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InternalMed_Harrison. Osteoporosis is common in patients with chronic cholestatic liver disease because of malabsorption of vitamin D and decreased calcium ingestion. The rate of bone resorption exceeds that of new bone formation in patients with cirrhosis, resulting in bone loss. Dual x-ray absorptiometry (DEXA) is a useful method for determining osteoporosis or osteopenia in patients with chronic liver disease. When a DEXA scan shows decreased bone mass, treatment should be administered with bisphosphonates that are effective at inhibiting resorption of bone and efficacious in the treatment of osteoporosis. Numerous hematologic manifestations of cirrhosis are present, including anemia from a variety of causes including hypersplenism, hemolysis, iron deficiency, and perhaps folate deficiency from malnutrition. Macrocytosis is a common abnormality in red blood cell morphology seen in patients with chronic liver disease, and neutropenia may be seen as a result of hypersplenism.


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InternalMed_Harrison. and/or nuclei, viral inclusion bodies, copper or iron deposition, other 366e-1 Atlas of Liver Biopsies inclusion bodies) and others involving the portal tracts (e.g., the Jules L. Dienstag, Atul K. Bhan the border of periportal hepatocytes in chronic hepatitis C, autoim- Although clinical and laboratory features yield clues to the extent of inflammatory processes (disease grade), the degree of scarring and architectural distortion (disease stage), and the nature of the disease process, the liver biopsy is felt to represent the gold standard for assessing the degree of liver injury and fibrosis. Examination of liver histology provides not only a basis for quantitative scoring of disease activity and progression but also a wealth of qualitative information that can direct and inform diagnosis and management.


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InternalMed_Harrison. A normal liver lobule consists of portal (zone 1), lobular (midzonal or zone 2), and central (zone 3) zones. The portal tract contains the hepatic artery (HA) and portal vein (PV), which represent the dual vascular supply to the liver, as well as the bile duct (BD). The lobular area contains cords of liver cells surrounded by vascular sinusoids, and the central zone consists of the central vein (CV), the terminal branch of the hepatic vein (see figure below).


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InternalMed_Harrison. Included in this atlas of liver biopsies are examples of common morphologic features of acute and chronic liver disorders, some involving the lobular areas (e.g., the lobular inflammatory changes of acute hepatitis, apoptotic hepatocyte degeneration in acute and chronic hepatitis, virus antigen localization in hepatocyte cytoplasm mune hepatitis, and liver allograft rejection) or centrizonal areas (e.g., acute acetaminophen hepatotoxicity). Other histologic features of importance include hepatic steatosis (observed in alcoholic liver injury, nonalcoholic fatty liver disorders, and metabolic disorders–including mitochondrial injury–and in patients with chronic viral hepatitis); injury of bile ducts in the portal tract, an important diagnostic hallmark of primary biliary cirrhosis, primary sclerosing cholangitis, and liver allograft rejection; cholestasis in intrahepatic or extrahepatic biliary obstruction or in infiltrative disorders; ductular proliferation in the setting of marked


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InternalMed_Harrison. sclerosing cholangitis, and liver allograft rejection; cholestasis in intrahepatic or extrahepatic biliary obstruction or in infiltrative disorders; ductular proliferation in the setting of marked hepatocellular necrosis; plasma cell infiltration common in autoimmune hepatitis; portal inflammation affecting portal veins (“endothelialitis”) in liver allograft rejection; and mild-to-severe fibrosis, in varying distribution and pattern, as a consequence of liver injury common to many disorders. (All magnifications reflect the objective lens used.)


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InternalMed_Harrison. Figure 366e-2 Acute hepatitis, higher magnification, showing lobu-lar inflammation, hepatocellular ballooning, and acidophilic bodies (arrows) (H&E, 20×). CHAPTER 366e Atlas of Liver Biopsies Figure 366e-1 Acute hepatitis with lobular inflammation and hepa-tocellular ballooning (hematoxylin and eosin [H&E], 10×). Figure 366e-3 Chronic hepatitis C with portal lymphoid infiltrate and lymphoid follicle containing germinal center (H&E, 10×). PART 14 Disorders of the Gastrointestinal System Figure 366e-4 Chronic hepatitis C with portal and lobular inflam-mation and steatosis (H&E, 10×). Figure 366e-7 Chronic hepatitis B with hepatocellular cytoplasmic staining for hepatitis B surface antigen (immunoperoxidase, 20×). Figure 366e-5 Chronic hepatitis C with portal inflammation and interface hepatitis (erosion of the limiting plate of periportal hepato-cytes by infiltrating mononuclear cells) (H&E, 20×).


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InternalMed_Harrison. Figure 366e-5 Chronic hepatitis C with portal inflammation and interface hepatitis (erosion of the limiting plate of periportal hepato-cytes by infiltrating mononuclear cells) (H&E, 20×). Figure 366e-8 Chronic hepatitis B with hepatocellular nuclear stain-ing for hepatitis B core antigen (immunoperoxidase, 20×). Figure 366e-6 Lobular inflammation with acidophilic body (apop-totic body) surrounded by lymphoid cells (H&E, 40×). Figure 366e-9 Autoimmune hepatitis with portal and lobular inflammation, interface hepatitis, and cholestasis (H&E, 10×). Figure 366e-10 Autoimmune hepatitis, higher magnification, showing dense plasma cell infiltrate in the portal and periportal regions (H&E, 40×). Figure 366e-13 Cirrhosis with architectural alteration resulting from fibrosis and nodular hepatocellular regeneration (Masson trichrome, 2×).


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InternalMed_Harrison. Figure 366e-13 Cirrhosis with architectural alteration resulting from fibrosis and nodular hepatocellular regeneration (Masson trichrome, 2×). Figure 366e-11 Primary biliary cirrhosis with degenerating bile duct epithelium (“florid ductular lesion”) (arrow) surrounded by epi-thelioid granulomatous reaction and lymphoplasmacytic infiltrate (H&E, 40×). Figure 366e-14 Acute cellular rejection of orthotopic liver allograft demonstrating a mixed inflammatory cell infiltrate (lymphoid cells, eosinophils, neutrophils) of the portal tract as well as endothelialitis of the portal vein (arrow) and bile duct injury (H&E, 10×). Figure 366e-15 Liver allograft with cytomegalovirus infection showing hepatocytes with nuclear inclusions (arrows) surrounded by a neutrophilic and lymphoid infiltrate (H&E, 10×). Figure 366e-12 Chronic hepatitis C with bridging fibrosis (arrow) (Masson trichrome, 10×). CHAPTER 366e Atlas of Liver Biopsies PART 14 Disorders of the Gastrointestinal System


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InternalMed_Harrison. Figure 366e-12 Chronic hepatitis C with bridging fibrosis (arrow) (Masson trichrome, 10×). CHAPTER 366e Atlas of Liver Biopsies PART 14 Disorders of the Gastrointestinal System Figure 366e-16 Combined acetaminophen hepatotoxicity and alcoholic liver injury with extensive centrilobular areas of necrosis (H&E, 4×). Figure 366e-19 α1 Antitrypsin deficiency with higher magnification of PAS-positive, diastase-resistant globules (PAS, 40×). Figure 366e-17 Combined acetaminophen hepatotoxicity and alcoholic liver injury at higher magnification showing necrotic cen-trilobular area with Mallory bodies (H&E 20×). Figure 366e-20 Cirrhosis secondary to hemochromatosis with hepatocellular carcinoma; brown hemosiderin pigment (iron) is pres-ent in the cirrhotic liver, while the hepatocellular carcinoma nodules are hemosiderin-free (H&E, 4×).


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InternalMed_Harrison. Figure 366e-18 α1 Antitrypsin deficiency with cytoplasmic periodic acid–Schiff (PAS)-positive, diastase-resistant globules in many hepato-cytes, predominantly at the periphery of a cirrhotic nodule (PAS, 20×). Figure 366e-21 Cirrhosis secondary to hemochromatosis with hepatocellular carcinoma at higher magnification, demonstrating nodules of large malignant cells with highly disorganized architecture (H&E, 10×). Figure 366e-22 Hemochromatosis with iron stain demonstrating extensive iron deposition and characteristic pattern of pericanalicular distribution of iron (iron stain, 10×). Figure 366e-25 Primary sclerosing cholangitis showing peripheral cholestasis (green) and cytoplasmic red granular staining of hepatocytes for copper (rhodamine copper stain, 20×). Figure 366e-23 Primary sclerosing cholangitis showing cirrhosis and periductular fibrosis (Masson trichrome, 4×).


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InternalMed_Harrison. Figure 366e-23 Primary sclerosing cholangitis showing cirrhosis and periductular fibrosis (Masson trichrome, 4×). Figure 366e-26 Nonalcoholic steatohepatitis (NASH) showing steatosis, ballooned hepatocytes, and Mallory bodies with surrounding polymorphonuclear leukocytes (arrow) (H&E, 20×). Figure 366e-24 Primary sclerosing cholangitis showing the extra-hepatic bile duct (in a liver explant obtained at the time of hepatec-tomy for orthotopic liver transplantation) with marked mural chronic inflammation and fibrosis as well as peribiliary glands (H&E, 2×). Figure 366e-27 Nonalcoholic steatohepatitis (NASH) showing steatosis with perisinusoidal and pericellular fibrosis (H&E, 20×). CHAPTER 366e Atlas of Liver Biopsies PART 14 Disorders of the Gastrointestinal System


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InternalMed_Harrison. CHAPTER 366e Atlas of Liver Biopsies PART 14 Disorders of the Gastrointestinal System Figure 366e-28 Acute hepatitis with submassive hepatic necrosis Figure 366e-29 Wilson’s disease showing cirrhosis, extensive col-with marked parenchymal collapse, remnant islands of surviving lapse, and ductular reaction in a teenager with an acute presentation hepatocytes, and a marked ductular reaction (H&E, 10×). (H&E, 4×). Figure 366e-30 Wilson’s disease showing extensive hepatocyte cytoplasmic red granular staining for copper in a cirrhotic nodule (rhodanine copper stain, 20×).


