Acute hepatitis is an inflammatory process causing liver cell death either by necrosis or by triggering apoptosis (programmed cell death). A wide range of clinical entities can cause global hepatocyte injury of sudden onset. Worldwide, acute hepatitis is most commonly caused by infection with one of several types of viruses. Although these viral agents can be distinguished by serologic laboratory tests based on their antigenic properties, all produce clinically similar illnesses. Other less common infectious agents can result in liver injury (Table 14–1). Acute hepatitis is also sometimes caused by exposure to drugs (eg, isoniazid) or poisons (eg, ethanol).
The severity of illness in acute hepatitis ranges from asymptomatic and clinically unapparent to fulminant and potentially fatal. The clinical presentation of acute hepatitis can also be quite variable. Some patients are relatively asymptomatic, with abnormalities noted only by laboratory studies. Others may have a range of symptoms and signs, including anorexia, fatigue, weight loss, nausea, vomiting, right upper quadrant abdominal pain, jaundice, fever, splenomegaly, and ascites. The extent of hepatic dysfunction can also vary tremendously, correlating roughly with the severity of liver injury. The relative extent of cholestasis versus hepatocyte necrosis is also highly variable. The potential interrelationship of acute hepatitis, chronic hepatitis, and cirrhosis is illustrated in Figure 14–8.
Clinical syndromes associated with hepatitis: acute hepatitis (1), which is sometimes associated with intrahepatic cholestasis (2). Fulminant hepatitis (3) is associated with massive necrosis and has a high mortality rate. Chronic viral hepatitis may lead to a carrier state without (4) or with (5) continuing hepatocyte necrosis. Chronic hepatitis associated with continuing necrosis often progresses to cirrhosis, whereas that associated simply with a carrier state does not. (Redrawn, with permission, from Chandrasoma P et al, eds. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.)
Acute hepatitis is commonly caused by one of five major viruses: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). Table 14–8 summarizes important characteristics of these viral agents. Other viral agents that can cause acute hepatitis, though less commonly, include the Epstein-Barr virus (cause of infectious mononucleosis), cytomegalovirus, varicella virus, measles virus, herpes simplex virus, rubella virus, and yellow fever virus. A newly discovered DNA virus, SEN virus, may be associated with transfusion-associated acute hepatitis not attributable to other viruses. HAV, a small RNA virus, causes liver disease both by direct killing of hepatocytes and by stimulating the host’s immune response to infected hepatocytes. It is spread by the fecal-oral route from infected individuals. Although most cases are mild, hepatitis A occasionally causes fulminant liver failure and massive hepatocellular necrosis, resulting in death. Regardless of the severity, patients who recover do so completely, show no evidence of residual liver disease, and have antibodies that protect them from reinfection.
Table 14–8Characteristics of various types of viral hepatitis. ||Download (.pdf) Table 14–8 Characteristics of various types of viral hepatitis.
| ||Hepatitis A ||Hepatitis B ||Hepatitis C ||Hepatitis D ||Hepatitis E |
|Clinical presentation |
|Onset ||Abrupt ||Insidious ||Insidious ||Insidious ||Abrupt |
|Incubation period || || || || || |
| ||15–50 ||28–160 ||14–160 ||30–180 ||15–60 |
| ||30 ||80 ||50 || ||40 |
|Arthralgia, rash ||Uncommon ||Common ||Uncommon ||Uncommon ||Common |
|Fever ||Uncommon ||Uncommon ||Uncommon ||Common ||Common |
|Nausea, vomiting ||Common ||Common ||Common ||Common ||Common |
|Jaundice ||Uncommon in children ||Less common than hepatitis A ||Uncommon ||Common ||Common |
|Laboratory data |
|Duration of enzyme elevation ||Short ||Prolonged ||Prolonged ||Like hepatitis B ||Short |
|Virus type ||RNA ||DNA ||RNA ||RNA ||RNA |
|Family ||Picornavirus ||Hepadnavirus ||Flavivirus ||Delta Viridae ||Caliciviridae |
|Serologic tests |
|Antigen ||Yes ||Yes ||No ||No ||Yes |
|Antibody ||Yes ||Yes ||Yes ||Yes ||Yes |
|Severity of acute disease ||Mild ||Moderate ||Mild ||Can be severe ||Severe in pregnant woman |
|Mortality rate ||Low (<0.5%) ||Low (<0.5%) ||Low ||High (5%) ||Moderate to high (0.2–1% in general population but as high as 15–20% in pregnant woman) |
|Chronic hepatitis ||No ||Yes ||Yes ||Yes ||Yes but almost exclusively among immunocompromised persons |
|Associated with malignancy ||No ||Yes ||Yes ||Yes ||No |
|Oral ||+ ||± ||– ||– ||+ |
|Percutaneous ||Rare ||+ ||+ ||+ ||+ |
|Sexual ||+ ||+ ||+ ||+ ||– |
|Perinatal ||– ||+ ||+ ||Rare ||+ |
|Vaccine ||Yes ||Yes ||No ||No (vaccinate against HBV) ||No |
HBV is a DNA virus that is transmitted by sexual contact or by contact with infected blood or other bodily fluids. Perinatal and early childhood transmission is the most common mode of HBV acquisition worldwide, whereas sexual transmission is most common among adults in the United States. This virus does not kill the cells it infects. Rather, the infected hepatocytes die almost exclusively as a consequence of attack by the immune system after recognition of viral antigens on the hepatocyte surface. Although most cases of hepatitis B infection are asymptomatic or produce only mild disease, an excessive immune response can result in acute liver injury and even liver failure. In a minority of those infected as adults but a majority of individuals infected at birth, the immune response is inadequate to clear the virus and chronic hepatitis B develops. The incidence of infection has significantly declined in the era of HBV vaccination, although prevalence remains high, in part because of immigration of infected patients from endemic countries. Although the true burden of chronic hepatitis B infection in the United States is unknown, it is estimated that 1.25 million Americans are infected with HBV, with a likely higher prevalence among those who are foreign-born. Additionally, complications of HBV-induced liver disease result in 3000–5000 deaths each year in the United States.
HCV is a RNA virus, also transmitted by blood and body fluids, causes a form of hepatitis similar to HBV infection but with a far greater proportion of cases (60–85%) progressing to chronic hepatitis. Acute infection can be characterized by mild to moderate illness but is usually asymptomatic. However, chronic HCV can lead to life-threatening complications including cirrhosis and hepatocellular carcinoma (HCC), usually after decades of infection. It is estimated that between 2.7 and 3.9 million Americans are infected with HCV, many unaware of their infection, and the rate of attributable mortality is rising at 12,000 deaths each year. The Centers for Disease Control and Prevention (CDC) estimates that persons born during 1945–1965 account for approximately three fourths of all HCV infections in the United States. End-stage liver disease due to HCV is the most common indication for liver transplantation in the United States.
HDV, also known as delta agent, is a defective RNA virus that requires helper functions of HBV to cause infection. Thus, individuals who are chronically infected with HBV are at high risk for HDV infection, whereas those who have been vaccinated against HBV are at no risk. HDV infection occurs either as coinfection with HBV or superinfection in the setting of chronic HBV. HDV infection causes a much more severe form of hepatitis both in terms of the proportion of fulminant cases and in the percentage of cases that progress to chronic hepatitis. In North America, HDV coinfection primarily occurs in high-risk groups such as injection drug users and hemophiliacs, and in up to 9% of those high-risk patients who have chronic HBV infection. In the United States, the prevalence of HDV coinfection in the general HBV-infected population is not well known.
HEV is an unclassified RNA virus, and like HAV, it is spread via the fecal-oral route. The clinical disease is generally benign and self-limited, resembling hepatitis A, but HEV infection may result in acute liver failure in pregnant women. More recently, it has been recognized that HEV is an underdiagnosed cause of many cases of “idiopathic” hepatitis in nonpregnant patients, cases of presumed drug-induced liver injury, and even chronic hepatitis in immune-compromised hosts. HEV remains an under-recognized clinical entity because there is no laboratory test for HEV viral load in routine clinical practice.
Most cases of drug-induced liver injury present as acute hepatitis, although some present as cholestasis or other patterns (Table 14–6). The incidence of drug-induced hepatitis has been rising. Although fewer than 10% of drug-induced liver injury cases progress to acute liver failure, acetaminophen is now the most common cause of acute liver failure in the United States and the United Kingdom. Hepatic toxins can be further subdivided into those for which hepatic toxicity is predictable and dose dependent for most individuals (eg, acetaminophen) and those that cause unpredictable (idiosyncratic) reactions without relationship to dose. The pathogenesis of drug-induced liver injury is not well understood; Table 14–9 and Figure 14–9 summarize speculations on the mechanisms of idiosyncratic and dose-related drug-induced liver injury. Idiosyncratic reactions to drugs may be due to genetic predisposition in susceptible individuals to certain pathways of drug metabolism that generate toxic intermediates. Prominent examples of drugs causing acute liver failure that have been withdrawn from the U.S. market include bromfenac, a nonsteroidal anti-inflammatory drug (NSAID), and troglitazone sulfate, a thiazolidinedione used as an insulin-sensitizing agent in diabetes mellitus. Other thiazolidinediones such as rosiglitazone and pioglitazone do not seem to have the same complication, although routine testing of transaminases has been recommended for those taking the drugs. HMG-CoA reductase inhibitors (eg, “statins”) are associated with elevated levels of transaminases in less than 3% of individuals but very rarely result in clinical acute liver failure.
