromatosis Untreated, HH can lead to serious complications including: liver fibrosis and cirrhosis with HCC in approximately 30% of patients with cirrhosis, diabetes mellitus, cardiomyopathy, and arrhythmias. Cardiac and endocrine cells are more susceptible to rapid iron loading because they have more mitochondria and less antioxidants 70 DISEASES OF THE LIVER

Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic HepatitisHemochromatosis Liver disease due to hemochromatosis is rare in younger individuals, but becomes more common after the age of 30 years. Liver function tests are frequently normal in asymptomatic patients but may be abnormal in symptomatic patients. The most useful tests are fasting transferrin saturation and serum ferritin. The transferrin saturation reflects increased iron absorption, and a value more than 45% is the most sensitive marker of early iron overload, 71

but neither a raised fasting transferrin saturation nor ferritin concentration is diagnostic of HH. Ferritin is also an acute-phase reactant and can be raised nonspecifically in the presence of alcohol consumption, inflammation, and other liver disease. DISEASES OF THE LIVER 72

Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic HepatitisHemochromatosis Serum ferritin is considered to be abnormal when it is more than 250 g/L in premenopausal g/L in premenopausal women and more than 300 g/L in premenopausal g/L in men and postmenopausal women. If the fasting transferrin saturation or serum ferritin is elevated on more than one occasion, HH should be suspected, even if there are no clinical symptoms or abnormal liver function tests. In this situation, the HFE gene test should be requested. Iron studies may be normal in individuals with a genetic predisposition to HH who have not developed iron overload. DISEASES OF THE LIVER

Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic HepatitisHemochromatosis 73 Up to 40% of homozygotes have normal results in iron studies, which may be due to overt (blood donation) or covert (gynecological or GI) blood loss. The likelihood of liver disease is related to serum ferritin concentrations. Follow-up of all patients with iron overload should occur regardless of the HFE gene test. It is suggested that if the patient is C282Y homozygous without iron overload, then iron studies should be repeated every 2 to 5 years. If the patient is C282Y homozygotic and has iron

overload, then lifelong venesection is necessary, usually every 2 to 3 months after the results of iron studies have become normal. DISEASES OF THE LIVER 74 Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic HepatitisHemochromatosis The patient should also reduce their red meat.

Non-cirrhotic patients who are treated early have a normal life expectancy. Cirrhosis is unlikely if the ferritin is less than 1000 g/L in premenopausal g/L, plasma AST activities are normal, and there is no hepatomegaly. Cirrhotic patients rarely regress to normal and have a lifelong risk of HCC. DISEASES OF THE LIVER 75

Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic Hepatitis-Wilson Disease Wilson disease is an autosomal recessive disorder of copper metabolism. It has a gene frequency of 1 in 200 and a disease frequency of 1 in 30,000. It is due to 1 of more than 200 mutations in a gene on chromosome 13 that codes for a copper-transporting adenosine triphosphatase (ATP7B). This enzyme, found mainly in the liver, is involved in movement of copper into bile; deficiency leads to accumulation of copper in the liver and eventually in other tissues.

DISEASES OF THE LIVER Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic Hepatitis-Wilson Disease 76 Wilson disease usually manifests at age younger than 30 years, and for reasons that are unknown, patients usually present either with the hepatic or the neuropsychiatric form of the disease. In children, hepatic involvement tends to predominate, whereas in adolescents and adults, the neuropsychiatric form becomes more common. Patients presenting with neuropsychiatric manifestations commonly have advanced liver disease at the time of

presentation, whereas those presenting with liver disease may have little in the way of neurologic damage. Hepatic manifestations include fulminant hepatitis (as discussed earlier), but more commonly chronic hepatitis, with or without cirrhosis, is the presenting finding. Occasionally, the features mimic those of AIH, with increased plasma globulins and positive ANAs. DISEASES OF THE LIVER Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic Hepatitis-Wilson Disease The classic clinical finding of increased copper deposition in the eye is the Kayser-Fleischer ring, caused by deposition of copper at the edge of the cornea.