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InternalMed_Harrison. Figure 366e-30 Wilson’s disease showing extensive hepatocyte cytoplasmic red granular staining for copper in a cirrhotic nodule (rhodanine copper stain, 20×). Genetic, Metabolic, and Infiltrative Diseases Affecting the Liver Bruce R. Bacon There are a number of disorders of the liver that fit within the 367e categories of genetic, metabolic, and infiltrative disorders (Table 367e-1). Inherited disorders include hemochromatosis, Wilson’s disease, α1 antitrypsin (α1AT) deficiency, and cystic fibrosis (CF). Hemochromatosis is the most common inherited disorder affecting white populations, with the genetic susceptibility for the disease being identified in 1 in 250 individuals. Over the past 15 years, it has become increasingly apparent that nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes found in the U.S. population. This disorder is discussed in greater detail in Chap. 364. Infiltrative disorders of the liver are relatively rare.


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InternalMed_Harrison. GENETIC LIVER DISEASES Hereditary Hemochromatosis Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism (Chap. 428). Our knowledge of the disease and its phenotypic expression has changed since 1996, when the gene for HH, called HFE, was identified, allowing for genetic testing for the two major mutations (C282Y and H63D) that are responsible for HFE-related HH. Subsequently, several additional genes/proteins involved in the regulation of iron homeostasis have been identified, contributing to a better understanding of cellular iron uptake and release and the characterization of additional causes of inherited iron overload (Table 367e-2).


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InternalMed_Harrison. Most patients with HH are asymptomatic; however, when patients present with symptoms, they are frequently nonspecific and include weakness, fatigue, lethargy, and weight loss. Specific, organ-related symptoms include abdominal pain, arthralgias, and symptoms and signs of chronic liver disease. Increasingly, most patients are now identified before they have symptoms, either through family studies or from the performance of screening iron studies. Several prospective population studies have shown that C282Y homozygosity is found in about 1 in 250 individuals of northern European descent, with the heterozygote frequency seen in approximately 1 in 10 individuals. It is important to consider HH in patients who present with the symptoms TAbLE 367e-1 GEnETIC, METAboLIC, AnD InfILTRATIvE DIsEAsEs AffECTInG THE LIvER Abbreviations: HAMP, hepcidin; HJV, hemojuvelin; TfR2, transferrin receptor 2.


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InternalMed_Harrison. and signs known to occur in established HH. When confronted with abnormal serum iron studies, clinicians should not wait for typical symptoms or findings of HH to appear before considering the diagnosis. However, once the diagnosis of HH is considered, either by an evaluation of abnormal screening iron studies in the context of family studies, in a patient with an abnormal genetic test, or in the evaluation of a patient with any of the typical symptoms (Table 367e-3) or clinical findings (Table 367e-4), definitive diagnosis is relatively straightforward. Transferrin saturation (serum iron divided by total iron-binding capacity [TIBC] or transferrin, times 100%) and ferritin levels should be obtained. Both of these will be elevated in a symptomatic patient. It must be remembered that ferritin is an acute-phase reactant and can be elevated in a number of other inflammatory disorders, such as rheumatoid arthritis, or in various neoplastic diseases, such as lymphoma or other cancers.


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InternalMed_Harrison. is an acute-phase reactant and can be elevated in a number of other inflammatory disorders, such as rheumatoid arthritis, or in various neoplastic diseases, such as lymphoma or other cancers. Also, serum ferritin is elevated in a majority of patients with nonalcoholic steatohepatitis (NASH), hepatitis C, and alcoholic liver disease in the absence of iron overload.


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InternalMed_Harrison. At present, if patients have an elevated transferrin saturation or ferritin level, genetic testing should be performed; if they are a C282Y homozygote or a compound heterozygote (C282Y/H63D), the diagnosis is confirmed. If liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) are elevated or the ferritin is >1000 μg/L, the patient should be considered for liver biopsy because there is an increased frequency of advanced fibrosis in these individuals. If liver biopsy is performed, iron deposition is found in a periportal distribution with a periportal to pericentral gradient; iron is found predominantly in parenchymal cells, and Kupffer cells are spared. CHAPTER 367e Genetic, Metabolic, and Infiltrative Diseases Affecting the Liver


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InternalMed_Harrison. CHAPTER 367e Genetic, Metabolic, and Infiltrative Diseases Affecting the Liver Hepatomegaly 60–85 Cirrhosis 50–95 Skin pigmentation 40–80 Arthritis (second, third metacarpophalangeal joints) 40–60 Clinical diabetes 10–60 Splenomegaly 10–40 Loss of body hair 10–30 Testicular atrophy 10–30 Dilated cardiomyopathy 0–30 Treatment of HH is relatively straightforward with weekly phlebotomy aimed to reduce iron stores, recognizing that each unit of blood contains 200–250 mg of iron. If patients are diagnosed and treated before the development of hepatic fibrosis, all complications of the disease can be avoided. Maintenance phlebotomy is required in most patients and usually can be achieved with 1 unit of blood removed every 2–3 months. Family studies should be performed with transferrin saturation, ferritin, and genetic testing offered to all first-degree relatives.


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InternalMed_Harrison. Wilson’s Disease Wilson’s disease is an inherited disorder of copper homeostasis first described in 1912 (Chap. 429). The Wilson’s disease gene was discovered in 1993, with the identification of ATP7B. This P-type ATPase is involved in copper transport and is necessary for the export of copper from the hepatocyte. Thus, in patients with mutations in ATP7B, copper is retained in the liver, leading to increased copper storage and ultimately liver disease as a result.


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InternalMed_Harrison. The clinical presentation of Wilson’s disease is variable and includes chronic hepatitis, hepatic steatosis, and cirrhosis in adolescents and young adults. Neurologic manifestations indicate that liver disease is present and include speech disorders and various movement disorders. Diagnosis includes the demonstration of a reduced ceruloplasmin level, increased urinary excretion of copper, the presence of Kayser-Fleischer rings in the corneas of the eyes, and an elevated hepatic copper level, in the appropriate clinical setting. The genetic diagnosis of Wilson’s disease is difficult because >500 mutations in ATP7B have been described with different degrees of frequency and penetration in certain populations. PART 14 Disorders of the Gastrointestinal System


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InternalMed_Harrison. PART 14 Disorders of the Gastrointestinal System Treatment consists of copper-chelating medications such as D-penicillamine and trientine. A role for zinc acetate has also been established. Medical treatment is lifelong, and severe relapses leading to liver failure and death can occur with cessation of therapy. Liver transplantation is curative with respect to the underlying metabolic defect and restores the normal phenotype with respect to copper homeostasis.


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InternalMed_Harrison. α1 Antitrypsin Deficiency α1AT deficiency was first described in the late 1960s in patients with severe pulmonary disease. α1AT is a 52-kDa glycoprotein produced in hepatocytes, phagocytes, and epithelial cells in the lungs, which inhibits serine proteases, primarily neutrophil elastase. In α1AT deficiency, increased amounts of neutrophil elastase can result in progressive lung injury from degradation of elastin, leading to premature emphysema. In the 1970s, α1AT deficiency was discovered as a cause of neonatal liver disease, so-called “neonatal hepatitis.” It is now known to be a cause of liver disease in infancy, early childhood, and adolescence, and in adults.


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InternalMed_Harrison. In α1AT deficiency, variants in the proteinase inhibitor (Pi) gene located on chromosome 14 alter α1AT structure, interfering with hepatocellular export. Aggregated, deformed polymers of α1AT accumulate in the hepatocyte endoplasmic reticulum. There are over 75 different α1AT variants. Conventional nomenclature identifies normal variants as PiMM; these individuals have normal blood levels of α1AT. The most common abnormal variants are called S and Z. Individuals homozygous for the Z mutation (PiZZ) have low levels of α1AT (about 15% of normal), and these patients are susceptible to liver and/or lung disease, yet only a proportion (about 25%) of PiZZ patients develop disease manifestations. Null variants have undetectable levels of α1AT and are susceptible to premature lung disease.


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InternalMed_Harrison. α1AT deficiency has been identified in all populations; however, the disorder is most common in patients of northern European and Iberian descent. The disorder affects about 1 in 1500 to 2000 individuals in North America. The natural history of α1AT deficiency is quite variable because many individuals with the PiZZ variant never develop disease, whereas others can develop childhood cirrhosis leading to liver transplantation. In adults, the diagnosis often comes in the course of evaluation of patients with abnormal liver test abnormalities or in a workup for cirrhosis. A hint to diagnosis may be coexistent lung disease at a relatively young age or a family history of liver and/or lung disease. Patients may have symptoms of pulmonary disease with cough and dyspnea. Liver disease may be asymptomatic other than fatigue, or patients may present with complications of decompensated liver disease.


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InternalMed_Harrison. Diagnosis of α1AT deficiency is confirmed by blood tests showing reduced levels of serum α1AT, accompanied by Pi determinations. Most patients with liver disease have either PiZZ or PiSZ; occasionally, patients with PiMZ have reduced levels of α1AT, but they usually do not have a low enough level to cause disease. Liver biopsy is often performed to determine stage of hepatic fibrosis and shows characteristic PAS-positive, diastase-resistant globules in the periphery of the hepatic lobule.


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InternalMed_Harrison. Treatment of α1AT deficiency is usually nonspecific and supportive. For patients with liver involvement, other sources of liver injury, such as alcohol, should be avoided. Evidence for other liver diseases (e.g., viral hepatitis B and C, hemochromatosis, NAFLD) should be sought and treated if possible. Smoking can worsen lung disease progression in α1AT deficiency and should be discontinued. Patients with lung disease may be eligible to receive infusions of α1AT, which has been shown to halt further damage to the lungs. If liver disease becomes decompensated, transplantation should be pursued and is curative. Following transplant, patients express the Pi phenotype of the donor. Finally, risk of hepatocellular carcinoma is significantly increased in patients with cirrhosis due to α1AT deficiency.