Potential mechanisms of drug-induced liver injury. The normal hepatocyte may be affected adversely by drugs through (A) disruption of intracellular calcium homeostasis that leads to the disassembly of actin fibrils at the surface of the hepatocyte, resulting in blebbing of the cell membrane, rupture, and cell lysis; (B) disruption of actin filaments next to the canaliculus (the specialized portion of the cell responsible for bile excretion), leading to loss of villous processes and the interruption of transport pumps such as multidrug resistance-associated protein 3 (MRP3), which in turn prevents the excretion of bilirubin and other organic compounds; (C) covalent binding of heme-containing cytochrome P450–metabolizing enzymes to the drug, thus creating nonfunctioning adducts; (D) migration of these enzyme-drug adducts to the cell surface in vesicles to serve as target immunogens for cytolytic attack by T cells, stimulating an immune response involving cytolytic T cells and cytokines; (E) activation of apoptotic pathways by tumor necrosis factor (TNF) receptor or Fas (DD denotes death domain), triggering the cascade of intercellular caspases, resulting in programmed cell death; or (F) inhibition of mitochondrial function by a dual effect on both β-oxidation and the respiratory-chain enzymes, leading to failure of free fatty acid metabolism, a lack of aerobic respiration, and accumulation of lactate and reactive oxygen species (which may disrupt mitochondrial DNA). Toxic metabolites excreted in bile may damage bile-duct epithelium (not shown). CTLs, cytolytic T lymphocytes. (Reproduced, with permission, from Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003;349:474.)
Table 14–9Idiosyncratic drug reactions and the cells that are affected. ||Download (.pdf) Table 14–9 Idiosyncratic drug reactions and the cells that are affected.
|Type of Reaction ||Effect on Cells ||Examples of Drugs |
|Hepatocellular ||Direct effect or production by enzyme-drug adduct leads to cell dysfunction, membrane dysfunction, cytotoxic T-cell response ||Isoniazid, trazodone, diclofenac, nefazodone, venlafaxine, lovastatin |
|Cholestasis ||Injury to canalicular membrane and transporters ||Chlorpromazine, estrogen, erythromycin and its derivatives |
|Immunoallergic ||Enzyme-drug adducts on cell surface induce IgE response ||Halothane, phenytoin, sulfamethoxazole |
|Granulomatous ||Macrophages, lymphocytes infiltrate hepatic lobule ||Diltiazem, sulfa drugs, quinidine |
|Microvesicular fat ||Altered mitochondrial respiration, oxidation leads to lactic acidosis and triglyceride accumulation ||Didanosine, tetracycline, acetylsalicylic acid, valproic acid |
|Steatohepatitis ||Multifactorial ||Amiodarone, tamoxifen |
|Autoimmune ||Cytotoxic lymphocyte response directed at hepatocyte membrane components ||Nitrofurantoin, methyldopa, lovastatin, minocycline |
|Fibrosis ||Activation of stellate cells ||Methotrexate, excess vitamin A |
|Vascular collapse ||Causes ischemic or hypoxic injury ||Nicotinic acid, cocaine, methylene-dioxymethamphetamine |
|Oncogenesis ||Encourages tumor formation ||Oral contraceptives, androgens |
|Mixed ||Cytoplasmic and canalicular injury, direct damage to bile ducts ||Amoxicillin-clavulanate, carbamazepine, herbs, cyclosporine, methimazole, troglitazone |
The time course of acute hepatitis is highly variable. In hepatitis A jaundice is typically seen 4–8 weeks after exposure, whereas in hepatitis B jaundice occurs usually from 8–20 weeks after exposure (Figure 14–10). Drug- and toxin-induced hepatitis typically occurs at any time during or shortly after exposure and resolves with discontinuance of the offending agent. This is usually the case for both idiosyncratic and dose-dependent reactions.
(A) Serum antibody and antigen levels in hepatitis A and hepatitis B. (AST, aspartate aminotransferase, a marker for hepatocellular injury and necrosis; IgM anti-HAV, early antibody response to hepatitis A infection; IgG anti-HAV, late antibody response to hepatitis A infection; HBsAg, hepatitis B surface antigen, a marker of active viral gene expression; HBeAg, hepatitis B early antigen, a marker of infectivity.) Antibodies to the surface or early antigens (anti-HBs or anti-HBe) indicate immunity. (Redrawn, with permission, from Chandrasoma P et al, eds. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.) (B) Course of acute, resolving HCV infection. (ALT, Alanine aminotransferase; HCV RNA, hepatitis C viral load; anti-HCV, HCV antibody.) (Redrawn, with permission, from Hoofnagle JH. Course and outcome of hepatitis C. Hepatology. 2002 Nov;36(5 Suppl 1):S21–9.)
Acute hepatitis typically resolves in 3–6 months. Hepatic injury continuing for more than 6 months is arbitrarily defined as chronic hepatitis and suggests, in the absence of continued exposure to a noxious agent, that immune or other mechanisms are at work.
The viral agents responsible for acute hepatitis first infect the hepatocyte. During the incubation period, intense viral replication in the liver cell leads to the appearance of viral components (first antigens, later antibodies) in urine, stool, and body fluids. Liver cell death and an associated inflammatory response then ensue, followed by changes in laboratory tests of liver function and the appearance of various symptoms and signs of liver disease.
Liver damage—Host immunologic response plays an important though incompletely understood role in the pathogenesis of liver damage. In hepatitis B, for example, the virus is probably not directly cytopathic. Indeed, there are asymptomatic HBV carriers who have normal liver function and histologic features. Instead, the host’s cellular immune response has an important role in causing liver cell injury. Patients with defects in cell-mediated immunity are more likely to remain chronically infected with HBV than to clear the infection. Histologic specimens from patients with HBV-related liver injury demonstrate lymphocytes next to necrotic liver cells. It is thought that cytolytic T lymphocytes become sensitized to recognize hepatitis B viral antigens (eg, small quantities of hepatitis B surface antigen [HBsAg]) and host antigens on the surfaces of HBV-infected liver cells.
Extrahepatic manifestations—Immune factors may also be important in the pathogenesis of the extrahepatic manifestations of acute viral hepatitis. For example, in hepatitis B, a serum sickness-like prodrome characterized by fever, urticarial rash and angioedema, and arthralgias and arthritis appears to be related to immune complex–mediated tissue damage. During the early prodrome, circulating immune complexes are composed of HBsAg in high titer in association with small quantities of anti-HBs. These circulating immune complexes are deposited in blood vessel walls, leading to activation of the complement cascade. In patients with arthritis, serum complement levels are depressed, and complement can be detected in circulating immune complexes containing HBsAg, anti-HBs, immunoglobulin (Ig) G, IgM, IgA, and fibrin.
Cryoglobulinemia is a common finding in chronic hepatitis C infection. Diabetes mellitus also occurs frequently in patients with HCV infection and is now considered an extrahepatic manifestation of HCV. Although the mechanism of diabetes in HCV is not fully understood, it is thought to be predominantly related to an increase in insulin resistance. Insulin resistance also appears to improve following HCV therapy.
Immune factors are thought to be important in the pathogenesis of some clinical manifestations in patients who become chronic HBsAg carriers after acute hepatitis. For example, in patients developing glomerulonephritis with nephrotic syndrome, histopathologic investigation demonstrates deposition of HBsAg, immunoglobulin, and complement in the glomerular basement membrane. In patients developing polyarteritis nodosa, similar deposits have been demonstrated in affected small and medium-sized arteries.
Other more rare extrahepatic manifestations include papular acrodermatitis, and Guillain-Barré syndrome for HBV, and idiopathic thrombocytopenic purpura, lichen planus, Sjögren syndrome, lymphoproliferative diseases, membranoproliferative glomerulonephritis, and porphyria cutanea tarda for HCV.
Ethanol has both direct and indirect toxic effects on the liver as well as effects on many other organ systems of the body. Its direct effects may result from increasing the fluidity of biologic membranes and thereby disrupting cellular functions. Its indirect effects on the liver are in part a consequence of its metabolism. Ethanol is sequentially oxidized to acetaldehyde and then to acetate, with the generation of NADH and adenosine triphosphate (ATP). As a result of the high ratio of reduced to oxidized NAD that is generated, the pathways of fatty acid oxidation and gluconeogenesis are inhibited, whereas fatty acid synthesis is promoted. Ethanol can also quantitatively and qualitatively alter the pattern of gene expression in various tissues but especially in the liver, resulting in impaired homeostasis and greater sensitivity to other toxins. These and other biochemical mechanisms may contribute to the common observation of fat accumulation in the liver of alcoholics and the tendency of hypoglycemia to develop in alcoholics whose liver glycogen has been depleted by fasting. Ethanol metabolism also affects the liver by generating acetaldehyde, which reacts with primary amino groups to inactivate enzymes, resulting in direct toxicity to the hepatocyte in which it is generated. Furthermore, proteins so modified may activate the immune system against antigens that were previously tolerated as “self.”
There is considerable variation among individuals in the amount of ethanol required to cause acute liver injury. Whether nutritional, genetic, or other factors are responsible for these differences has not been determined. The mechanisms thought to be responsible for ethanol-induced liver injury are listed in Table 14–10.