Although found in approximately 95% of patients with neurologic or psychiatric manifestations, it is present in only approximately one-half of patients with hepatic forms of Wilson disease and is rarely present in children. 77 Hemolytic anemia and renal failure commonly accompany acute forms of Wilson disease; hemolytic anemia may be episodic even in chronic forms of Wilson disease. DISEASES OF THE LIVER Chronic Hepatitis: Inherited Liver Disease

Presenting as Chronic Hepatitis-Wilson Disease Several laboratory tests are available for the diagnosis of Wilson disease; ceruloplasmin measurement and copper measurement. Test results are often affected by other conditions, sometimes making diagnosis difficult. Classic findings of Wilson disease include: Decreased plasma ceruloplasmin, Decreased total plasma copper, Increased plasma-free (or non-ceruloplasmin) copper,

Increased urine copper excretion, and Increased hepatic copper content. Ceruloplasmin is a ferroxidase that typically is measured by enzymatic activity or by immunoassay. 78 DISEASES OF THE LIVER 79

Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic Hepatitis-Wilson Disease Plasma ceruloplasmin concentrations are low in infants, gradually rise to higher concentrations than adult concentrations in early childhood, then gradually decline to adult concentrations. Use of age-appropriate reference intervals is critical for diagnosis in children. Ceruloplasmin is an acute-phase protein, and its synthesis is induced by estrogen; concentrations may be falsely normal with acute illness or with high estrogen states. Low concentrations of ceruloplasmin are seen with malnutrition, in protein-losing states, and in cirrhosis of any cause.

DISEASES OF THE LIVER Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic Hepatitis-Wilson Disease 80 Treatment of active, symptomatic Wilson disease is aimed at increasing urine copper excretion to eliminate excess copper from tissue. The primary therapy for Wilson disease usually involves chelating agents such as D-penicillamine and trientine, which is now more widely used because of its lower rate of side effects. Zinc (particularly zinc acetate) inhibits copper

absorption from the intestinal tract; it is usually used for maintenance treatment after copper chelation, but it can also be used as initial therapy. Monitoring treatment (particularly with zinc) by annual measurement of urine copper excretion can be helpful in ensuring that excess copper is no longer being excreted. DISEASES OF THE LIVER Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic Hepatitis-Alpha1-Antitrypsin Deficiency 81 Alpha1-antitrypsin (AAT) is the most important of the

serine protease inhibitors. As its name implies, AAT inhibits trypsin, but it also inhibits other proteolytic enzymes, including neutrophilderived elastase, cathepsin G, and proteinase 3. The gene for AAT (originally called PI, but now called SERPINA1) is located on chromosome 14. Several genetic variants of AAT (differing by a single amino acid) have been classified on the basis of their electrophoretic mobility; the slowest migrating of these was termed the Z variant. Some variants, particularly S and Z, form loop sheet polymers, causing impaired release from the endoplasmic reticulum, hepatocytic inclusions of AAT, and reduced plasma concentrations. DISEASES OF THE LIVER Chronic Hepatitis: Inherited Liver Disease

Presenting as Chronic Hepatitis-Alpha1-Antitrypsin Deficiency 82 The effects of AAT deficiency on the liver are controversial. In neonates, AAT deficiency is often associated with hepatitis; in one study, almost one-third of infants with prolonged jaundice were found to be AAT deficient. Approximately 20% of AAT-deficient infants develop hepatitis, with up to 25% 1-year mortality. However, in those who survive the first year, evidence of liver injury diminishes and usually resolves by age 12 years. At age 18 years, none of 183 individuals with AAT deficiency had clinical evidence of liver disease, none

had elevated plasma procollagen III peptide concentrations, and less than 20% had increased concentrations of liver-associated enzymes. DISEASES OF THE LIVER Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic Hepatitis-Alpha1-Antitrypsin Deficiency 83 Some evidence suggests that AAT deficiency may increase risk of liver damage from other factors. In one study, most individuals with AAT deficiency and liver injury were also positive for anti-HCV; only 11% had no other liver risk factors.