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InternalMed_Harrison. Cystic Fibrosis CF should also be considered as an inherited form of chronic liver disease, although the principal manifestations of CF include chronic lung disease and pancreatic insufficiency (Chap. 313). A small percentage of patients with CF who survive to adulthood have a form of biliary cirrhosis characterized by cholestatic liver enzyme abnormalities and the development of chronic liver disease. Ursodeoxycholic acid is occasionally helpful in improving liver test abnormalities and in reducing symptoms. The disease is slowly progressive. METABOLIC LIVER DISEASES Nonalcoholic Fatty Liver Disease NAFLD and NASH are common liver diseases causing abnormal liver test results and progressing to cirrhosis. NAFLD and NASH are discussed in detail in Chap. 364.


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InternalMed_Harrison. Lipid Storage Diseases There are a number of rare lipid storage diseases that involve the liver, including the inherited disorders of Gaucher’s disease and Niemann-Pick disease (Chap. 433e). Other rare disorders include abetalipoproteinemia, Tangier disease, Fabry’s disease, and types I and V hyperlipoproteinemia (Table 367e–5). Hepatomegaly is present due to increased fat deposition, and increased glycogen is found in the liver.


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InternalMed_Harrison. Porphyrias The porphyrias are a group of metabolic disorders in which there are defects in the biosynthesis of heme necessary for incorporation into numerous hemoproteins such as hemoglobin, myoglobin, catalase, and the cytochromes (Chap. 430). Porphyrias can present as either acute or chronic diseases, with the acute disorder causing recurring bouts of abdominal pain, and the chronic disorders characterized by painful skin lesions. Porphyria cutanea tarda (PCT) is the most commonly encountered porphyria. Patients present with characteristic vesicular lesions on sun-exposed areas of the skin, principally the dorsum of the hands, the tips of the ears, or the cheeks. About 40% of patients with PCT have mutations in the gene for hemochromatosis (HFE), and ~50% have hepatitis C; thus, iron studies and HFE mutation analysis as well as hepatitis C testing should be considered in all patients who present with PCT. PCT is also associated with excess alcohol use and some medications, most


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InternalMed_Harrison. studies and HFE mutation analysis as well as hepatitis C testing should be considered in all patients who present with PCT. PCT is also associated with excess alcohol use and some medications, most notably estrogens.


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InternalMed_Harrison. The mainstay of treatment of PCT is iron reduction by therapeutic phlebotomy, which is successful in reversing the skin lesions in the majority of patients. If hepatitis C is present, this should be treated as well. Acute intermittent porphyria presents with abdominal pain, with the diagnosis made by avoidance of certain precipitating factors such as starvation or certain diets. Intravenous heme as hematin has been used for treatment. INFILTRATIVE DISORDERS Amyloidosis Amyloidosis is a metabolic storage disease that results from deposition of insoluble proteins that are aberrantly folded and assembled and then deposited in a variety of tissues (Chap. 136).


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InternalMed_Harrison. Amyloidosis is divided into two types, primary and secondary, based 367e-3 on the broad concepts of association with myeloma (primary) or chronic inflammatory illnesses (secondary). The disease is generally considered rare, although, in certain disease states or in certain populations, it can be more common. For example, when associated with familial Mediterranean fever, it is seen in high frequency in Sephardic Jews and Armenians living in Armenia and less frequently in Ashkenazi Jews, Turks, and Arabs. Amyloidosis frequently affects patients suffering from tuberculosis and leprosy and can be seen in upwards of 10–15% of patients with ankylosing spondylitis, rheumatoid arthritis, or Crohn’s disease. In one surgical pathology series, amyloid was found in <1% of cases. The liver is commonly involved in cases of systemic amyloidosis, but it is frequently not clinically apparent and only documented at autopsy. Pathologic findings in the liver include positive staining with the Congo red


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InternalMed_Harrison. involved in cases of systemic amyloidosis, but it is frequently not clinically apparent and only documented at autopsy. Pathologic findings in the liver include positive staining with the Congo red histochemical stain where there is an apple-green birefringence noted under polarizing light.


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InternalMed_Harrison. Granulomas Granulomas are frequently found in the liver when patients are being evaluated for cholestatic liver enzyme abnormalities. Granulomas can be seen in primary biliary cirrhosis, but there are other characteristic clinical (e.g., pruritus, fatigue) and laboratory findings (cholestatic liver tests, antimitochondrial antibody) that allow for a definitive diagnosis of that disorder. Granulomatous infiltration can also be seen as the principal hepatic manifestation of sarcoidosis, and this is the most common presentation of hepatic granulomas (Chap. 390). The vast majority of these patients do not require any specific treatment other than what would normally be used for treatment of their sarcoidosis. A small subset, however, can develop a particularly bothersome desmoplastic reaction with a significant increase in fibrosis, which can progress to cirrhosis and liver failure. These patients may require treatment with immunosuppressive therapy and may require liver transplantation.


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InternalMed_Harrison. with a significant increase in fibrosis, which can progress to cirrhosis and liver failure. These patients may require treatment with immunosuppressive therapy and may require liver transplantation. In patients who have granulomas in the liver not associated with sarcoidosis, treatment is rarely needed.


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InternalMed_Harrison. Diagnosis requires liver biopsy, and it is important to establish a diagnosis so that a cause for the elevated liver enzymes is carefully identified. Some medications can cause granulomatous infiltration of the liver, the most notable of which is allopurinol. Lymphoma Involvement of the liver with lymphoma can sometimes be with bulky mass lesions but can also be as a difficult-to-diagnose infiltrative disorder that does not show any characteristic findings on abdominal imaging studies (Chap. 134). Patients may present with severe liver disease, jaundice, hypoalbuminemia, mild to moderately elevated aminotransferases, and an elevated alkaline phosphatase. A liver biopsy is required for diagnosis and should be considered when routine blood testing does not lead to a diagnosis of the liver dysfunction. CHAPTER 367e Genetic, Metabolic, and Infiltrative Diseases Affecting the Liver


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InternalMed_Harrison. Liver TransplantationCHAPTER 368liver Transplantation Raymond T. Chung, Jules L. Dienstag Liver transplantation—the replacement of the native, diseased liver by a normal organ (allograft)—has matured from an experimental pro-cedure reserved for desperately ill patients to an accepted, lifesaving operation applied more optimally in the natural history of end-stage 368 liver disease. The preferred and technically most advanced approach is orthotopic transplantation, in which the native organ is removed and the donor organ is inserted in the same anatomic location. Pioneered in the 1960s by Thomas Starzl at the University of Colorado and, later, at the University of Pittsburgh and by Roy Calne in Cambridge, England, liver transplantation is now performed routinely worldwide. Success measured as 1-year survival has improved from ~30% in the 1970s to >90% today. These improved prospects for prolonged survival resulted from refinements in operative technique, improvements in organ


InternalMed_Harrison

InternalMed_Harrison. measured as 1-year survival has improved from ~30% in the 1970s to >90% today. These improved prospects for prolonged survival resulted from refinements in operative technique, improvements in organ procurement and preservation, advances in immunosuppressive therapy, and, perhaps most influentially, more enlightened patient selection and timing. Despite the perioperative morbidity and mortality, the technical and management challenges of the procedure, and its costs, liver transplantation has become the approach of choice for selected patients whose chronic or acute liver disease is progressive, life-threatening, and unresponsive to medical therapy. Based on the current level of success, the number of liver transplants has continued to grow each year; in 2012, 6256 patients received liver allografts in the United States. Still, the demand for new livers continues to outpace availability; as of mid-2013, 15,806 patients in the United States were on a waiting list for a donor liver. In


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InternalMed_Harrison. allografts in the United States. Still, the demand for new livers continues to outpace availability; as of mid-2013, 15,806 patients in the United States were on a waiting list for a donor liver. In response to this drastic shortage of donor organs, many transplantation centers supplement cadaver-organ liver transplantation with living-donor transplantation.


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InternalMed_Harrison. Potential candidates for liver transplantation are children and adults who, in the absence of contraindications (see below), suffer from severe, irreversible liver disease for which alternative medical or surgical treatments have been exhausted or are unavailable. Timing of the operation is of critical importance. Indeed, improved timing and better patient selection are felt to have contributed more to the increased 2068 success of liver transplantation in the 1980s and beyond than all the impressive technical and immunologic advances combined. Although the disease should be advanced, and although opportunities for spontaneous or medically induced stabilization or recovery should be allowed, the procedure should be done sufficiently early to give the surgical procedure a fair chance for success. Ideally, transplantation should be considered in patients with end-stage liver disease who are experiencing or have experienced a life-threatening complication of hepatic decompensation or


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InternalMed_Harrison. success. Ideally, transplantation should be considered in patients with end-stage liver disease who are experiencing or have experienced a life-threatening complication of hepatic decompensation or whose quality of life has deteriorated to unacceptable levels. Although patients with well-compensated cirrhosis can survive for many years, many patients with quasi-stable chronic liver disease have much more advanced disease than may be apparent. As discussed below, the better the status of the patient prior to transplantation, the higher will be its anticipated success rate. The decision about when to transplant is complex and requires the combined judgment of an experienced team of hepatologists, transplant surgeons, anesthesiologists, and specialists in support services, not to mention the well-informed consent of the patient and the patient’s family.


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InternalMed_Harrison. Indications for transplantation in children are listed in Table 368-1. The most common is biliary atresia. Inherited or genetic disorders of metabolism associated with liver failure constitute another major indication for transplantation in children and adolescents. In Crigler-Najjar disease type I and in certain hereditary disorders of the urea cycle and of amino acid or lactate-pyruvate metabolism, transplantation may be the only way to prevent impending deterioration of central nervous system function, despite the fact that the native liver is structurally normal. Combined heart and liver transplantation has yielded dramatic improvement in cardiac function and in cholesterol levels in children with homozygous familial hypercholesterolemia; combined liver and kidney transplantation has been successful in patients with primary hyperoxaluria type I. In hemophiliacs with transfusion-associated hepatitis and liver failure, liver transplantation has been associated with recovery of


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InternalMed_Harrison. has been successful in patients with primary hyperoxaluria type I. In hemophiliacs with transfusion-associated hepatitis and liver failure, liver transplantation has been associated with recovery of normal factor VIII synthesis.