Table 14–10Mechanisms of hepatocyte injury by ethanol. ||Download (.pdf) Table 14–10 Mechanisms of hepatocyte injury by ethanol.
|Disorganizes the lipid portion of cell membranes, leading to adaptive changes in their composition |
|Increased fluidity and permeability of membranes |
|Impaired assembly of glycoproteins into membranes |
|Impaired secretion of glycoproteins |
|Impaired binding and internalization of large ligands |
|Formation of abnormal mitochondria |
|Impairment of transport of small ligands |
|Impairment of membrane-bound enzymes |
|Adaptive changes in lipid composition, leading to increased lipid peroxidation |
|Abnormal display of antigens on the plasma membrane |
|Alters the capacity of liver cells to cope with environmental toxins |
|Induces xenobiotic metabolizing enzymes |
|Directly inhibits xenobiotic metabolizing enzymes |
|Induces deficiency in mechanisms protecting against injury due to reactive metabolites |
|Enhances the toxicity of O2 |
|Oxidation of ethanol produces acetaldehyde, a toxic and reactive intermediate |
|Inhibits export of proteins from the liver |
|Modifies hepatic protein synthesis in fasted animals |
|Alters the metabolism of cofactors essential for enzymatic activity—pyridoxine, folate, choline, zinc, vitamin E |
|Alters the oxidation-reduction potential of the liver cell |
|Induces malnutrition |
In uncomplicated acute hepatitis, the typical histologic findings consist of (1) focal liver cell degeneration and necrosis, with cell dropout, ballooning, and acidophilic degeneration (shrunken cells with eosinophilic cytoplasm and pyknotic nuclei); (2) inflammation of portal areas, with infiltration by mononuclear cells (small lymphocytes, plasma cells, eosinophils); (3) prominence of Kupffer cells and bile ducts; and (4) cholestasis (arrested bile flow) with bile plugs. Characteristically, although the regular pattern of the cords of hepatocytes is disrupted, the reticulin framework is preserved. This reticular framework provides scaffolding for liver cells when they regenerate.
Recovery from acute hepatitis from any cause is characterized histologically by regeneration of hepatocytes, with numerous mitotic figures and multinucleated cells, and by a largely complete restoration of normal lobular architecture.
Less commonly in acute hepatitis (1–5% of patients), there will be a more severe histologic lesion called bridging hepatic necrosis (also called subacute, submassive, or confluent necrosis). Bridging is said to occur between lobules because necrosis involves contiguous groups of hepatocytes, resulting in large areas of hepatic cell loss and collapse of the reticulin framework. Necrotic zones (“bridges”) consisting of condensed reticulin, inflammatory debris, and degenerating liver cells link adjacent portal or central areas or may involve entire lobules.
Rarely, in massive hepatic necrosis or fulminant hepatitis (<1% of patients), the liver becomes small, shrunken, and soft (acute yellow atrophy). Histologic examination reveals massive hepatocyte necrosis in most of the lobules, leading to extensive collapse and condensation of the reticulin framework and portal structures (bile ducts and vessels).
The pathology of alcoholic hepatitis is different from that of viral hepatitis in some ways. The specific pathologic features of alcoholic hepatitis include accumulation of Mallory hyalin and infiltration of polymorphonuclear leukocytes.
Acute viral hepatitis usually is manifested in three phases: the prodrome, the icteric phase, and the convalescent phase.
Prodrome—The prodrome, typically lasting 3 or 4 days, is characterized by three sets of symptoms and signs: (1) nonspecific constitutional symptoms and signs: malaise, fatigue, and mild fever; (2) GI symptoms and signs: anorexia, nausea, vomiting, altered senses of olfaction and taste (loss of taste for coffee or cigarettes), and right upper quadrant abdominal discomfort (reflecting the enlarged liver); and (3) extrahepatic symptoms and signs: headache, photophobia, cough, coryza, myalgias, urticarial skin rash, arthralgias or arthritis (10–15% of patients with HBV), and, rarely, hematuria and proteinuria.
Icteric phase—The icteric phase typically lasts for 1–4 weeks. The constitutional symptoms usually improve, although mild weight loss may occur. Pruritus occurs if cholestasis is severe. Right upper quadrant abdominal pain as a result of the enlarged and tender liver, which was present in the prodromal phase, continues. Splenomegaly is noted in 10–20% of patients.
Jaundice may be observed as a yellowing of the scleras, skin, or mucous membranes. Jaundice is generally not appreciated on physical examination before the serum bilirubin rises above 2.5 mg/dL (41.75 μmol/L). Direct hyperbilirubinemia is elevation of the level of conjugated bilirubin in the bloodstream. Its occurrence indicates unimpaired ability of hepatocytes to conjugate bilirubin but a defect in the excretion of bilirubin into the bile as a result of intrahepatic cholestasis or posthepatic obstructive biliary tract disease, with overflow of conjugated bilirubin out of hepatocytes and into the bloodstream.
Changes in stool color (lightening) and urine color (darkening) often precede clinically evident jaundice. This reflects loss of bilirubin metabolites from the stool as a consequence of disrupted bile flow. Water-soluble (conjugated) bilirubin metabolites are excreted in the urine, whereas water-insoluble metabolites accumulate in tissues, giving rise to jaundice. Note that in most cases of acute viral hepatitis the degree of liver impairment is sufficiently mild that jaundice does not develop.
Ecchymoses suggest coagulopathy, which may be due to loss of vitamin K absorptive capacity from the intestine (caused by cholestasis) or decreased coagulation factor synthesis. Rarely, loss of clearance of activated clotting factors triggers disseminated intravascular coagulation. Coagulopathy in which the prothrombin time can be corrected by vitamin K injections but not by oral vitamin K suggests cholestatic disease, because vitamin K uptake from the gut is dependent on bile flow. If the prothrombin time cannot be corrected with either oral or parenteral vitamin K, inability to synthesize clotting factor polypeptides (eg, as a result of massive hepatocellular dysfunction) should be suspected. Correction of prothrombin time with oral vitamin K alone suggests a nutritional deficiency rather than liver disease as the basis for the coagulopathy.
Tests for serum levels of various enzymes normally localized primarily within hepatocytes provide an indication of the extent of liver cell necrosis. For unclear reasons, perhaps related to liver cell polarity, certain forms of liver disease typically result in disproportionate elevations in some parameters. Thus, in alcoholic hepatitis but not in viral hepatitis, AST is often disproportionately elevated relative to ALT (AST:ALT ratio >2.0). One hypothesis is that this is due to pyridoxine deficiency in alcoholics. Likewise, in cholestasis, alkaline phosphatase is commonly disproportionately elevated relative to AST or ALT.
Measurement of antigen and antibody titers is a convenient way to assess whether an episode of acute hepatitis is due to viral infection. Moreover, because IgM antibodies are produced early after exposure to antigens (ie, soon after onset of illness), the presence of IgM antibodies to either HAV or to core antigen of HBV (HBcAg) is strong evidence that an episode of acute hepatitis is due to the corresponding viral infection. Several months after onset of illness, IgM antibody titers wane and are replaced by antibodies of the IgG class, indicating immunity to recurrence of infection by the same virus. Presence of hepatitis B “e” antigen (HBeAg) correlates well with a high degree of infectivity (Table 14–11). However, more sensitive DNA tests have shown low levels of viral DNA in the blood of many who are HBeAg negative and who are thus still infectious.
Table 14–11Commonly encountered serologic patterns in hepatitis B infection. ||Download (.pdf) Table 14–11 Commonly encountered serologic patterns in hepatitis B infection.
|HBsAg ||Anti-HBs ||Anti-HBc ||HBeAg ||Anti-HBe || |
|+ ||− ||IgM ||+ ||− || |
|+ ||− ||IgG ||+ ||− || |
|+ ||− ||IgG ||− ||+ || |
Late acute or chronic HBV infection, low infectivity
HBeAg-negative (“precore-mutant”) hepatitis B (chronic or, rarely, acute)
|+ ||+ ||+ ||+/− ||+/− || |
HBsAg of one subtype and heterotypic anti-HBs (common)
Process of seroconversion from HBsAg to anti-HBs (rare)
|− ||− ||IgM ||+/− ||+/− || |
Acute HBV infection
|− ||− ||IgG ||− ||+/− || |
Low-level HBV carrier
Remote past HBV infection
|− ||+ ||IgG ||− ||+/− || |
|− ||+ ||− ||− ||− || |
Immunization with HBsAg (after vaccination)
Remote past HBV infection (?)
Subtle or profound mental status changes are seen in fulminant hepatic necrosis. Encephalopathy is believed to be related in part to failure of detoxification of ammonia, which normally occurs through the urea cycle. Other products such as γ-aminobutyric acid (GABA) may not be metabolized. Although ammonia is a neurotoxin, it remains unclear whether it is the major agent of CNS dysfunction or whether elevated blood levels of GABA (or other compounds) may act synergistically to alter mental status because of its role as a major inhibitory neurotransmitter. In addition to encephalopathic changes caused by accumulation of toxins, acute hepatic failure is associated with encephalopathy from cerebral edema caused by increased intracranial pressure, perhaps related to alterations in the blood-brain barrier.
Renal dysfunction may complicate fulminant hepatic failure. Affected patients may develop prerenal azotemia when the glomerular filtration rate falls secondary to intravascular volume depletion. A state of intravascular volume depletion can be induced by the combination of decreased oral intake, vomiting, and formation of ascites. If uncorrected, this process can lead to acute tubular necrosis and acute kidney injury. Other causes of renal dysfunction in fulminant hepatic failure include toxins (eg, acetaminophen or Amanita poisoning) or hepatorenal syndrome. Serum creatinine is a more accurate measure than blood urea nitrogen of renal impairment in fulminant hepatic failure resulting from decreased hepatic urea production. Other complications of fulminant hepatic failure include cardiovascular dysfunction as a result of systemic vasodilation and hypotension, pulmonary edema, coagulopathy, sepsis, and hypoglycemia.