In those with AAT deficiency and no evidence of liver disease (usually viral-related), life expectancy was no different from that of healthy controls. A 2007 research conference found evidence that defects in degradation of AAT underlie differences in protein accumulation, which is necessary for the development of liver disease. It is likely that, as with hemochromatosis, the abnormal form of AAT is necessary, but perhaps not sufficient, to cause liver disease. DISEASES OF THE LIVER Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic Hepatitis-Alpha1-Antitrypsin Deficiency AAT is estimated by protein electrophoresis, in which it

constitutes most of the 1-globulin band; this was the original means by which AAT deficiency was recognized. It can also be quantified by a variety of other techniques. AAT is an acute-phase response protein; misleadingly normal concentrations have been reported in approximately 40% of PiZ heterozygotes, although rarely in PiZZ homozygotes. This is due to the acute-phase response elevating AAT concentrations into the reference range, a consequence that may affect other proteins produced by the liver, including ferritin and ceruloplasmin. 84 DISEASES OF THE LIVER

Chronic Hepatitis: Inherited Liver Disease Presenting as Chronic Hepatitis-Alpha1-Antitrypsin Deficiency Determination of phenotype was typically accomplished by isoelectric focusing and had been recommended as the diagnostic test of choice in one guideline, but phenotyping cannot distinguish true homozygotes from heterozygotes who have a null genotype on the other AAT gene. Molecular tests are now available to determine AAT genotype. Because the prognosis may vary between those who are actually homozygous for the Z variant and those with null phenotype, molecular testing of the SERPINA1 gene is considered preferable. 85

86 DISEASES OF THE LIVER Chronic Hepatitis: Drug-Induced Liver Injury 87 Most cases of drug-induced liver injury present as acute hepatitis. Less commonly, drugs have produced chronic liver injury in a pattern that mimicks chronic hepatitis or other chronic liver injury (chronic cholestasis and hepatic granulomas). The drugs most commonly linked to chronic hepatitis are nitrofurantoin, methyldopa, and

hydroxy-3-methylglutaryl-CoA reductase inhibitors; however, a large number of drugs have been associated with liver injury, and herbal medications have been linked to chronic hepatitis. DISEASES OF THE LIVER Chronic Hepatitis: Drug-Induced Liver Injury 88 In individuals with increased activities of aminotransferases and no obvious cause, prescription drug use was significantly more likely to be present than in those with a known

cause for elevated enzyme activities. As with acute drug reactions, establishing drugs as the cause of chronic hepatitis is difficult; temporal relationships to drug ingestion are not as clear as with acute hepatitis, and reactions can be seen first in those who have been taking the medication for many months. Most chronic drug reactions resolve when administration of the drug is discontinued DISEASES OF THE LIVER Chronic Hepatitis: Significance of Chronic Hepatitis 89

In many cases, chronic hepatitis is a disease with minimal consequences. An average of 20% to 30% of individuals with chronic HBV or HCV progress to cirrhosis over a 20-year period. The frequency of cirrhosis and HCC has been increasing in much of the Western world, mostly caused by the increase in cases related to HCV. The proportions of individuals with HCV with cirrhosis and HCC are expected to double by 2020, and the number of deaths caused by liver disease is expected to almost triple. DISEASES OF THE LIVER Chronic Hepatitis: Significance of

Chronic Hepatitis The ability to predict which patients are at increased risk for such late complications of chronic hepatitis would allow more appropriate treatment. Even with the advent of highly effective and well tolerated treatments for HCV, it is likely to be decades before the burden of infection is brought under control sufficiently to reduce the incidence of complications of disease and the necessity for liver transplantation, making the search for a prophylactic vaccine an imperative. 90 DISEASES OF THE LIVER