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InternalMed_Harrison. Liver transplantation is indicated for end-stage cirrhosis of all causes (Table 368-1). In sclerosing cholangitis and Caroli’s disease (multiple cystic dilatations of the intrahepatic biliary tree), recurrent infections and sepsis associated with inflammatory and fibrotic obstruction of the biliary tree may be an indication for transplantation. Because prior biliary surgery complicates and is a relative contraindication for liver transplantation, surgical diversion of the biliary tree has been all but abandoned for patients with sclerosing cholangitis. In patients who


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InternalMed_Harrison. Biliary atresia Primary biliary cirrhosis Neonatal hepatitis Secondary biliary cirrhosis Congenital hepatic fibrosis Primary sclerosing cholangitis Alagille’s syndromeα Autoimmune hepatitis Byler’s diseaseb Caroli’s diseasec α1-Antitrypsin deficiency Cryptogenic cirrhosis Inherited disorders of metabolism Chronic hepatitis with cirrhosis αArteriohepatic dysplasia, with paucity of bile ducts, and congenital malformations, including pulmonary stenosis. bIntrahepatic cholestasis, progressive liver failure, and mental and growth retardation. cMultiple cystic dilatations of the intrahepatic biliary tree.


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InternalMed_Harrison. undergo transplantation for hepatic vein thrombosis (Budd-Chiari syndrome), postoperative anticoagulation is essential; underlying myeloproliferative disorders may have to be treated but are not a contraindication to liver transplantation. If a donor organ can be located quickly, before life-threatening complications—including cerebral edema—set in, patients with acute liver failure are candidates for liver transplantation. Routine candidates for liver transplantation are patients with alcoholic cirrhosis, chronic viral hepatitis, and primary hepatocellular malignancies. Although all three of these categories are considered to be high risk, liver transplantation can be offered to carefully selected patients. Currently, chronic hepatitis C and alcoholic liver disease are the most common indications for liver transplantation, accounting for over 40% of all adult candidates who undergo the procedure. Patients with alcoholic cirrhosis can be considered as candidates for transplantation if


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InternalMed_Harrison. for liver transplantation, accounting for over 40% of all adult candidates who undergo the procedure. Patients with alcoholic cirrhosis can be considered as candidates for transplantation if they meet strict criteria for abstinence and reform; however, these criteria still do not prevent recidivism in up to a quarter of cases. In highly selected cases in a limited number of centers, transplantation for severe acute alcoholic hepatitis has been performed with success; however, because patients with acute alcoholic hepatitis are still actively using alcohol, and because continued alcohol abuse remains a concern, acute alcoholic hepatitis is not a routine indication for liver transplantation. Patients with chronic hepatitis C have early allograft and patient survival comparable to those of other subsets of patients after transplantation; however, reinfection in the donor organ is universal, recurrent hepatitis C is insidiously progressive, allograft cirrhosis develops in 20–30% at 5


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InternalMed_Harrison. of other subsets of patients after transplantation; however, reinfection in the donor organ is universal, recurrent hepatitis C is insidiously progressive, allograft cirrhosis develops in 20–30% at 5 years, and cirrhosis and late organ failure occur at a higher frequency beyond 5 years. With the introduction of highly effective direct acting antiviral agents targeting HCV, it is expected that allograft outcomes will improve significantly in the coming years. In patients with chronic hepatitis B, in the absence of measures to prevent recurrent hepatitis B, survival after transplantation is reduced by approximately 10–20%; however, prophylactic use of hepatitis B immune globulin (HBIg) during and after transplantation increases the success of transplantation to a level comparable to that seen in patients with nonviral causes of liver decompensation. Specific oral antiviral drugs (e.g., entecavir, tenofovir disoproxil fumarate) (Chap. 362) can be used both for prophylaxis against and for


InternalMed_Harrison

InternalMed_Harrison. in patients with nonviral causes of liver decompensation. Specific oral antiviral drugs (e.g., entecavir, tenofovir disoproxil fumarate) (Chap. 362) can be used both for prophylaxis against and for treatment of recurrent hepatitis B, facilitating further the management of patients undergoing liver transplantation for end-stage hepatitis B; most transplantation centers rely on antiviral drugs with or without HBIg to manage patients with hepatitis B. Issues of disease recurrence are discussed in more detail below. Patients with nonmetastatic primary hepatobiliary tumors—primary hepatocellular carcinoma (HCC), cholangiocarcinoma, hepatoblastoma, angiosarcoma, epithelioid hemangioendothelioma, and multiple or massive hepatic adenomata—have undergone liver transplantation; however, for some hepatobiliary malignancies, overall survival is significantly lower than that for other categories of liver disease. Most transplantation centers have reported 5-year recurrence-free survival rates in


InternalMed_Harrison

InternalMed_Harrison. malignancies, overall survival is significantly lower than that for other categories of liver disease. Most transplantation centers have reported 5-year recurrence-free survival rates in patients with unresectable HCC for single tumors <5 cm in diameter or for three or fewer lesions all <3 cm comparable to those seen in patients undergoing transplantation for nonmalignant indications. Consequently, liver transplantation is currently restricted to patients whose hepatic malignancies meet these criteria. Expanded criteria for patients with HCC continue to be evaluated. Because the likelihood of recurrent cholangiocarcinoma is very high, only highly selected patients with limited disease are being evaluated for transplantation after intensive chemotherapy and radiation.


InternalMed_Harrison

InternalMed_Harrison. Absolute contraindications for transplantation include life-threatening systemic diseases, uncontrolled extrahepatic bacterial or fungal infections, preexisting advanced cardiovascular or pulmonary disease, multiple uncorrectable life-threatening congenital anomalies, metastatic malignancy, and active drug or alcohol abuse (Table 368–2). Because carefully selected patients in their sixties and even seventies have undergone transplantation successfully, advanced age per se is no longer considered an absolute contraindication; however, in older patients a more thorough preoperative evaluation should be undertaken to Active, untreated sepsis Prior extensive hepatobiliary surgery Uncorrectable, life-limiting congeni-Portal vein thrombosis tal anomalies Active substance or alcohol abuse Renal failure not attributable to liver disease Metastatic malignancy to the liver Severe malnutrition/wasting AIDS HIV seropositivity with failure to control HIV viremia or CD4 <100/μL


InternalMed_Harrison

InternalMed_Harrison. Severe hypoxemia secondary to right-to-left intrapulmonary shunts (PO2 <50 mmHg) exclude ischemic cardiac disease and other comorbid conditions. Advanced age (>70 years), however, should be considered a relative contraindication—that is, a factor to be taken into account with other relative contraindications. Other relative contraindications include portal vein thrombosis, HIV infection, preexisting renal disease not associated with liver disease (which may prompt consideration of combined liver and kidney transplantation), intrahepatic or biliary sepsis, severe hypoxemia (Po2 <50 mmHg) resulting from right-toleft intrapulmonary shunts, portopulmonary hypertension with high mean pulmonary artery pressures (>35 mmHg), previous extensive hepatobiliary surgery, any uncontrolled serious psychiatric disorder, and lack of sufficient social supports. Any one of these relative contraindications is insufficient in and of itself to preclude transplantation. For example, the problem of portal


InternalMed_Harrison

InternalMed_Harrison. disorder, and lack of sufficient social supports. Any one of these relative contraindications is insufficient in and of itself to preclude transplantation. For example, the problem of portal vein thrombosis can be overcome by constructing a graft from the donor liver portal vein to the recipient’s superior mesenteric vein. Now that highly active antiretroviral therapy has dramatically improved the survival of persons with HIV infection (Chap. 226), and because end-stage liver disease caused by chronic hepatitis C and B has emerged as a serious source of morbidity and mortality in the HIV-infected population, liver transplantation has now been performed successfully in selected HIV-positive persons who have excellent control of HIV infection. Selected patients with CD4± T cell counts >100/μL and with pharmacologic suppression of HIV viremia have undergone transplantation for end-stage liver disease. HIV-infected persons who have received liver allografts for end-stage liver disease


InternalMed_Harrison

InternalMed_Harrison. and with pharmacologic suppression of HIV viremia have undergone transplantation for end-stage liver disease. HIV-infected persons who have received liver allografts for end-stage liver disease resulting from chronic hepatitis B have experienced survival rates compared to those of HIV-negative persons undergoing transplantation for the same indication. In contrast, recurrent hepatitis C virus (HCV) in the allograft has limited long-term success in persons with HCV-related end-stage liver disease. Again, it is expected that the availability of direct acting antiviral agents targeting HCV, will significantly improve allograft outcomes.