Describe the range of clinical presentations of acute hepatitis.
Which viruses can cause hepatitis?
What are some extrahepatic manifestations of viral hepatitis?
What is the basis for the extrahepatic manifestations of viral hepatitis?
Chronic hepatitis is a category of disorders characterized by the combination of liver cell necrosis and inflammation of varying severity persisting for more than 6 months. It may be due to viral infection; drugs and toxins; genetic, metabolic, or autoimmune factors; or unknown causes. The severity ranges from an asymptomatic stable illness characterized only by laboratory test abnormalities to a severe, gradually progressive illness culminating in cirrhosis, liver failure, and death. Based on clinical, laboratory, and biopsy findings, chronic hepatitis is best assessed with regard to (1) distribution and severity of inflammation, (2) degree of fibrosis, and (3) etiology, which has important prognostic implications. A simplified scoring system for assessment of liver biopsies for chronic hepatitis is presented in Table 14–12.
Table 14–12Three simple systems for histologic grading and staging of chronic hepatitis. ||Download (.pdf) Table 14–12 Three simple systems for histologic grading and staging of chronic hepatitis.
|International Association for the Study of the Liver ||Batts-Ludwig ||Metavir |
|Grade (activity, inflammation) |
|Minimal chronic hepatitis ||Grade 1 ||A1 |
|Mild chronic hepatitis ||Grade 2 ||A1 |
|Moderate chronic hepatitis ||Grade 3 ||A2 |
|Severe chronic hepatitis ||Grade 4 ||A3 |
|Stage (fibrosis) |
|Mild: Portal fibrosis ||Stage 1 ||F1 |
|Moderate: Periportal fibrosis ||Stage 2 ||F1 |
|Severe: Bridging fibrosis (few) ||Stage 3 ||F2 |
|Severe: Bridging fibrosis (many) ||Stage 3 ||F3 |
|Cirrhosis ||Stage 4 ||F4 |
Patients may present with fatigue, malaise, low-grade fever, anorexia, weight loss, mild intermittent jaundice, and mild hepatosplenomegaly. Others are initially asymptomatic and present late in the course of the disease with complications of cirrhosis, including variceal bleeding, coagulopathy, encephalopathy, jaundice, and ascites. In contrast to chronic persistent hepatitis, some patients with chronic active hepatitis, particularly those without serologic evidence of antecedent HBV infection, present with extrahepatic symptoms such as skin rash, diarrhea, arthritis, and various autoimmune disorders (Table 14–13).
Table 14–13Extrahepatic manifestations of chronic viral hepatitis. ||Download (.pdf) Table 14–13 Extrahepatic manifestations of chronic viral hepatitis.
|Primarily hepatitis C |
|Thyroid autoimmune disorders |
|Diabetes mellitus |
|Autoimmune thrombocytopenic purpura and hemolytic anemia |
|Sjögren syndrome and sialadenitis |
|Arthritis and arthralgias |
|Essential mixed cryoglobulinemia |
|Monoclonal gammopathies |
|B-cell non-Hodgkin lymphoma |
|Membranoproliferative glomerulonephritis |
|Porphyria cutanea tarda |
|Lichen planus |
|Leukocytoclastic vasculitis |
|Primarily hepatitis B |
|Serum sickness–like syndrome |
|Polyarteritis nodosa |
|Immune-complex glomerulonephritis |
Either type of chronic hepatitis can be caused by infection with several hepatitis viruses (eg, hepatitis B with or without hepatitis D superinfection and hepatitis C); a variety of drugs and poisons (eg, ethanol, isoniazid, acetaminophen), often in amounts insufficient to cause symptomatic acute hepatitis; genetic and metabolic disorders (eg, α1-antitrypsin deficiency, Wilson disease); or immune-mediated injury of unknown origin. Table 14–1 summarizes known causes of chronic hepatitis. Less than 5% of otherwise healthy adults with acute hepatitis B remain chronically infected with HBV; the risk is higher in those who are immunocompromised or of young age (ranging from 90% in newborns of HBeAg-positive mothers to 25–30% in infants and children younger than 5 years). Among those chronically infected, about two thirds develop mild chronic hepatitis and one third develop severe chronic hepatitis (see later discussion). Those with HDV coinfection progress to chronic hepatitis at higher rates than seen with isolated HBV infection. HDV superinfection is also associated with a high incidence of acute liver failure. Finally, 60–85% of individuals exposed to acute hepatitis C develop chronic hepatitis, and rates are not significantly affected by age, mode of acquisition, or coinfections.
Many cases of chronic hepatitis are thought to represent an immune-mediated attack on the liver occurring as a result of persistence of certain hepatitis viruses or after prolonged exposure to certain drugs or noxious substances (Table 14–14). In some, no mechanism has been recognized. Evidence that the disorder is immune mediated is that liver biopsies reveal inflammation (infiltration of lymphocytes) in characteristic regions of the liver architecture (eg, portal versus lobular). Furthermore, a variety of autoimmune disorders occur with high frequency in patients with chronic hepatitis (Table 14–13).
Table 14–14Drugs implicated in the etiology of chronic hepatitis. ||Download (.pdf) Table 14–14 Drugs implicated in the etiology of chronic hepatitis.
Viral hepatitis is the most common cause of chronic liver disease in the United States. In approximately 5% of adult cases of HBV infection and 60–85% of hepatitis C infections, the immune response is inadequate to clear the liver of virus, resulting in persistent infection. The individual becomes a chronic carrier, intermittently producing the virus and hence remaining infectious to others. Biochemically, these patients are often found to have viral DNA integrated into their genomes in a manner that results in abnormal expression of certain viral proteins with or without production of intact virus. Viral antigens expressed on the hepatocyte cell surface are associated with class I HLA determinants, thus eliciting lymphocyte cytotoxicity and resulting in hepatitis. The severity of chronic hepatitis is largely dependent on the activity of viral replication and the response by the host’s immune system.
Chronic hepatitis B infection predisposes the patient to the development of hepatocellular carcinoma (HCC). Although in the setting of HBV infection most cases of HCC occur in the presence of cirrhosis, 10–30% of cases occur in the absence of cirrhosis or advanced fibrosis. It remains unclear whether hepatitis B infection is the initiator or simply a promoter in the process of tumorigenesis. In hepatitis C infection, HCC develops exclusively in the setting of cirrhosis.
Alcoholic Chronic Hepatitis
Chronic liver disease in response to some poisons or toxins may represent triggering of an underlying genetic predisposition to immune attack on the liver. In alcoholic hepatitis, however, repeated episodes of acute injury ultimately cause necrosis, fibrosis, and regeneration, leading eventually to cirrhosis (Figure 14–11). As in other forms of liver disease, there is considerable variation in the extent of symptoms before development of cirrhosis.
Changes in the hepatic subendothelial space during fibrosing liver injury. Cellular and matrix alterations in the space of Disse are critical events in the pathogenesis of hepatic fibrosis. The activation of lipocytes, characterized by proliferation and increased fibrogenesis, is associated with the replacement of the normal low-density matrix with a high-density matrix. These alterations are likely to underlie, at least in part, the loss of both endothelial fenestrations (pores) and hepatocytic microvilli typical of chronic liver injury. (Redrawn, with permission, from Bissell DM. The cellular basis of hepatic fibrosis. N Engl J Med. 1993;328:1828.)
Nonalcoholic Fatty Liver Disease
In light of increasing obesity in the United States, there has been a significant increase in the prevalence of nonalcoholic fatty liver disease (NAFLD), a form of chronic liver disease that is associated with the metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) refers to the presence of hepatic steatosis, with or without inflammation and fibrosis when no other causes for secondary hepatic fat accumulation (eg, heavy alcohol consumption) are present. NAFLD is an umbrella term for a spectrum of liver disease severity, ranging from nonalcoholic fatty liver (NAFL), where inflammation is minimal, to nonalcoholic steatohepatitis (NASH), where active inflammation poses a risk for fibrosis and progression to cirrhosis. On biopsy, the inflammation associated with NASH may be histologically indistinguishable from alcoholic steatohepatitis.
NAFLD is prevalent worldwide and is the most common liver disease in Western industrialized countries. In the United States, the estimated prevalence of NAFLD ranges from 10% to 46%, and the prevalence of NASH is from 3% to 5%, with variation by age, gender, and ethnicity. NAFLD is strongly associated with metabolic risk factors such as obesity, dyslipidemia, insulin resistance, and type 2 diabetes mellitus, and the rising incidence of NAFLD parallels rising rates of obesity worldwide.
The pathogenesis of NAFLD has not been fully elucidated, but the most widely supported theory implicates insulin resistance as the key mechanism leading to hepatic steatosis and steatohepatitis. Additional oxidative injury may also play a role. In general, patients with simple steatosis have low risk of histologic progression, but patients with NASH can progress to cirrhosis and end-stage liver disease and are at risk for HCC. Long-term studies of patients with NAFL and NASH have revealed that such patients have increased overall mortality and that the most common cause of death in these patients is cardiovascular disease. Moreover, patients with NASH (but not NAFL) have increased rates of liver-related mortality. Management of NAFLD is centered around risk factor modification and treatment of metabolic comorbidities. Vitamin E is the only agent that has been shown to improve liver histology in a subgroup of adults who are nondiabetic with biopsy-proven NASH.