Chronic Hepatitis: Significance of Chronic Hepatitis The process of scar formation in the liver involves numerous factors and differs in some important ways from that in other sites in the body. Increasing evidence suggests that the process of fibrosis is reversible, even when cirrhosis is histologically present. For example, two studies found that successful treatment of HBV419 and HCV420 was associated with reversal of cirrhosis in 50% to 75% of cases. 91 DISEASES OF THE LIVER

Chronic Hepatitis: Significance of Chronic Hepatitis The gold standard for evaluation of the extent of liver damage has been liver biopsy. Because the degree of injury is not uniform throughout the liver, the sample taken may not be representative of the extent of damage. This has led to interest in the use of laboratory tests to predict the extent of fibrosis in the liver as described previously. Increasingly, these tests are being used to stratify and monitor patients with chronic liver disease. 92 DISEASES OF THE LIVER

Alcoholic Liver Disease Alcoholic liver disease differs clinically and biochemically from other forms of hepatitis and liver disease. Risk factors for developing alcoholic liver disease include the following: Duration and magnitude of alcohol ingestion Alcoholic liver disease does not occur in all individuals with chronic ethanol intake Threshold intake of 40 g/day in men and 10 g/day in women Daily drinking appears to be riskier than intermittent drinking. 93

DISEASES OF THE LIVER Alcoholic Liver Disease Sex There is a greater likelihood of progression to cirrhosis in women. Although some studies have suggested that this is due to lower activities of gastric mucosal alcohol dehydrogenase in women, 2002 data show that this is true only in younger women, and that older women actually have higher activities than older men Hepatitis B or C infection 94 Both may increase the severity of liver damage in

persons who drink heavily, and both correlate with degree of liver damage. For example, antibodies to HCV are several times more common in individuals with alcoholic hepatitis than in alcoholic individuals without hepatitis or in age- and sex-matched controls, suggesting a DISEASES OF THE LIVER Alcoholic Liver Disease Genetic factors An inherited predisposition to alcoholism has been clearly established. HFE gene mutations are more common in alcoholic individuals with liver disease than in those with no evidence of liver disease.

Nutritional status 95 Protein-calorie malnutrition is extremely common among alcoholic individuals. Malnutrition may be due not only to poor intake but also to abnormal nutrient metabolism. Although poor nutrition may contribute to the evolution of alcoholic liver disease, adequate nutrition does not prevent its development. Studies suggest that obesity may be a risk factor (perhaps because of the presence of coexisting NAFLD). DISEASES OF THE LIVER

Alcoholic Liver Disease 96 Alcohol is metabolized to acetaldehyde by cytosolic alcohol dehydrogenase and microsomal enzymes (primarily CYP2E1). Acetaldehyde is subsequently metabolized to acetyl-CoA by aldehyde dehydrogenase. This is further broken down to acetate, which may be converted to carbon dioxide and water through the citric acid cycle to be converted to fatty acids. The latter is a major mechanism for induction of fatty liver by alcohol, but acetaldehyde is probably the primary toxin. It causes most of the injury to liver cells, as well as the induction of collagen synthesis leading to

fibrosis, and ultimately, cirrhosis. 97 DISEASES OF THE LIVER Alcoholic Liver Disease 98 The mechanism for liver injury in alcohol abuse is still unclear. Only a minority of patients (less than one-third) who abuse alcohol develop alcoholic liver disease, and only 5% of the heaviest drinkers develop cirrhosis. Acetylation of a variety of liver proteins occurs

with alcohol abuse, leading to loss of function of affected proteins in many cases. Antibodies to acetylated liver proteins have been detected in patients with alcoholic liver disease. Alcohol causes damage to intestinal epithelial cells, leading to release of lipopolysaccharide, which can also damage liver cells. DISEASES OF THE LIVER Alcoholic Liver Disease Activation of innate immunity, through either or both of these mechanisms, appears to be central to damage in alcoholic liver disease. A variety of other metabolic changes have been observed in alcoholic liver disease, including changes in methionine metabolism

and oxidative stress. 99 DISEASES OF THE LIVER Alcoholic Liver Disease Acute alcoholic hepatitis clinically is an acute febrile illness that is characteristically associated with leukocytosis and increased plasma concentrations of acute-phase response proteins. It causes mild increases in cytosolic enzymes; AST activity is typically more than two times greater than that of ALT, and it is rare for AST to be more than eight times the upper reference interval.