InternalMed_Harrison

InternalMed_Harrison. Cadaver donor livers for transplantation are procured primarily from victims of head trauma. Organs from brain-dead donors up to age 60 are acceptable if the following criteria are met: hemodynamic stability, adequate oxygenation, absence of bacterial or fungal infection, absence 2069 of abdominal trauma, absence of hepatic dysfunction, and serologic exclusion of hepatitis B (HBV) and C viruses and HIV. Occasionally, organs from donors with hepatitis B and C are used (e.g., for recipients with prior hepatitis B and C, respectively). Organs from donors with antibodies to hepatitis B core antigen (anti-HBc) can also be used when the need is especially urgent, and recipients of these organs are treated prophylactically with antiviral drugs. Cardiovascular and respiratory functions are maintained artificially until the liver can be removed. Transplantation of organs procured from deceased donors who have succumbed to cardiac death can be performed successfully under selected


InternalMed_Harrison

InternalMed_Harrison. are maintained artificially until the liver can be removed. Transplantation of organs procured from deceased donors who have succumbed to cardiac death can be performed successfully under selected circumstances, when ischemic time is minimized and liver histology preserved. Compatibility in ABO blood group and organ size between donor and recipient are important considerations in donor selection; however, ABO-incompatible, split liver, or reduced-donor-organ transplants can be performed in emergencies or marked donor scarcity. Tissue typing for human leukocyte antigen (HLA) matching is not required, and preformed cytotoxic HLA antibodies do not preclude liver transplantation. Following perfusion with cold electrolyte solution, the donor liver is removed and packed in ice. The use of University of Wisconsin (UW) solution, rich in lactobionate and raffinose, has permitted the extension of cold ischemic time up to 20 h; however, 12 h may be a more reasonable limit. Improved techniques


InternalMed_Harrison

InternalMed_Harrison. of Wisconsin (UW) solution, rich in lactobionate and raffinose, has permitted the extension of cold ischemic time up to 20 h; however, 12 h may be a more reasonable limit. Improved techniques for harvesting multiple organs from the same donor have increased the availability of donor livers, but the availability of donor livers is far outstripped by the demand. Currently in the United States, all donor livers are distributed through a nationwide organ-sharing network (United Network for Organ Sharing [UNOS]) designed to allocate available organs based on regional considerations and recipient acuity. Recipients who have the highest disease severity generally have the highest priority, but allocation strategies that balance highest urgency against best outcomes continue to evolve to distribute cadaver organs most effectively. Allocation based on the Child-Turcotte-Pugh (CTP) score, which uses five clinical variables (encephalopathy stage, ascites, bilirubin, albumin, and prothrombin


InternalMed_Harrison

InternalMed_Harrison. cadaver organs most effectively. Allocation based on the Child-Turcotte-Pugh (CTP) score, which uses five clinical variables (encephalopathy stage, ascites, bilirubin, albumin, and prothrombin time) and waiting time, has been replaced by allocation based on urgency alone, calculated by the Model for End-Stage Liver Disease (MELD) score. The MELD score is based on a mathematical model that includes bilirubin, creatinine, and prothrombin time expressed as international normalized ratio (INR) (Table 368-3). Neither waiting time (except as a tie breaker between two potential recipients with the same MELD scores) nor posttransplantation outcome is taken into account, but use of the MELD score


InternalMed_Harrison

InternalMed_Harrison. Status 1 Fulminant hepatic failure (including primary graft nonfunction and hepatic artery thrombosis within 7 days after transplantation as well as acute decompensated Wilson’s disease)α The Model for End-Stage Liver Disease (MELD) score, on a continuous scale,b determines allocation of the remainder of donor organs. This model is based on the following calculation: 3.78 × loge bilirubin (mg/100 mL) ± 11.2 × loge international normalized ratio (INR) ± 9.57 × loge creatinine (mg/100 mL) ± 6.43 (v 0 for alcoholic and cholestatic liver disease, × 1 for all other types of liver disease).c,d,e Online calculators to determine MELD scores are available, such as the following: http://optn.transplant.hrsa.gov/resources/professionalresources .asp?index=9.


InternalMed_Harrison

InternalMed_Harrison. aFor children <18 years of age, status 1 includes acute or chronic liver failure plus hospitalization in an intensive care unit or inborn errors of metabolism. Status 1 is retained for those persons with fulminant hepatic failure and supersedes the MELD score. bThe MELD scale is continuous, with 34 levels ranging between 6 and 40. Donor organs usually do not become available unless the MELD score exceeds 20. cPatients with stage T2 hepatocellular carcinoma receive 22 disease-specific points. dCreatinine is included because renal function is a validated predictor of survival in patients with liver disease. For adults undergoing dialysis twice a week, the creatinine in the equation is set to 4 mg/100 mL. eFor children <18 years of age, the Pediatric End-Stage Liver Disease (PELD) scale is used. This scale is based on albumin, bilirubin, INR, growth failure, and age. Status 1 is retained.


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InternalMed_Harrison. 2070 has been shown to reduce waiting list mortality, to reduce waiting time prior to transplantation, to be the best predictor of pretransplantation mortality, to satisfy the prevailing view that medical need should be the decisive determinant, and to eliminate both the subjectivity inherent in the CTP scoring system (presence and degree of ascites and hepatic encephalopathy) and the differences in waiting times among different regions of the country. Recent data indicate that liver recipients with MELD scores <15 experienced higher posttransplantation mortality rates than similarly classified patients who remained on the wait list. This observation led to the modification of UNOS policy to allocate donor organs to candidates with MELD scores exceeding 15 within the local or regional procurement organization before offering the organ to local patients whose scores are <15. In addition, serum sodium, another important predictor of survival in liver transplantation candidates, is taken


InternalMed_Harrison

InternalMed_Harrison. organization before offering the organ to local patients whose scores are <15. In addition, serum sodium, another important predictor of survival in liver transplantation candidates, is taken into consideration in allocating donor livers. The highest priority (status 1) continues to be reserved for patients with fulminant hepatic failure or primary graft nonfunction. Because candidates for liver transplantation who have HCC may not be sufficiently decompensated to compete for donor organs based on urgency criteria alone, and because protracted waiting for cadaver donor organs often results in tumor growth beyond acceptable limits for transplantation, such patients are assigned disease-specific MELD points (Table 368–3). Other disease-specific MELD exceptions include portopulmonary hypertension, hepatopulmonary syndrome, familial amyloid polyneuropathy, primary hyperoxaluria (necessitating liver-kidney transplantation), cystic fibrosis liver disease, and highly selected cases of hilar


InternalMed_Harrison

InternalMed_Harrison. hepatopulmonary syndrome, familial amyloid polyneuropathy, primary hyperoxaluria (necessitating liver-kidney transplantation), cystic fibrosis liver disease, and highly selected cases of hilar cholangiocarcinoma.


InternalMed_Harrison

InternalMed_Harrison. Occasionally, especially for liver transplantation in children, one cadaver organ can be split between two recipients (one adult and one child). A more viable alternative, transplantation of the right lobe of the liver from a healthy adult donor into an adult recipient, has gained increased popularity. Living donor transplantation of the left lobe (left lateral segment), introduced in the early 1990s to alleviate the extreme shortage of donor organs for small children, accounts currently for approximately one-third of all liver transplantation procedures in children. Driven by the shortage of cadaver organs, living donor transplantation involving the more sizable right lobe is being considered with increasing frequency in adults; however, living donor liver transplantation cannot be expected to solve the donor organ shortage; 246 such procedures were done in 2012, representing only about 4% of all liver transplant operations done in the United States.


InternalMed_Harrison

InternalMed_Harrison. Living donor transplantation can reduce waiting time and coldischemia time; is done under elective, rather than emergency, circumstances; and may be lifesaving in recipients who cannot afford to wait for a cadaver donor. The downside, of course, is the risk to the healthy donor (a mean of 10 weeks of medical disability; biliary complications in ~5%; postoperative complications such as wound infection, small-bowel obstruction, and incisional hernias in 9–19%; and even, in 0.2–0.4%, death) as well as the increased frequency of biliary (15–32%) and vascular (10%) complications in the recipient. Potential donors must participate voluntarily without coercion, and transplantation teams should go to great lengths to exclude subtle coercive or inappropriate psychological factors as well as outline carefully to both donor and recipient the potential benefits and risks of the procedure. Donors for the procedure should be 18–60 years old; have a compatible blood type with the recipient; have no


InternalMed_Harrison

InternalMed_Harrison. carefully to both donor and recipient the potential benefits and risks of the procedure. Donors for the procedure should be 18–60 years old; have a compatible blood type with the recipient; have no chronic medical problems or history of major abdominal surgery; be related genetically or emotionally to the recipient; and pass an exhaustive series of clinical, biochemical, and serologic evaluations to unearth disqualifying medical disorders. The recipient should meet the same UNOS criteria for liver transplantation as recipients of a cadaver donor allograft. Comprehensive outcome data on adult-to-adult living donor liver transplantation are being collected (www.nih-a2all.org).


InternalMed_Harrison

InternalMed_Harrison. Removal of the recipient’s native liver is technically difficult, particularly in the presence of portal hypertension with its associated collateral circulation and extensive varices and especially in the presence of scarring from previous abdominal operations. The combination of portal hypertension and coagulopathy (elevated prothrombin time and thrombocytopenia) may translate into large blood product transfusion requirements. After the portal vein and infrahepatic and suprahepatic inferior vena cavae are dissected, the hepatic artery and common bile duct are dissected. Then the native liver is removed and the donor organ inserted. During the anhepatic phase, coagulopathy, hypoglycemia, hypocalcemia, and hypothermia are encountered and must be managed by the anesthesiology team. Caval, portal vein, hepatic artery, and bile duct anastomoses are performed in succession, the last by end-to-end suturing of the donor and recipient common bile ducts (Fig. 368-1) or by choledochojejunostomy


InternalMed_Harrison

InternalMed_Harrison. vein, hepatic artery, and bile duct anastomoses are performed in succession, the last by end-to-end suturing of the donor and recipient common bile ducts (Fig. 368-1) or by choledochojejunostomy to a Roux-en-Y loop if the recipient common bile duct cannot be used for reconstruction (e.g., in sclerosing cholangitis). A typical transplant operation lasts 8 h, with a range of 6–18 h. Because of excessive bleeding, large volumes of blood, blood products, and volume expanders may be required during surgery; however, blood requirements have fallen sharply with improvements in surgical technique, blood-salvage interventions, and experience.


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InternalMed_Harrison. FIGURE 368-1 The anastomoses in orthotopic liver transplanta-tion. The anastomoses are performed in the following sequence: (1) suprahepatic and infrahepatic vena cava, (2) portal vein, (3) hepatic artery, and (4) common bile duct-to-duct anastomosis. (Adapted from JL Dienstag, AB Cosimi: N Engl J Med 367:1483, 2012.)