Idiopathic Chronic Hepatitis
Some patients develop chronic hepatitis in the absence of evidence of preceding viral hepatitis or exposure to noxious agents (Figure 14–12). These patients typically have serologic evidence of disordered immunoregulation, manifested as hyperglobulinemia and circulating autoantibodies. Nearly 75% of these patients are women, and many have other autoimmune disorders. A genetic predisposition is strongly suggested. Most patients with autoimmune hepatitis show histologic improvement in liver biopsies after treatment with systemic corticosteroids. The clinical response, however, can be variable. Primary biliary cirrhosis and autoimmune cholangitis represent cholestatic forms of an autoimmune-mediated liver disease.
Chronic hepatitis, showing marked lymphocytic infiltration and fibrosis of the portal areas. The lymphocytes extend into the peripheral part of the lobule through the limiting plate. There is ongoing necrosis of hepatocytes in the peripheral part of the lobule (piecemeal necrosis). (Reproduced, with permission, from Chandrasoma P et al, eds. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.)
All forms of chronic hepatitis share the common histopathologic features of (1) inflammatory infiltration of hepatic portal areas with mononuclear cells, especially lymphocytes and plasma cells, and (2) necrosis of hepatocytes within the parenchyma or immediately adjacent to portal areas (periportal hepatitis, or “piecemeal necrosis”).
In mild chronic hepatitis, the overall architecture of the liver is preserved. Histologically, the liver reveals a characteristic lymphocyte and plasma cell infiltrate confined to the portal triad without disruption of the limiting plate and no evidence of active hepatocyte necrosis. There is little or no fibrosis, and what there is generally is restricted to the portal area; there is no sign of cirrhosis. A “cobblestone” appearance of liver cells is seen, indicating regeneration of hepatocytes.
In more severe cases of chronic hepatitis, the portal areas are expanded and densely infiltrated by lymphocytes, histiocytes, and plasma cells. There is necrosis of hepatocytes at the periphery of the lobule, with erosion of the limiting plate surrounding the portal triads (piecemeal necrosis; Figure 14–12). More severe cases also show evidence of necrosis and fibrosis between portal triads. There is disruption of normal liver architecture by bands of scar tissue and inflammatory cells that link portal areas to one another and to central areas (bridging necrosis). These connective tissue bridges are evidence of remodeling of hepatic architecture, a crucial step in the development of cirrhosis. Fibrosis may extend from the portal areas into the lobules, isolating hepatocytes into clusters and enveloping bile ducts. Regeneration of hepatocytes is seen with mitotic figures, multinucleated cells, rosette formation, and regenerative pseudolobules. Progression to cirrhosis is signaled by extensive fibrosis, loss of zonal architecture, and regenerating nodules.
Some patients with mild chronic hepatitis are entirely asymptomatic and identified only in the course of routine blood testing; others have an insidious onset of nonspecific symptoms such as anorexia, malaise, and fatigue or hepatic symptoms such as right upper quadrant abdominal discomfort or pain. Fatigue in chronic hepatitis may be related to a change in the hypothalamic-adrenal neuroendocrine axis brought about by altered endogenous opioidergic neurotransmission. Jaundice, if present, is usually mild. There may be mild tender hepatomegaly and occasional splenomegaly. Palmar erythema and spider telangiectases are seen in severe cases. Other extrahepatic manifestations are unusual. By definition, signs of cirrhosis and portal hypertension (eg, ascites, collateral circulation, and encephalopathy) are absent. Laboratory studies show mild to moderate increases in serum aminotransferase, bilirubin, and globulin levels. Serum albumin and the prothrombin time are normal until late in the progression of liver disease.
The clinical manifestations of chronic hepatitis probably reflect the role of a systemic genetically controlled immune disorder in the pathogenesis of severe disease. Acne, hirsutism, and amenorrhea may occur as a reflection of the hormonal effects of chronic liver disease. Laboratory studies in patients with severe chronic hepatitis are invariably abnormal to various degrees. However, these abnormalities do not correlate with clinical severity. Thus, the serum bilirubin, alkaline phosphatase, and globulin levels may be normal and aminotransferase levels only mildly elevated at the same time that a liver biopsy reveals severe chronic hepatitis. However, an elevated prothrombin time usually reflects severe disease.
The natural history and treatment of chronic hepatitis varies depending on its cause. The complications of severe chronic hepatitis are those of progression to cirrhosis: variceal bleeding, encephalopathy, coagulopathy, hypersplenism, and ascites. These are largely due to portosystemic shunting rather than diminished hepatocyte reserve (see later discussion).
What are the categories of chronic hepatitis based on histologic findings on liver biopsy?
What are the causes of chronic hepatitis?
What are the consequences of chronic hepatitis?
Cirrhosis is an irreversible distortion of normal liver architecture characterized by hepatic injury, fibrosis, and nodular regeneration. The clinical presentations of cirrhosis are a consequence of both progressive hepatocellular dysfunction and portal hypertension (Figure 14–13). As with other presentations of liver disease, not all patients with cirrhosis develop life-threatening complications. Indeed, in nearly 40% of cases of cirrhosis, it is diagnosed at autopsy in patients who did not manifest obvious signs of end-stage liver disease.
Clinical effects of cirrhosis of the liver. (Redrawn, with permission, from Chandrasoma P et al, eds. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.)
The causes of cirrhosis are listed in Table 14–1. The initial injury can be due to a wide range of processes. A crucial feature is that the liver injury is not acute and self-limited but rather chronic and progressive. In the United States, alcohol abuse is the most common cause of cirrhosis. In other countries, infectious agents (particularly HBV and HCV) are the most common causes. Other causes include chronic biliary obstruction, drugs, genetic and metabolic disorders, chronic heart failure, and primary (autoimmune) biliary cirrhosis.
Increased or altered synthesis of collagen and other connective tissue or basement membrane components of the extracellular matrix is implicated in the development of hepatic fibrosis and thus in the pathogenesis of cirrhosis. The role of the extracellular matrix in cellular function is an important area of research, and studies suggest that it is involved in modulating the activities of the cells with which it is in contact. Thus, fibrosis may affect not only the mechanics of blood flow through the liver but also the functions of the cells themselves.
Hepatic fibrosis occurs in three situations: (1) secondary to inflammation and subsequent activation of immune responses, (2) as part of the process of wound healing, and (3) in response to agents that induce primary fibrogenesis. HBV and Schistosoma species are good examples of agents that lead to hepatic fibrosis by stimulating an immune response. Agents such as carbon tetrachloride that attack and kill hepatocytes directly can produce fibrosis as part of wound healing. In both immune responses and wound healing, the fibrosis is triggered indirectly by the effects of cytokines released from invading inflammatory cells. Finally, certain agents such as ethanol and iron may cause primary fibrogenesis by directly increasing collagen gene transcription and thus increasing also the amount of connective tissue secreted by cells.
The actual culprit in all of these mechanisms of increased fibrogenesis may be the fat-storing cells (stellate cells) of the hepatic reticuloendothelial system. In response to cytokines, they differentiate from quiescent stellate cells in which vitamin A is stored into myofibroblasts, which lose their vitamin A storage capacity and become actively engaged in extracellular matrix production. In addition to the stellate cells, fibrogenic cells are also derived from portal fibroblasts, circulating fibrocytes, bone marrow, and epithelial-mesenchymal cell transition. It appears that hepatic fibrosis occurs in two stages (Figure 14–14). The first stage is characterized by a change in extracellular matrix composition from non–cross-linked, non–fibril-forming collagen to collagen that is more dense and subject to cross-link formation. At this stage, liver injury is still reversible. The second stage involves formation of subendothelial collagen cross-links, proliferation of myoepithelial cells, and distortion of hepatic architecture with the appearance of regenerating nodules. Cirrhosis remains a dynamic state in which certain interventions, even at these advanced stages, may yield benefits such as regression of scar tissue and improvements in clinical outcomes.
Pathways of hepatic stellate cell activation. Features of stellate cell activation can be distinguished between those that stimulate initiation and those that contribute to perpetuation. Initiation is provoked by soluble stimuli that include oxidant stress signals (reactive oxygen intermediates), apoptotic bodies, lipopolysaccharide (LPS), and paracrine stimuli from neighboring cell types including hepatic macrophages (Kupffer cells), sinusoidal endothelium, and hepatocytes. Perpetuation follows, characterized by a number of specific phenotypic changes including proliferation, contractility, fibrogenesis, altered matrix degradation, chemotaxis, and inflammatory signaling. (FGF, fibroblast growth factor; ET-1, endothelin-1; NK, natural killer; NO, nitric oxide; MT, membrane type.) (Reproduced, with permission, from Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 2000 Jan 28:275(4):2247–50.))
The manner in which alcohol causes chronic liver disease and cirrhosis is not well understood. However, chronic alcohol abuse is associated with impaired protein synthesis and secretion, mitochondrial injury, lipid peroxidation, formation of acetaldehyde and its interaction with cellular proteins and membrane lipids, cellular hypoxia, and both cell-mediated and antibody-mediated cytotoxicity. The relative importance of each of these factors in producing cell injury is unknown. Genetic, nutritional, and environmental factors (including simultaneous exposure to other hepatotoxins) also influence the development of liver disease in chronic alcoholics. Finally, acute liver injury (eg, from exposure to alcohol or other toxins) from which a person with a normal liver would fully recover may be sufficient to produce irreversible decompensation (eg, hepatorenal syndrome) in a patient with underlying hepatic cirrhosis.