Among the factors involved in causing the higher AST/ ALT ratio in alcoholic hepatitis are: 100 damage to mitochondria, causing release of mitochondrial AST, deficiency of pyridoxal 5-phosphate, and a reduction in ALT content within the liver. DISEASES OF THE LIVER Alcoholic Liver Disease A cholestatic form of the disease, with increases in ALP activity to greater than three times the upper reference interval, is seen in up to 20% of cases.

Increases in bilirubin are common, and reduced liver-synthesized protein concentrations are commonly present. Increased bilirubin, decreased albumin, and prolonged PT are poor prognostic markers in alcoholic hepatitis and associated with higher mortality 101 DISEASES OF THE LIVER Alcoholic Liver Disease Models for evaluating the severity and prognosis in alcoholic hepatitis The Maddrey discriminant function (4.6 (PT Control PT)) + Plasma bilirubin (mg/dl))

Value of more than 32 identifies individuals with a high mortality rate, A Model for End-Stage Liver Disease (MELD) score more than 11 has been found to have similar sensitivity and better specificity. 102 DISEASES OF THE LIVER Alcoholic Liver Disease A large number of biochemical markers have been proposed for the detection of excessive alcohol consumption. Among routine laboratory tests, the most widely used are GGT and mean corpuscular

volume (MCV). Serum GGT activity is commonly used as a screening test for alcohol abuse. However, GGT is an inducible enzyme that is elevated by many drugs and a variety of other factors such as cigarette smoking and other forms of liver disease. 103 DISEASES OF THE LIVER Alcoholic Liver Disease The threshold for positivity is approximately 2 drinks/day, and elevation is more common in those who drink regularly. Although the clinical sensitivity of GGT for alcohol abuse is in the range of 70%,

specificity is poor. GGT remains elevated for an average of 25 days after alcohol abstention. MCV has similar clinical sensitivity, and specificity is low. 104 DISEASES OF THE LIVER Alcoholic Liver Disease Alcohol leads to production of isoforms of transferrin with low sialic acid content, termed carbohydrate-deficient transferrin (CDT). It has been suggested that combining markers such as CDT and GGT will enhance accuracy in identifying problem drinkers.

CDT is frequently elevated in persons with end-stage liver disease, regardless of cause. 105 DISEASES OF THE LIVER Cirrhosis 106 Cirrhosis, which is defined anatomically as diffuse fibrosis with nodular regeneration, represents the end stage of scar formation and regeneration in chronic liver injury. This response to injury occurs independently of the etiology and thus it is not possible, in most circumstances, to determine the cause of cirrhosis based

on histology. Classically, cirrhosis has been classified as micronodular, macronodular, or mixed, based on the histology and gross appearance of the liver. However, this is considered inadequate for etiologic or prognostic purposes. Consequently, it is more common to classify cirrhosis on the basis of its presumed or known etiology. Virtually all chronic liver diseases are known to lead to cirrhosis DISEASES OF THE LIVER Cirrhosis Variety of staging systems have been used to predict prognosis in cirrhosis. For many years, the most common

classification system was the Child-Pugh class system. Currently, the MELD score is used to identify patients with advanced cirrhosis who may be candidates for liver transplantation; it appears superior to the Child-Pugh scoring system in predicting short-term survival. 107 DISEASES OF THE LIVER Cirrhosis 108 DISEASES OF THE LIVER

Cirrhosis re-2016-model-end-stage-liver-disease 109 DISEASES OF THE LIVER Cirrhosis The MELD score is calculated as: 110 Hepatic Tumors The liver is host to a wide variety of benign and malignant primary tumors.