InternalMed_Harrison

InternalMed_Harrison. As noted above, emerging alternatives to orthotopic liver transplantation include split-liver grafts, in which one donor organ is divided and inserted into two recipients; and living donor procedures, in which part of the left (for children), the left (for children or small adults), or the right (for adults) lobe of the liver is harvested from a living donor for transplantation into the recipient. In the adult procedure, once the right lobe is removed from the donor, the donor right hepatic vein is anastomosed to the recipient right hepatic vein remnant, followed by donor-to-recipient anastomoses of the portal vein and then the hepatic artery. Finally, the biliary anastomosis is performed, duct-to-duct if practical or via Roux-en-Y anastomosis. Heterotopic liver transplantation, in which the donor liver is inserted without removal of the native liver, has met with very limited success and acceptance, except in a very small number of centers. In attempts to support desperately ill


InternalMed_Harrison

InternalMed_Harrison. the donor liver is inserted without removal of the native liver, has met with very limited success and acceptance, except in a very small number of centers. In attempts to support desperately ill patients until a suitable donor organ can be identified, several transplantation centers are studying extracorporeal perfusion with bioartificial liver cartridges constructed from hepatocytes bound to hollow fiber systems and used as temporary hepatic-assist devices, but their efficacy remains to be established. Areas of research with the potential to overcome the shortage of donor organs include hepatocyte transplantation and xenotransplantation with genetically modified organs of nonhuman origin (e.g., swine).


InternalMed_Harrison

InternalMed_Harrison. The introduction in 1980 of cyclosporine as an immunosuppressive agent contributed substantially to the improvement in survival after liver transplantation. Cyclosporine, a calcineurin inhibitor, blocks early activation of T cells and is specific for T cell functions that result from the interaction of the T cell with its receptor and that involve the cal-cium-dependent signal transduction pathway. As a result, the activity of cyclosporine leads to inhibition of lymphokine gene activation, blocking interleukins 2, 3, and 4, tumor necrosis factor a, and other lymphokines. Cyclosporine also inhibits B cell functions. This process occurs without affecting rapidly dividing cells in the bone marrow, which may account for the reduced frequency of posttransplantation systemic infections. The most common and important side effect of cyclosporine therapy is nephrotoxicity. Cyclosporine causes dose-dependent renal tubular injury and direct renal artery vasospasm. Following renal function is


InternalMed_Harrison

InternalMed_Harrison. most common and important side effect of cyclosporine therapy is nephrotoxicity. Cyclosporine causes dose-dependent renal tubular injury and direct renal artery vasospasm. Following renal function is therefore important in monitoring cyclosporine therapy, perhaps even a more reliable indicator than blood levels of the drug. Nephrotoxicity is reversible and can be managed by dose reduction. Other adverse effects of cyclosporine therapy include hypertension, hyperkalemia, tremor, hirsutism, glucose intolerance, and gingival hyperplasia.


InternalMed_Harrison

InternalMed_Harrison. Tacrolimus, a macrolide lactone antibiotic isolated from a Japanese soil fungus, Streptomyces tsukubaensis, has the same mechanism of action as cyclosporine but is 10–100 times more potent. Initially applied as “rescue” therapy for patients in whom rejection occurred despite the use of cyclosporine, tacrolimus was shown to be associated with a reduced frequency of acute, refractory, and chronic rejection. Although patient and graft survival are the same with these two drugs, the advantage of tacrolimus in minimizing episodes of rejection, reducing the need for additional glucocorticoid doses, and reducing the likelihood of bacterial and cytomegalovirus (CMV) infection has simplified the management of patients undergoing liver transplantation. In addition, the oral absorption of tacrolimus is more predictable than that of cyclosporine, especially during the early postoperative period when T-tube drainage interferes with the enterohepatic circulation of cyclosporine. As a result, in


InternalMed_Harrison

InternalMed_Harrison. is more predictable than that of cyclosporine, especially during the early postoperative period when T-tube drainage interferes with the enterohepatic circulation of cyclosporine. As a result, in most transplantation centers, tacrolimus has now supplanted cyclosporine for primary immunosuppression, and many centers rely on oral rather than IV administration from the outset. For transplantation centers that prefer cyclosporine, a better-absorbed microemulsion preparation is available.


InternalMed_Harrison

InternalMed_Harrison. Although more potent than cyclosporine, tacrolimus is also more toxic and more likely to be discontinued for adverse events. The toxicity of tacrolimus is similar to that of cyclosporine; nephrotoxicity and neurotoxicity are the most commonly encountered adverse effects, and neurotoxicity (tremor, seizures, hallucinations, psychoses, coma) is more likely and more severe in tacrolimus-treated patients. Both drugs can cause diabetes mellitus, but tacrolimus does not cause hirsutism or gingival hyperplasia. Because of overlapping toxicity between cyclosporine and tacrolimus, especially nephrotoxicity, and because tacrolimus reduces cyclosporine clearance, these two drugs should not be used together. Because 99% of tacrolimus is metabolized by the liver, hepatic dysfunction reduces its clearance; in primary graft nonfunction (when, for technical reasons or because of ischemic damage prior to its insertion, the allograft is defective and does not function normally from the outset),


InternalMed_Harrison

InternalMed_Harrison. clearance; in primary graft nonfunction (when, for technical reasons or because of ischemic damage prior to its insertion, the allograft is defective and does not function normally from the outset), tacrolimus doses have to be reduced substantially, especially in children. Both cyclosporine and tacrolimus are metabolized by the cytochrome P450 IIIA system, and, therefore, drugs that induce cytochrome P450 (e.g., phenytoin, phenobarbital, carbamazepine, rifampin) reduce available levels of cyclosporine and tacrolimus; and drugs that inhibit cytochrome P450 (e.g., erythromycin, fluconazole, ketoconazole, clotrimazole, itraconazole, verapamil, diltiazem, danazol, metoclopramide, the HIV protease inhibitor ritonavir, and the HCV protease inhibitors telaprevir and boceprevir) increase cyclosporine and tacrolimus blood levels. Indeed, itraconazole is used occasionally to help boost tacrolimus levels. Like azathioprine, cyclosporine and tacrolimus appear to be associated with 2071 a risk of


InternalMed_Harrison

InternalMed_Harrison. and tacrolimus blood levels. Indeed, itraconazole is used occasionally to help boost tacrolimus levels. Like azathioprine, cyclosporine and tacrolimus appear to be associated with 2071 a risk of lymphoproliferative malignancies (see below), which may occur earlier after cyclosporine or tacrolimus than after azathioprine therapy. Because of these side effects, combinations of cyclosporine or tacrolimus with prednisone and an antimetabolite (azathioprine or mycophenolic acid, see below)—all at reduced doses—are preferable regimens for immunosuppressive therapy.


InternalMed_Harrison

InternalMed_Harrison. Mycophenolic acid, a nonnucleoside purine metabolism inhibitor derived as a fermentation product from several Penicillium species, is another immunosuppressive drug being used for patients undergo ing liver transplantation. Mycophenolate has been shown to be better than azathioprine, when used with other standard immunosuppressive drugs, in preventing rejection after renal transplantation and has been adopted widely as well for use in liver transplantation. The most common adverse effects of mycophenolate are bone marrow suppression and gastrointestinal complaints.


InternalMed_Harrison

InternalMed_Harrison. In patients with pretransplantation renal dysfunction or renal deterioration that occurs intraoperatively or immediately postoperatively, tacrolimus or cyclosporine therapy may not be practical; under these circumstances, induction or maintenance of immunosuppression with antithymocyte globulin (ATG, thymoglobulin) or monoclonal antibodies to T cells, OKT3, may be appropriate. Therapy with these agents has been especially effective in reversing acute rejection in the posttransplantation period and is the standard treatment for acute rejection that fails to respond to methylprednisolone boluses. Available data support the use of thymoglobulin induction to delay calcineurin inhibitor use and its attendant nephrotoxicity. IV infusions of thymoglobulin may be complicated by fever and chills, which can be ameliorated by premedication with antipyretics and a low dose of glucocorticoids. Infusions of OKT3 may be complicated by fever, chills, and diarrhea, or by pulmonary edema, which can be


InternalMed_Harrison

InternalMed_Harrison. which can be ameliorated by premedication with antipyretics and a low dose of glucocorticoids. Infusions of OKT3 may be complicated by fever, chills, and diarrhea, or by pulmonary edema, which can be fatal. Because OKT3 is such a potent immunosuppressive agent, its use is also more likely to be complicated by opportunistic infection or lymphoproliferative disorders; therefore, because of the availability of alternative immunosuppressive drugs, OKT3 is now used sparingly.


InternalMed_Harrison

InternalMed_Harrison. Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), blocks later events in T cell activation, is approved for use in kidney transplantation, but is not approved for use in liver transplant recipients because of the reported association with an increased frequency of hepatic artery thrombosis in the first month posttransplantation. In patients with calcineurin inhibitor–related nephrotoxicity, conversion to sirolimus has been demonstrated to be effective in preventing rejection with accompanying improvements in renal function. Because of its profound antiproliferative effects, sirolimus has also been suggested to be a useful immunosuppressive agent in patients with a prior or current history of malignancy, such as HCC. Side effects include hyperlipidemia, peripheral edema, oral ulcers, and interstitial pneumonitis. Everolimus is a hydroxyethyl derivative of sirolimus that, when used in conjunction with low-dose tacrolimus, also provides successful protection against


InternalMed_Harrison

InternalMed_Harrison. oral ulcers, and interstitial pneumonitis. Everolimus is a hydroxyethyl derivative of sirolimus that, when used in conjunction with low-dose tacrolimus, also provides successful protection against acute rejection, with decreased renal impairment compared to that associated with standard tacrolimus dosing. Everolimus and sirolimus share a similar adverse events profile; therefore, neither of these agents is approved for routine use in liver allograft recipients.