The liver may be large or small, but it always has a firm and often nodular consistency. Although several noninvasive methods for staging the extent of fibrosis exist, including use of serum biomarkers and imaging techniques to measure liver stiffness (eg, elastography), these methods are accurate for severe (fibrosis stage F3) or minimal (F1) fibrosis, but not intermediate stages in between. Liver biopsy remains the only method for definitively diagnosing significant fibrosis (F ≥ 2) and cirrhosis (F4). Histologically, all forms of cirrhosis are characterized by three findings: (1) marked distortion of hepatic architecture, (2) scarring as a result of increased deposition of fibrous tissue and collagen, and (3) regenerative nodules surrounded by scar tissue. When the nodules are small (<3 mm) and uniform in size, the process is termed micronodular cirrhosis. In macronodular cirrhosis, the nodules are more than 3 mm and variable in size. Cirrhosis from alcohol abuse is usually micronodular but can be macronodular or both micronodular and macronodular. Scarring may be most severe in central regions, or dense bands of connective tissue may join portal and central areas.
More specific histopathologic findings may help to establish the cause of cirrhosis. For example, invasion and destruction of bile ducts by granulomas suggests primary (autoimmune) biliary cirrhosis; extensive iron deposition in hepatocytes and bile ducts suggests hemochromatosis; and alcoholic hyalin and infiltration with polymorphonuclear cells suggest alcoholic cirrhosis.
The clinical manifestations of progressive hepatocellular dysfunction in cirrhosis are similar to those of acute or chronic hepatitis and include constitutional symptoms and signs: fatigue, loss of vigor, and weight loss; GI symptoms and signs: nausea, vomiting, jaundice, and tender hepatomegaly; and extrahepatic symptoms and signs: palmar erythema, spider angiomas, muscle wasting, parotid and lacrimal gland enlargement, gynecomastia and testicular atrophy in men, menstrual irregularities in women, and coagulopathy.
Clinical manifestations of portal hypertension include ascites, portosystemic shunting, encephalopathy, splenomegaly, and esophageal and gastric varices with intermittent hemorrhage (Table 14–15).
Table 14–15Manifestations of cirrhosis. ||Download (.pdf) Table 14–15 Manifestations of cirrhosis.
|Due to portal hypertension with portal-to-systemic shunting |
|Ascites and increased risk of spontaneous bacterial peritonitis |
|Increased risk of sepsis |
|Increased risk of disseminated intravascular coagulation |
|Splenomegaly with thrombocytopenia |
|Drug sensitivity |
|Bile acid deficiency with malabsorption of fat and fat-soluble vitamins |
|Due to loss of hepatocytes |
|Coagulopathy due to deficient clotting factor synthesis |
|Peripheral edema due to hypoalbuminemia |
|Hepatic coma |
|Other complications |
|Hepatorenal syndrome |
|Hepatocellular carcinoma |
|Hepatopulmonary syndrome |
Portal hypertension is defined by a portal venous pressure gradient greater than 5 mm Hg. Portal hypertension is due to a rise in intrahepatic vascular resistance. The cirrhotic liver loses the physiologic characteristic of a low-pressure circuit for blood flow seen in the normal liver. The increased blood pressure within the sinusoids is transmitted back to the portal vein. Because the portal vein lacks valves, this elevated pressure is transmitted back to other vascular beds, resulting in splenomegaly, portal-to-systemic shunting, and many of the complications of cirrhosis discussed later.
Abdominal ascites refers to the presence of excess fluid within the peritoneal cavity. Patients with ascites develop physical examination findings of increasing abdominal girth, a fluid wave, a ballotable liver, and shifting dullness. Ascites can develop in patients with conditions other than liver disease, including protein-calorie malnutrition (from hypoalbuminemia) and cancer (from lymphatic obstruction). In patients with liver disease, ascites is due to portal hypertension and can be confirmed by the presence of a serum-to-ascites albumin gradient (SAAG) of 1.1 g/dL (11 g/L) or more. Calculating the SAAG involves measuring on the same day the albumin concentration in serum and ascitic fluid (via abdominal paracentesis) and subtracting the ascitic fluid value from the serum value. Ascites can develop in approximately 50% of patients with compensated cirrhosis over a 10-year follow-up period, and it is associated with significant morbidity and mortality.
It is useful to recognize that liver disease with ascites formation occurs in a wide clinical spectrum. At one end is fully compensated portal hypertension with no ascites present because the volume of ascites generated is less than the approximately 800–1200 mL/d capacity of the peritoneal lymphatic drainage. At the other extreme is the typically fatal hepatorenal syndrome, in which patients with liver disease, usually with massive ascites, succumb to rapidly progressing acute kidney injury. The hepatorenal syndrome seems to be precipitated by intense and inappropriate renal vasoconstriction and is characterized by extreme sodium retention typical of prerenal azotemia but in the absence of true volume depletion (see Chapter 16). Nonetheless, the presence of clinically apparent ascites in a patient with liver disease is associated with poor long-term survival. Over the years, various mechanisms have been proposed to explain ascites formation. No single hypothesis of pathogenesis easily explains all findings at all points in time during the natural history of portal hypertension. Portal hypertension and inappropriate renal retention of sodium are important elements of all theories. The end result of ascites occurs when excess peritoneal fluid exceeds the capacity of lymphatic drainage, leading to increased hydrostatic pressure. The fluid can then be seen to visibly weep from the lymphatics and pool in the abdominal cavity as ascites.
The underfill/vasodilatation hypothesis proposes that the primary event in ascites formation is vascular, with reduced effective circulating volume leading to the activation of the renin-angiotensin system and subsequent renal sodium retention. The classic underfill hypothesis postulates that elevated hepatic sinusoidal pressure leads to sequestration of blood in the splanchnic venous bed. This results in underfilling of the central vein with diversion of intravascular volume to the hepatic lymphatics, which, like the central vein, drain the space of Disse. The peripheral arterial vasodilatation or splanchnic vasodilatation hypothesis adds the idea that, with portal-to-systemic shunting, vasodilatory products (eg, nitric oxide) that are normally cleared by the liver are instead delivered to the systemic circulation, where they cause peripheral arteriolar vasodilation, particularly in the splanchnic arterial bed. The resultant reduced arterial vascular resistance (Figure 14–15) is associated with decreased central filling pressures, decreased renal arterial perfusion, reflex renal arterial vasoconstriction, and increased renal tubular sodium resorption. Retention of sodium expands the intravascular volume, which exacerbates portal venous hypertension. The imbalance between hydrostatic versus oncotic pressure in the portal vein results in ascites formation. Although the splanchnic vasodilatation hypothesis accounts for many of the findings in ascites formation, the use of transhepatic intrajugular portal-to-systemic shunting (TIPS) as a means of decompressing the portal vein in patients with ascites provides a counterargument. As a result of the procedure, peripheral arteriolar vasodilation appears to increase (perhaps as a result of shunting of vasodilators such as nitric oxide that are normally cleared by the liver), yet ascites is generally dramatically improved.
Those who support the overflow hypothesis have proposed that the primary event in the development of ascites is inappropriate renal sodium retention. In this view, ascites is the consequence of overflow of fluid from the intravascular volume-expanded portal system into the peritoneal cavity. But what triggers the inappropriate renal sodium retention? One possibility is that there may exist a hepatorenal reflex by which elevated sinusoidal pressure triggers increased sympathetic tone or endothelin-1 secretion. Either of these pathways could cause an inappropriate degree of renal vasoconstriction, a decrease in glomerular filtration rate, and, by tubuloglomerular feedback (see Chapter 16), sodium retention. Note that endothelin-1 is both a renal vasoconstrictor and a stimulant of epinephrine secretion, which in turn stimulates more endothelin-1 secretion. Alternatively, it is possible that an as yet unidentified product from the diseased liver interferes with atrial natriuretic peptide (ANP) action at the kidney or is in some other way responsible for an inappropriate increase in renal sodium retention. Supporters of the overflow hypothesis point to the fact that many cirrhotic patients have sodium handling defects in the absence of ascites and do not have a measurable increase in renin-angiotensin activity. However, studies have shown that the renal sodium retention in these patients can be reversed by the use of an angiotensin II receptor antagonist.
Most likely, multiple mechanisms contribute to the development of ascites and to its perpetuation, worsening, or improvement in diverse clinical situations. Regardless of the initial events, once fully established, many if not all of the mechanisms described in Figure 14–15 are likely to contribute to ascites formation.
Proposed mechanism for ascites formation in cirrhosis through the splanchnic vasodilation hypothesis. This hypothesis incorporates elements of the underfill and vasodilation theories. (Redrawn, with permission, from Gines P et al. Management of cirrhosis and ascites. N Engl J Med. 2004;350:1646.)
Hepatorenal syndrome refers to a distinct form of kidney injury resulting from renal vasoconstriction that develops in response to the systemic and splanchnic arterial vasodilation in patients with advanced liver disease. The incidence of hepatorenal syndrome in patients who develop decompensated liver disease is 18% within 1 year of diagnosis and up to 40% at 5 years. This disorder generally occurs in patients with cirrhosis and ascites and is characterized by a progressive rise in serum creatinine (>1.5 mg/dL) with no improvement after 48 hours of withholding diuretics and volume expansion with albumin, in the absence of shock, ingestion of nephrotoxic agents, or underlying parenchymal kidney disease. The urine produced is notable for an extremely low sodium content (<10 mmol/L) and an absence of casts, resembling the findings in prerenal azotemia. Yet when central venous pressures are measured, the patient does not show intravascular volume depletion and the disorder does not respond to hydration with normal saline. The renal abnormalities of the hepatorenal syndrome appear to be functional because no pathologic changes are identifiable in the kidney. In addition, when a kidney is transplanted from a patient dying of hepatorenal syndrome, it functions well in a recipient without liver disease. While diagnostic criteria for hepatorenal syndrome have been developed and recently modified, diagnosing and differentiating hepatorenal syndrome from other causes of acute kidney injury in cirrhotic patients can be a difficult task. Other than hepatorenal syndrome, acute tubular necrosis and other causes of prerenal azotemia are the most common diagnoses in this setting.