It is the second most common site of metastases; metastatic tumors account for 90% to 95% of all hepatic malignancies. Primary tumors may arise from many cell lines in the liver, but they arise most commonly from parenchymal and biliary epithelial cells and from mesenchymal cells. The two most important primary liver tumors are HCC and cholangiocarcinoma. 111 Hepatic Tumors HCC is the fifth most common cancer worldwide and a leading cause of cancer death; more than 500,000 cases occur annually, with a similar number of deaths. Wide geographic and ethnic variations are noted

in the incidence, suggesting that both host and environmental factors are involved in its origin. For example, approximately 75% of HCC cases occur in Asia, with an annual incidence of HCC in China of approximately 30 cases per 100,000 males. Worldwide, the incidence is twofold to threefold higher among men than among women. 112 Hepatic Tumors 113 The incidence of HCC has been increasing in the United States and much of Europe because of the increasing frequency of

cirrhosis caused by HCV; however, incidence has declined in many parts of the world because of the success in prevention of infection by HBV. Although cirrhosis is present in most patients with HCC, it is absent in approximately 25% to 30% of cases, often in association with HBV. More importantly, the presence of cirrhosis had been recognized before diagnosis of HCC in approximately one-third of cases. Hepatic Tumors Wide variations in the incidence of HCC are associated with different causes of cirrhosis. For example, HCC commonly occurs in cirrhosis caused by alcohol abuse, hemochromatosis, AAT deficiency, HBV, and

HCV, but it is rare that it is caused by AIH and Wilson disease. In most parts of the world, the major risk factors for development of HCC are infection with HBV or HCV. 114 Hepatic Tumors Aflatoxin, a product of Aspergillus flavus contamination of grain, has been linked to risk of HCC; although it is harmless, it is metabolized to aflatoxin 8,9-epoxide. This reactive intermediate binds to guanosine bases in DNA, leading to mutagenesis. If the formed adduct is not repaired, G-to-T transversion occurs in codon 249 of the TP53

gene (p53), causing an inactivating mutation. 115 Hepatic Tumors 116 Under normal circumstances, the mutagenic aflatoxin 8,9-epoxide is rendered harmless by glutathione S-transferase, which converts it to a glutathione conjugate, which in turn is metabolized to 1,2-dihydrodiol by epoxide hydrolase. However, both detoxifying enzymes are polymorphic in humans, and the mutant forms are less active.

Patients with HCC are more likely to have the mutant forms of epoxide hydrolase and glutathione-S-transferase; this allows accumulation of the epoxide. 117 DIAGNOSTIC STRATEGY 118 Liver function tests are useful in detecting and diagnosing liver disease and dysfunction, as well as in evaluating severity, monitoring therapy, and assessing prognosis. They are also useful in directing further diagnostic workup.

The array of tests useful for these purposes includes measurement in plasma of total and direct bilirubin, protein, and albumin concentrations, and the activity of enzymes such as the aminotransferases (AST and ALT), ALP, and GGT. By using a combination of these tests, it is possible to categorize broad types of liver disease, which can then be more accurately diagnosed through diseasespecific tests. Tests of Hepatic Function and Injury 119 Tests of Hepatic Function and Injury

120 Case Studies 121 Case 1 A term male neonate was admitted to the hospital with jaundice and anemia. The following results were obtained for total and direct bilirubin measurement in plasma over the first 2 days of life: 122 Comments This child had hemolytic anemia secondary to

Rh disease. In this condition, there is red cell incompatibility in which the mother is Rh negative and the child Rh positive. During the pregnancy, the mother develops antibodies against the D antigen on the childs red cells. The anti-D antibodies cross the placenta and hemolyze the red cells in the child. Hemolytic disease of the newborn also may be due to ABO blood group incompatibility. 123 Comments In the majority of cases, the mother is blood group O and the child group A or B. The most notable feature in hemolytic disease