InternalMed_Harrison

InternalMed_Harrison. The most important principle of immunosuppression is that the ideal approach strikes a balance between immunosuppression and immunologic competence. In general, given sufficient immunosuppression, acute liver allograft rejection is nearly always reversible. On one hand, incompletely treated acute rejection predisposes to the development of chronic rejection, which can threaten graft survival. On the other hand, if the cumulative dose of immunosuppressive therapy is too large, the patient may succumb to opportunistic infection. In hepatitis C, pulse glucocorticoids or OKT3 use accelerate recurrent allograft hepatitis. Further complicating matters, acute rejection can be difficult to distinguish histologically from recurrent hepatitis


InternalMed_Harrison

InternalMed_Harrison. C. Therefore, immunosuppressive drugs must be used judiciously, with strict attention to the infectious consequences of such therapy and careful confirmation of the diagnosis of acute rejection. In this vein, efforts have been made to minimize the use of glucocorticoids, a 2072 mainstay of immunosuppressive regimens, and steroid-free immunosuppression can be achieved in some instances. Patients who undergo liver transplantation for autoimmune diseases such as primary biliary cirrhosis, autoimmune hepatitis, and primary sclerosing cholangitis are less likely to achieve freedom from glucocorticoids.


InternalMed_Harrison

InternalMed_Harrison. Complications of liver transplantation can be divided into nonhepatic and hepatic categories (Tables 368-4 and 368-5). In addition, both immediate postoperative and late complications are encountered. As a rule, patients who undergo liver transplantation have been chronically ill for protracted periods and may be malnourished and wasted. The impact of such chronic illness and the multisystem failure that accompanies liver failure continue to require attention in the postoperative period. Because of the massive fluid losses and fluid shifts that occur during the operation, patients may remain fluid-overloaded during the immediate postoperative period, straining cardiovascular reserve; this effect can be amplified in the face of transient renal dysfunction and pulmonary capillary vascular permeability. Continuous monitoring of cardiovascular and pulmonary function, measures to maintain the integrity of the intravascular compartment and to treat extravascular volume overload, and


InternalMed_Harrison

InternalMed_Harrison. permeability. Continuous monitoring of cardiovascular and pulmonary function, measures to maintain the integrity of the intravascular compartment and to treat extravascular volume overload, and scrupulous attention to potential sources and sites of infection are of paramount importance. Cardiovascular instability may also result from the electrolyte imbalance that may accompany reperfusion of the donor liver as well as from restoration of systemic vascular resistance following implantation. Pulmonary function may be compromised further by paralysis of the right hemidiaphragm associated with phrenic nerve injury. The hyperdynamic state with increased cardiac output that is characteristic of patients with liver failure reverses rapidly after successful liver transplantation.


InternalMed_Harrison

InternalMed_Harrison. Other immediate management issues include renal dysfunction. Prerenal azotemia, acute kidney injury associated with hypoperfusion (acute tubular necrosis), and renal toxicity caused by antibiotics, ↓ Renal blood flow secondary to ↑ intraabdominal pressure Hematologic Anemia secondary to gastrointestinal and/or intraabdominal bleeding Hemolytic anemia, aplastic anemia Thrombocytopenia Infection Bacterial: early, common postoperative infections Fungal/parasitic: late, opportunistic infections Viral: late, opportunistic infections, recurrent hepatitis Diseases of donor Infectious Malignant


InternalMed_Harrison

InternalMed_Harrison. Fungal/parasitic: late, opportunistic infections Viral: late, opportunistic infections, recurrent hepatitis Diseases of donor Infectious Malignant Hepatic Dysfunction Unique to Liver Transplantation tacrolimus, or cyclosporine are encountered frequently in the postoperative period, sometimes necessitating dialysis. Hemolytic-uremic syndrome can be associated with cyclosporine, tacrolimus, or OKT3. Occasionally, postoperative intraperitoneal bleeding may be sufficient to increase intraabdominal pressure, which, in turn, may reduce renal blood flow; this effect is rapidly reversible when abdominal distention is relieved by exploratory laparotomy to identify and ligate the bleeding site and to remove intraperitoneal clot.


InternalMed_Harrison

InternalMed_Harrison. Anemia may also result from acute upper gastrointestinal bleeding or from transient hemolytic anemia, which may be autoimmune, especially when blood group O livers are transplanted into blood group A or B recipients. This autoimmune hemolytic anemia is mediated by donor intrahepatic lymphocytes that recognize red blood cell A or B antigens on recipient erythrocytes. Transient in nature, this process resolves once the donor liver is repopulated by recipient bone marrow–derived lymphocytes; the hemolysis can be treated by transfusing blood group O red blood cells and/or by administering higher doses of glucocorticoids. Transient thrombocytopenia is also commonly encountered. Aplastic anemia, a late occurrence, is rare but has been reported in almost 30% of patients who underwent liver transplantation for acute, severe hepatitis of unknown cause.


InternalMed_Harrison

InternalMed_Harrison. Bacterial, fungal, or viral infections are common and may be life-threatening postoperatively. Early after transplant surgery, common postoperative infections predominate—pneumonia, wound infections, infected intraabdominal collections, urinary tract infections, and IV line infections—rather than opportunistic infections; these infections may involve the biliary tree and liver as well. Beyond the first postoperative month, the toll of immunosuppression becomes evident, and opportunistic infections—CMV, herpes viruses, fungal infections (Aspergillus, Candida, cryptococcal disease), mycobacterial infections, parasitic infections (Pneumocystis, Toxoplasma), bacterial infections (Nocardia, Legionella, Listeria)—predominate. Rarely, early infections represent those transmitted with the donor liver, either infections present in the donor or infections acquired during procurement processing. De novo viral hepatitis infections acquired from the donor organ or, almost unheard of now, from


InternalMed_Harrison

InternalMed_Harrison. liver, either infections present in the donor or infections acquired during procurement processing. De novo viral hepatitis infections acquired from the donor organ or, almost unheard of now, from transfused blood products occur after typical incubation periods for these agents (well beyond the first month). Obviously, infections in an immunosuppressed host demand early recognition and prompt management; prophylactic antibiotic therapy is administered routinely in the immediate postoperative period. Use of sulfamethoxazole with trimethoprim reduces the incidence of postoperative Pneumocystis carinii pneumonia. Antiviral prophylaxis for CMV with ganciclovir should be administered in patients at high risk (e.g., when a CMV-seropositive donor organ is implanted into a CMVseronegative recipient).


InternalMed_Harrison

InternalMed_Harrison. Neuropsychiatric complications include seizures (commonly associated with cyclosporine and tacrolimus toxicity), metabolic encephalopathy, depression, and difficult psychosocial adjustment. Rarely, diseases are transmitted by the allograft from the donor to the recipient. In addition to viral and bacterial infections, malignancies of donor origin have occurred. Posttransplantation lymphoproliferative disorders, especially B cell lymphoma, are a recognized complication associated with immunosuppressive drugs such as azathioprine, tacrolimus, and cyclosporine (see above). Epstein-Barr virus has been shown to play a contributory role in some of these tumors, which may regress when immunosuppressive therapy is reduced. De novo neoplasms appear at increased frequency after liver transplantation, particularly squamous cell carcinomas of the skin. Routine screening should be performed.


InternalMed_Harrison

InternalMed_Harrison. Long-term complications after liver transplantation attributable primarily to immunosuppressive medications include diabetes mellitus and osteoporosis (associated with glucocorticoids and calcineurin inhibitors) as well as hypertension, hyperlipidemia, and chronic renal insufficiency (associated with cyclosporine and tacrolimus). Monitoring and treating these disorders are routine components of posttransplantation care; in some cases, they respond to changes in immunosuppressive regimen, while in others, specific treatment of the disorder is introduced. Data from a large U.S. database showed that the prevalence of renal failure was 18% at year 5 and 25% at year 10 after liver transplantation. Similarly, the high frequency of diabetes, hypertension, hyperlipidemia, obesity, and the metabolic syndrome renders patients susceptible to cardiovascular disease after liver transplantation; although hepatic complications account for most of the mortality after liver transplantation, renal


InternalMed_Harrison

InternalMed_Harrison. syndrome renders patients susceptible to cardiovascular disease after liver transplantation; although hepatic complications account for most of the mortality after liver transplantation, renal failure and cardiovascular disease are the other leading causes of late mortality after liver transplantation.


InternalMed_Harrison

InternalMed_Harrison. Hepatic dysfunction after liver transplantation is similar to the hepatic complications encountered after major abdominal and cardiothoracic surgery; however, in addition, hepatic complications include primary graft failure, vascular compromise, failure or stricture of the biliary anastomoses, and rejection. As in nontransplantation surgery, postoperative jaundice may result from prehepatic, intrahepatic, and posthepatic sources. Prehepatic sources represent the massive hemoglobin pigment load from transfusions, hemolysis, hematomas, ecchymoses, and other collections of blood. Early intrahepatic liver injury includes effects of hepatotoxic drugs and anesthesia; hypoperfusion injury associated with hypotension, sepsis, and shock; and benign postoperative cholestasis. Late intrahepatic sources of liver injury include exacerbation of primary disease. Posthepatic sources of hepatic dysfunction include biliary obstruction and reduced renal clearance of conjugated bilirubin. Hepatic


InternalMed_Harrison

InternalMed_Harrison. sources of liver injury include exacerbation of primary disease. Posthepatic sources of hepatic dysfunction include biliary obstruction and reduced renal clearance of conjugated bilirubin. Hepatic complications unique to liver transplantation include primary graft failure associated with ischemic injury to the organ during harvesting; vascular compromise associated with thrombosis or stenosis of the portal vein or hepatic artery anastomoses; vascular anastomotic leak; stenosis, obstruction, or leakage of the anastomosed common bile duct; recurrence of primary hepatic disorder (see below); and rejection.