The hepatorenal syndrome can be classified into two types, each having different clinical and prognostic characteristics. Type 1 hepatorenal syndrome is rapidly progressive with a doubling of the serum creatinine concentration to a level greater than 2.5 mg/dL in less than 2 weeks. It is associated with multiorgan failure. By contrast, type 2 hepatorenal syndrome is characterized by less severe renal insufficiency, is more slowly progressive, and generally occurs in the setting of ascites resistant to diuretics. The onset of hepatorenal syndrome can be insidious or dramatic and can be precipitated by an acute event, such as infection (notably spontaneous bacterial peritonitis) or hypovolemia from GI bleeding or overdiuresis. Prognosis after development of hepatorenal syndrome is dismal (overall survival of 50% at 1 year). The untreated survival is in the range of weeks for type 1 hepatorenal syndrome and 4–6 months for type 2 hepatorenal syndrome.
The pathophysiology of hepatorenal syndrome is related to the distinct hemodynamic and circulatory changes that occur in patients with severe hepatic dysfunction. Portal hypertension triggers arterial vasodilation in the splanchnic circulation and subsequent reduction in systemic vascular resistance, which can no longer be compensated for by an augmented cardiac output. Increased production or activity of vasodilators within the splanchnic circulation, particularly nitric oxide, carbon monoxide, and endogenous cannabinoids, leads to such arterial vasodilation. In advanced cirrhosis, arterial pressure must be maintained through the activation of vasoconstrictor systems, including the renin-angiotensin system and the sympathetic nervous system, as well as excess secretion of antidiuretic hormone (arginine vasopressin). These compensatory mechanisms help maintain effective arterial blood volume and relatively normal arterial pressure but lead to intrarenal vasoconstriction and hypoperfusion, which impairs renal function. By the same mechanisms, affected patients may develop further retention of sodium and free water, worsening edema and ascites.
The best approach to the management of the hepatorenal syndrome, based on knowledge of its pathogenesis, is the administration of vasoconstrictor drugs. Use of the vasopressin analog, terlipressin, together with albumin, can be considered as initial therapy for hepatorenal syndrome. Terlipressin is effective in approximately 40–50% of patients with type 1 hepatorenal syndrome; data on use of vasoconstrictors in type 2 hepatorenal syndrome is limited. Renal replacement therapy in the form of hemodialysis or continuous venovenous hemofiltration has been used, particularly in patients awaiting transplantation or in those with acute, potentially reversible hepatorenal syndrome. There is no evidence, however, that renal replacement therapy improves the prognosis of patients with cirrhosis who are not candidates for a liver transplant. Liver transplantation remains the optimal treatment for patients with hepatorenal syndrome.
Hypoalbuminemia and Peripheral Edema
Progressive worsening of hepatocellular function in cirrhosis can result in a fall in the concentration of albumin and other serum proteins synthesized by the liver. As the concentration of these plasma proteins decreases, the plasma oncotic pressure is lowered, thereby tilting the balance of hemodynamic forces toward the development of both peripheral edema and ascites.
These hemodynamic changes further contribute to an avid sodium-retaining state despite total body water and sodium overload seen by urinalysis in the cirrhotic patient. Serum sodium may be low as a result of superimposed water retention caused by antidiuretic hormone release triggered by volume stimuli. There are typically no obvious clinical manifestations until the serum sodium concentration falls below 120 mEq/L, at which point neurologic symptoms can occur. Attempts to raise the serum sodium, including fluid restriction and administration of vasopressin receptor antagonists (eg, tolvaptan and conivaptan) are generally not recommended due to adverse effects and lack of clear benefit. Hyponatremia is simply a late manifestation of end-stage liver disease and a strong predictor of mortality in patients with cirrhosis.
A low serum potassium and metabolic alkalosis may be observed as a consequence of elevated aldosterone levels responding to renin release (and angiotensin II release) by the kidneys, which sense afferent intravascular depletion.
Spontaneous Bacterial Peritonitis
Spontaneous bacterial peritonitis is defined as infection of ascitic fluid in the absence of an intra-abdominal event (such as a bowel perforation or another surgically treatable source) that would account for the entry of pathogenic organisms into the peritoneal space. This complication carries a high mortality rate and is predictive of poor overall prognosis. The presence of infection is confirmed by an elevated ascitic fluid absolute polymorphonuclear leukocyte count of 250 cells/μL or more and definitively by a positive ascitic fluid bacterial culture. Symptoms and signs include fever, hypotension, abdominal pain or tenderness, decreased or absent bowel sounds, and abrupt onset of hepatic encephalopathy in a patient with ascites. Alternatively, patients with spontaneous bacterial peritonitis can have subtle or no symptoms, and hence, a high index of suspicion may be required for timely diagnosis.
Patients with advanced liver disease with large-volume ascites or very low ascitic fluid protein levels, prior history of spontaneous bacterial peritonitis, and episodes of upper GI bleeding are at increased risk for this complication. Ascitic fluid is an excellent culture medium for a variety of pathogens, including Enterobacteriaceae (chiefly Escherichia coli), group D streptococci (enterococci), Streptococcus pneumoniae, and viridans streptococci. The greater risk in patients with low ascitic fluid protein levels may be due to a low level of opsonic activity in the fluid.
While the exact pathogenesis of spontaneous bacterial peritonitis is not known, cirrhosis predisposes to the development of GI bacterial overgrowth and increased intestinal permeability. Peritonitis may occur because of bacterial seeding of the ascitic fluid via the blood or lymph or by bacteria traversing the gut wall. Enteric organisms may also enter the portal venous blood via the portosystemic collaterals, bypassing the reticuloendothelial system of the liver.
Gastroesophageal Varices and Bleeding
As blood flow through the liver is progressively impeded, hepatic portal venous pressure rises. In response to the elevated portal venous pressure, there is a decrease in blood vessel wall thickness and enlargement of blood vessels that anastomose with the portal vein, such as those on the surface of the bowel and lower esophagus. These enlarged vessels are termed gastroesophageal varices. They eventually develop in approximately 50% of patients with cirrhosis, generally when the portal hypertensive gradient exceeds 12 mm Hg. Physical examination may reveal enlargement of hemorrhoidal and periumbilical vessels. Gastroesophageal varices are of more significance clinically, however, because of their tendency to rupture. Variceal hemorrhage occurs in 25–40% of patients with cirrhosis and is a leading cause of morbidity and mortality in these individuals. Each episode of active variceal bleeding is associated with a 30% mortality risk, and survivors have a 70% risk of recurrent bleeding within 1 year. GI bleeding from varices and other sources (eg, duodenal ulcer, gastritis) in patients with cirrhosis is often exacerbated by concomitant coagulopathy (see later discussion).
Hepatic encephalopathy presents as a range of reversible neuropsychiatric abnormalities that occur as a consequence of advanced decompensated liver disease or portal-to-systemic shunting (see Table 14–16 for common precipitants). Neuropsychiatric symptoms can be episodic or persistent. Changes in the sleep pattern starting with hypersomnia and progressing to reversal of the sleep-wake cycle are often an early sign. Cognitive changes range from mild confusion, apathy, and agitation, to marked confusion, obtundation, and even coma. More advanced neurologic features include tremor, bradykinesia, asterixis (flapping motions of outstretched, dorsiflexed hands), hyperactive deep tendon reflexes, and less commonly, transient decerebrate posturing and flaccidity. Cerebral edema, which is an important accompanying feature in patients with encephalopathy in acute liver disease, is not seen in cirrhotic patients with encephalopathy. Subtle changes of hepatic encephalopathy are present in up to 15% of patients with advanced liver disease and may only be detectable by a number of specialized measures, such as psychometric testing. Such patients have sometimes been referred to as having subclinical or minimal hepatic encephalopathy.
Table 14–16Common precipitants of hepatic encephalopathy. ||Download (.pdf) Table 14–16 Common precipitants of hepatic encephalopathy.
|Increased nitrogen load |
|Gastrointestinal bleeding |
|Excess dietary protein |
|Electrolyte imbalance |
|Opioids, tranquilizers, sedatives |
|Superimposed acute liver disease |
|Progressive liver disease |
Hepatic encephalopathy is diagnosed by history and clinical features in the appropriate context and after exclusion of other causes of altered mental status. Common precipitants of encephalopathy are onset of GI bleeding, increased dietary protein intake, and an increased catabolic rate resulting from infection (including spontaneous bacterial peritonitis). Similarly, because of compromised first-pass clearance of ingested drugs, affected patients are exquisitely sensitive to sedatives and other drugs normally metabolized in the liver. Other causes include electrolyte imbalance as a result of diuretics, vomiting, alcohol ingestion or withdrawal, or procedures such as TIPS. TIPS also exacerbates hepatic encephalopathy given direct bypass of portal venous blood flow into systemic circulation via the hepatic vein, while bypassing the hepatic parenchyma.