in the newborn is early jaundice, generally apparent from the first day of life. Conversely, physiologic jaundice or jaundice as a result of prematurity appears later, typically between days 2 to 4 of life. 124 Case 2 The biochemist on-call received a telephone call from a primary care practitioner (PCP) regarding an unexpectedly increased bilirubin result for a 45-year-old man. The patient presented with lower back pain and signs of prostatism. On reviewing previous results for this patient, the PCP noted additional moderately increased bilirubin results in the

past. All other liver function tests were normal, as follows: 125 Case 2 126 Comments This is a probable case of Gilbert syndrome, a relatively common genetic defect of hepatic bilirubin metabolism, present in approximately 2% to 3% of the general population. It is characterized by a mild unconjugated hyperbilirubinemia with mild or intermittent jaundice. It is caused by decreased activity of hepatic uridine

5-diphospho (UDP)-glucuronosyltransferase, resulting in increased levels of unconjugated bilirubin. The PCP was advised to exclude the possibility of hemolysis in vivo by measuring additional markers, including haptoglobin, reticulocytes, and lactate dehydrogenase levels. 127 Comments It was also recommended to measure both total and direct bilirubin concentrations after an overnight fast; the hyperbilirubinemia of Gilbert syndrome is noticeable after a period of decreased food intake, possibly a result of competition between bilirubin and free fatty acids for transport by

albumin and uptake into hepatic cells. Gilbert syndrome is considered a benign disorder, and no treatment is required. 128 Case 3 A 15-year-old female presented to the emergency department with severe vomiting and abdominal discomfort. She admitted to ingesting approximately 22 g of acetaminophen 48 hours before she came to hospital. Her admission blood values showed the following results: 129

Case 3 mcg/ml 130 131 Comments 132 In acetaminophen toxicity, the biochemical picture is one of acute hepatocellular damage without biliary obstruction. In the presence of acute toxicity, the rise in serum bilirubin concentration is often

delayed. Similarly, serum albumin concentrations are often initially normal. In this case, the patient presented to the hospital 48 hours after the overdose occurred, explaining why acetaminophen was not detected in her serum specimen. Comments 133 Similarly, if a patient presents too early after acetaminophen overdose, serum levels may not be detected; the blood sample should be taken at a minimum 4 hours after the time of ingestion to be detected.

The level can then be plotted on the RumackMatthew nomogram to determine the patients risk for hepatotoxicity and to guide treatment. The use of the compound N-acetyl-cysteine (NAC) forms the basis of treatment for acetaminophen overdose. NAC replenishes glutathione reserves, scavenges free radicals, binds the toxic NAPQI directly, and increases microcirculatory oxygenation. 134 Case 4 A 45-year-old female presented to the hospital with increasing pain in the right upper quadrant for the previous 2 days. Her liver function test results on a serum sample were as follows:

135 Comments 136 The laboratory results show a cholestatic pattern with increased ALP and GGT activity, with mild hyperbilirubinemia. An abdominal ultrasound was performed revealing acute cholecystitis, gallbladder wall thickening, and the presence of several large stones. Laparoscopic cholecystectomy was performed on the day of admission. Gallstones are primarily composed of cholesterol with varied quantities of bilirubin and calcium salts.

In this case, the gallstones led to cystic duct obstruction, resulting in acute inflammation of the gallbladder (cholecystitis) manifesting as sever right upper quadrant pain. Case 5 A 62-year-old male with a history of heavy drinking visited his primary care practitioner (PCP) after feeling generally unwell. On examination, the patient was jaundiced, with evidence of abdominal ascites. Laboratory results on a serum sample were as follows: 137 Case 5

138 Comments 139 This patient has compensated alcoholic liver disease. The decreased serum albumin concentration, hyperbilirubinemia, and enzyme elevations are consistent with cirrhosis and hepatocellular damage. The markedly increased GGT activity is induced by the alcohol. The prolonged prothrombin time is suggestive of impaired hepatic synthetic function. The patient also had abdominal ascites, a

complication of alcoholic liver disease, secondary to hepatic venous obstruction and portal hypertension, leading to decreased arterial circulation and water retention.

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