The pathogenesis of hepatic encephalopathy is likely multifactorial and complex. One proposed mechanism is related to toxins in the gut such as ammonia, derived from metabolic degradation of urea or protein; glutamine, derived from degradation of ammonia; or mercaptans, derived from degradation of sulfur-containing compounds; and manganese. Because of anatomic or functional portal-systemic shunts, these toxins bypass the liver’s detoxification processes and produce alterations in mental status. Exposure to these toxins can cause astrocyte swelling and structural changes in neurons. In addition, high ammonia levels can result in abnormal cerebral blood flow and glucose metabolism. Increased levels of ammonia, glutamine, and mercaptans can be found in the blood and cerebrospinal fluid. There is also an increase in cerebral manganese deposition in patients with cirrhosis. However, blood ammonia and spinal fluid glutamine levels correlate poorly with the presence and severity of encephalopathy. In addition, the role of manganese in hepatic encephalopathy remains unclear.
Alternatively, there may be impairment of the normal blood-brain barrier, rendering the CNS susceptible to various noxious agents. Increased levels of other substances, including metabolic products such as short-chain fatty acids and endogenous benzodiazepine-like metabolites, have also been found in the blood. Importantly, some patients show improvement in encephalopathy when treated with flumazenil, a benzodiazepine receptor antagonist.
Another proposed mechanism postulates a role for GABA, the principal inhibitory neurotransmitter of the brain. GABA is produced in the gut, and increased levels are found in the blood of patients with liver failure. More recently, cerebral and systematic inflammation has been implicated in the pathogenesis of hepatic encephalopathy. Although the exact mechanisms are not known, possibilities include cytokine-mediated changes in blood-brain barrier permeability, potential changes in glutamate uptake by astrocytes, and changes in expression of GABA receptors.
Once the diagnosis is made, it is helpful to grade the severity of hepatic encephalopathy. Stages I through IV are based on degree of behavioral changes, intellectual dysfunction, and alterations in consciousness. Therapy includes management of potential precipitants and is directed at reduction of intestinal ammonia production or increasing the removal of ammonia from the circulation. Nonabsorbable synthetic disaccharides (eg, lactulose) are catabolized by colonic bacteria to short-chain fatty acids, which lower luminal pH. This change in pH favors the formation of ammonium (NH4+), which reduces absorption of ammonia (NH3) into the circulation. Disaccharides such as lactulose are thus the mainstay of therapy. As discussed above in the section Altered Metabolism of Ammonia, the antibiotic rifaximin has been used in conjunction with lactulose for treatment of hepatic encephalopathy.
Factors contributing to coagulopathy in cirrhosis include loss of hepatic synthesis of clotting factors, some of which have a half-life of just a few hours. Under these circumstances, a minor or self-limited source of bleeding can become massive.
Hepatocytes are also functionally involved in the maintenance of a normal coagulation cascade through the absorption of vitamin K (a fat-soluble vitamin whose absorption is dependent on bile flow), which is necessary for the activation of some clotting factors (II, VII, IX, X). An ominous sign of the severity of liver disease is the development of a coagulopathy that does not respond to parenteral vitamin K, suggesting deficient clotting factor synthesis rather than impaired absorption of vitamin K because of fat malabsorption. Finally, loss of the liver’s capacity to remove activated clotting factors and fibrin degradation products may play a role in the increased susceptibility to disseminated intravascular coagulation, a syndrome of coagulation factor consumption that results in uncontrolled simultaneous clotting and bleeding.
Splenomegaly and Hypersplenism
Enlargement of the spleen is a consequence of elevated portal venous pressure and consequent engorgement of the organ. Thrombocytopenia and hemolytic anemia occur because of sequestering of formed elements of the blood in the spleen, from which they are normally cleared as they age and are damaged.
The 5-year cumulative risk of HCC in patients with cirrhosis ranges from 5% to 30% depending on the patient’s sex, ethnicity, liver disease cause, and stage of cirrhosis. In the United States, the incidence of HCC has been rising over the past few decades, with over 20,000 new cases diagnosed each year, attributable to increased prevalence of NAFLD, HCV cirrhosis, and chronic HBV infections due to immigration from high prevalence regions. Several etiologic factors have been identified in the development of this tumor, although cirrhosis is present in the vast majority (80–90%) of patients who develop HCC.
The risk of developing HCC is increased 100-fold in those with chronic hepatitis B infection, and worldwide, HBV accounts for over 50% of all HCC cases and nearly all childhood cases. While HCC can occur in the absence of cirrhosis, over 70% of HBV-related cases occur in those with advanced fibrosis or cirrhosis. Risk factors for HCC in this population include male sex, older age or longer duration of infection, coinfection (HCV, HDV, HIV), mycotoxin aflatoxin exposure, genotype C, and in particular, high levels of viral replication, as evidenced by persistent elevation of HBV viral load.
In patients with chronic hepatitis C, the risk of developing HCC is increased 15- to 20-fold, with risk limited to those with advanced fibrosis and cirrhosis. It has been projected that the incidence of HCV-related HCC cases in the United States will continue to rise over the next several decades. Risk factors for HCC development include male sex, older age and duration of chronic HCV infection, coinfections (HBV, HIV), heavy alcohol use, obesity, and metabolic factors.
Chronic hepatitis B and C account for 60–70% of all HCC cases in the United States. While any cause of cirrhosis can lead to HCC, alcoholic cirrhosis and nonalcoholic steatohepatitis account for most of the remaining U.S. cases. Obesity and the metabolic syndrome are increasingly recognized as risk factors for liver cancer.
Up to one third of patients with decompensated cirrhosis have problems associated with oxygenation and may present with shortness of breath. There are three main pulmonary complications of cirrhosis to consider: hepatopulmonary syndrome, portopulmonary syndrome, and hepatic hydrothorax. In addition, mild hypoxemia can be caused by massive ascites, with resulting diaphragmatic elevation and ventilation/perfusion mismatch.
The hepatopulmonary syndrome consists of the triad of advanced liver failure, hypoxemia, and intrapulmonary vascular dilation and shunting. The cause of pulmonary precapillary and capillary vasodilatation is unknown, but substances such as nitric oxide, endothelin, and arachidonic acid are thought to be involved. As a result of ventilation-perfusion mismatch, patients often present with platypnea, dyspnea that worsens in the upright position secondary to preferential perfusion of dilated vessels in the lung bases. Classically, contrast-enhanced echocardiography is used for definitive diagnosis and can reveal opacification of the left heart chambers within three to six cardiac cycles if a right-to-left intrapulmonary shunt is present. Liver transplantation leads to resolution of the hepatopulmonary syndrome. However, development of severe pulmonary hypertension in patients with advanced liver failure may be a contraindication to liver transplantation.
Portopulmonary hypertension refers to the development of pulmonary hypertension in patients with advanced liver disease and advanced portal hypertension. Patients can present with hypoxia, dyspnea on exertion, fatigue, and even signs of right heart failure. Patients have evidence of elevated pulmonary vascular resistance and a transpulmonary gradient in the setting of pulmonary arterial vasoconstriction. Targeted therapy (eg, epoprostenol, vasodilators) and management of right heart failure can delay progression, but prognosis is poor. Liver transplantation is associated with high operative risk when pulmonary hypertension becomes severe.
Individuals with cirrhosis and ascites can develop hepatic hydrothorax and present with shortness of breath, cough, or chest discomfort. In this condition, fluid accumulates in the pleural space due to small defects in the diaphragm, most commonly on the right side. Negative intrathoracic pressure generated during inspiration favors the passage of fluid from the intra-abdominal cavity to the pleural space. Diagnostic thoracentesis should be performed to exclude alternative causes of pleural effusion, particularly infection. Treatment aims to prevent or reduce fluid accumulation with diuretics, low sodium diet, and occasionally therapeutic thoracentesis (or paracentesis to decrease pressure from tense ascites) for highly symptomatic patients refractory to or intolerant of conservative measures. TIPS may benefit selected patients (eg, Child-Pugh class A or B with no encephalopathy) who are requiring repeated thoracenteses. If they are otherwise suitable candidates, patients with cirrhosis and persistent hepatic hydrothorax should be referred for liver transplantation.
Other findings on physical examination of patients with cirrhosis include spider angiomas (prominent blood vessels with a central arteriole and small vessels radiating from it seen in the skin, particularly on the face and upper trunk), Dupuytren contractures (fibrosis of the palmar fascia), testicular atrophy, gynecomastia (enlargement of breast tissue in men), palmar erythema, lacrimal and parotid gland enlargement, and diminished axillary and pubic hair (Figure 14–13). These findings are largely a consequence of estrogen excess resulting from decreased clearance of endogenous estrogens by the diseased liver combined with decreased hepatic synthesis of steroid hormone–binding globulin. Both of these mechanisms result in tissues receiving higher than normal concentrations of estrogens. In addition, a longer half-life of androgens may allow a greater degree of peripheral aromatization (conversion to estrogens by, eg, adipose tissue, hair follicles), further increasing estrogen-like effects in patients with cirrhosis. Xanthomas of the eyelids and extensor surfaces of tendons of the wrists and ankles can occur with chronic cholestasis such as occurs in primary biliary cirrhosis. Finally, profound muscle wasting and cachexia in cirrhosis probably reflect diminution of the liver’s synthesis of carbohydrate, lipid, and amino acids.
What are the defining features of cirrhosis?
What are the three categories of hepatic fibrosis? Name one agent causing each.
What are the two postulated stages in the development of cirrhosis?
What are some ways alcohol may injure the liver?
What are the major clinical manifestations of cirrhosis?
For each major clinical manifestation of cirrhosis, suggest a reasonable hypothesis to account for its pathogenesis.