InternalMed_Harrison

InternalMed_Harrison. Despite the use of immunosuppressive drugs, rejection of the transplanted liver still occurs in a proportion of patients, beginning 1–2 weeks after surgery. Clinical signs suggesting rejection are fever, right upper quadrant pain, and reduced bile pigment and volume. Leukocytosis may occur, but the most reliable indicators are increases in serum bilirubin and aminotransferase levels. Because these tests lack specificity, distinguishing among rejection, biliary obstruction, primary graft nonfunction, vascular compromise, viral hepatitis, CMV infection, drug hepatotoxicity, and recurrent primary disease may be difficult. Radiographic visualization of the biliary tree and/or percutaneous liver biopsy often help to establish the correct diagnosis. 2073 Morphologic features of acute rejection include a mixed portal cellular infiltrate, bile duct injury, and/or endothelial inflammation (“endothelialitis”); some of these findings are reminiscent of graft-versus-host disease, primary biliary


InternalMed_Harrison

InternalMed_Harrison. include a mixed portal cellular infiltrate, bile duct injury, and/or endothelial inflammation (“endothelialitis”); some of these findings are reminiscent of graft-versus-host disease, primary biliary cirrhosis, or recurrent allograft hepatitis C. As soon as transplant rejection is suspected, treatment consists of IV methylprednisolone in repeated boluses; if this fails to abort rejection, many centers use thymoglobulin or OKT3. Caution should be exercised when managing acute rejection with pulse glucocorticoids or OKT3 in patients with HCV infection, because of the high risk of triggering recurrent allograft hepatitis C.


InternalMed_Harrison

InternalMed_Harrison. Chronic rejection is a relatively rare outcome that can follow repeated bouts of acute rejection or that occurs unrelated to preceding rejection episodes. Morphologically, chronic rejection is characterized by progressive cholestasis, focal parenchymal necrosis, mononuclear infiltration, vascular lesions (intimal fibrosis, subintimal foam cells, fibrinoid necrosis), and fibrosis. This process may be reflected as ductopenia—the vanishing bile duct syndrome, which is more common in patients undergoing liver transplantation for autoimmune liver disease. Reversibility of chronic rejection is limited; in patients with therapy-resistant chronic rejection, retransplantation has yielded encouraging results.


InternalMed_Harrison

InternalMed_Harrison. The survival rate for patients undergoing liver transplantation has improved steadily since 1983. One-year survival rates have increased from ~70% in the early 1980s to 85–90% from 2003 to the present time. Currently, the 5-year survival rate exceeds 60%. An important observation is the relationship between clinical status before transplantation and outcome. For patients who undergo liver transplantation when their level of compensation is high (e.g., still working or only partially disabled), a 1-year survival rate of >85% is common. For those whose level of decompensation mandates continuous in-hospital care prior to transplantation, the 1-year survival rate is ~70%, whereas for those who are so decompensated that they require life support in an intensive care unit, the 1-year survival rate is ~50%. Since the adoption by UNOS in 2002 of the MELD system for organ allocation, posttransplantation survival has been found to be affected adversely for candidates with MELD scores >25,


InternalMed_Harrison

InternalMed_Harrison. rate is ~50%. Since the adoption by UNOS in 2002 of the MELD system for organ allocation, posttransplantation survival has been found to be affected adversely for candidates with MELD scores >25, considered high disease severity. Thus, irrespective of allocation scheme, high disease severity before transplantation corresponds to diminished posttransplantation survival. Another important distinction in survival has been drawn between highand low-risk patient categories. For patients who do not fit any “high-risk” designations, 1-year and 5-year survival rates of 85 and 80%, respectively, have been recorded. In contrast, among patients in high-risk categories—cancer, fulminant hepatitis, age >65, concurrent renal failure, respirator dependence, portal vein thrombosis, and history of a portacaval shunt or multiple right upper quadrant operations—survival statistics fall into the range of 60% at 1 year and 35% at 5 years. Survival after retransplantation for primary graft non-function is


InternalMed_Harrison

InternalMed_Harrison. shunt or multiple right upper quadrant operations—survival statistics fall into the range of 60% at 1 year and 35% at 5 years. Survival after retransplantation for primary graft non-function is ~50%. Causes of failure of liver transplantation vary with time. Failures within the first 3 months result primarily from technical complications, postoperative infections, and hemorrhage. Transplant failures after the first 3 months are more likely to result from infection, rejection, or recurrent disease (such as malignancy or viral hepatitis).


InternalMed_Harrison

InternalMed_Harrison. Features of autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis overlap with those of rejection or post-transplantation bile duct injury. Whether autoimmune hepatitis and sclerosing cholangitis recur after liver transplantation is controversial; data supporting recurrent autoimmune hepatitis (in up to one-third of patients in some series) are more convincing than those supporting recurrent sclerosing cholangitis. Similarly, reports of recurrent primary biliary cirrhosis after liver transplantation have appeared; however, the histologic features of primary biliary cirrhosis and chronic rejection are virtually indistinguishable and occur as frequently in patients with 2074 primary biliary cirrhosis as in patients undergoing transplantation for other reasons. The presence of a florid inflammatory bile duct lesion is highly suggestive of the recurrence of primary biliary cirrhosis, but even this lesion can be observed in acute rejection. Hereditary


InternalMed_Harrison

InternalMed_Harrison. The presence of a florid inflammatory bile duct lesion is highly suggestive of the recurrence of primary biliary cirrhosis, but even this lesion can be observed in acute rejection. Hereditary disorders such as Wilson’s disease and α1-antitrypsin deficiency have not recurred after liver transplantation; however, recurrence of disordered iron metabolism has been observed in some patients with hemochromatosis. Hepatic vein thrombosis (Budd-Chiari syndrome) may recur; this can be minimized by treating underlying myeloproliferative disorders and by anticoagulation. Because cholangiocarcinoma recurs almost invariably, few centers now offer transplantation to such patients; however, a few highly selected patients with operatively confirmed stage I or II cholangiocarcinoma who undergo liver transplantation combined with neoadjuvant chemoradiation may experience excellent outcomes. In patients with intrahepatic HCC who meet criteria for transplantation, 1and 5-year survivals are similar to


InternalMed_Harrison

InternalMed_Harrison. combined with neoadjuvant chemoradiation may experience excellent outcomes. In patients with intrahepatic HCC who meet criteria for transplantation, 1and 5-year survivals are similar to those observed in patients undergoing liver transplantation for nonmalignant disease. Finally, metabolic disorders such as nonalcoholic steatohepatitis recur frequently, especially if the underlying metabolic predisposition is not altered. The metabolic syndrome occurs commonly after liver transplantation as a result of recurrent nonalcoholic fatty liver, immunosuppressive medications, and/or, in patients with hepatitis C related to the impact of HCV infection on insulin resistance, diabetes and fatty liver. Hepatitis A can recur after transplantation for fulminant hepatitis A, but such acute reinfection has no serious clinical sequelae. In fulminant hepatitis B, recurrence is not the rule; however, in the absence of any prophylactic measures, hepatitis B usually recurs after transplantation for


InternalMed_Harrison

InternalMed_Harrison. has no serious clinical sequelae. In fulminant hepatitis B, recurrence is not the rule; however, in the absence of any prophylactic measures, hepatitis B usually recurs after transplantation for end-stage chronic hepatitis B. Before the introduction of prophylactic antiviral therapy, immunosuppressive therapy sufficient to prevent allograft rejection led inevitably to marked increases in hepatitis B viremia, regardless of pretransplantation levels. Overall graft and patient survival were poor, and some patients experienced a rapid recapitulation of severe injury—severe chronic hepatitis or even fulminant hepatitis—after transplantation. Also recognized in the era before availability of antiviral regimens was fibrosing cholestatic hepatitis, rapidly progressive liver injury associated with marked hyperbilirubinemia, substantial prolongation of the prothrombin time (both out of proportion to relatively modest elevations of aminotransferase activity), and rapidly progressive liver


InternalMed_Harrison

InternalMed_Harrison. with marked hyperbilirubinemia, substantial prolongation of the prothrombin time (both out of proportion to relatively modest elevations of aminotransferase activity), and rapidly progressive liver failure. This lesion has been suggested to represent a “choking off” of the hepatocyte by an overwhelming density of HBV proteins. Complications such as sepsis and pancreatitis were also observed more frequently in patients undergoing liver transplantation for hepatitis B prior to the introduction of antiviral therapy. The introduction of long-term prophylaxis with HBIg revolutionized liver transplantation for chronic hepatitis B. Preoperative hepatitis B vaccination, preoperative or postoperative interferon (IFN) therapy, or short-term (≤2 months) HBIg prophylaxis has not been shown to be effective, but a retrospective analysis of data from several hundred European patients followed for 3 years after transplantation has shown that long-term (≥6 months) prophylaxis with HBIg is associated


InternalMed_Harrison

InternalMed_Harrison. but a retrospective analysis of data from several hundred European patients followed for 3 years after transplantation has shown that long-term (≥6 months) prophylaxis with HBIg is associated with a lowering of the risk of HBV reinfection from ~75 to 35% and a reduction in mortality from ~50 to 20%. As a result of long-term HBIg use following liver transplantation for chronic hepatitis B, similar improvements in outcome have been observed in the United States, with 1-year survival rates between 75% and 90%. Currently, with HBIg prophylaxis, the outcome of liver transplantation for chronic hepatitis B is indistinguishable from that for chronic liver disease unassociated with chronic hepatitis B; essentially, medical concerns regarding liver transplantation for chronic hepatitis B have been eliminated. Passive immunoprophylaxis with HBIg is begun during the anhepatic stage of surgery, repeated daily for the first 6 postoperative days, and then continued with infusions that are given


InternalMed_Harrison

InternalMed_Harrison. eliminated. Passive immunoprophylaxis with HBIg is begun during the anhepatic stage of surgery, repeated daily for the first 6 postoperative days, and then continued with infusions that are given either at regular intervals of 4–6 weeks or, alternatively, when anti-hepatitis B surface (HBs) levels fall below a threshold of 100 mIU/mL. The current approach in most centers is to continue HBIg indefinitely, which can add approximately $20,000 per year to the cost of care; some centers are evaluating regimens that shift to less frequent administration or to IM administration in the late posttransplantation period or, in low-risk patients, maintenance with antiviral therapy (see below) alone. Still, “breakthrough” HBV infection occasionally occurs.


InternalMed_Harrison

InternalMed_Harrison. Further improving the outcome of liver transplantation for chronic hepatitis B is the current availability of such antiviral drugs as lamivudine, adefovir, entecavir, and tenofovir disoproxil fumarate (Chap. 362). When these drugs are administered to patients with decompensated liver disease, a proportion improve sufficiently to postpone imminent liver transplantation. In addition, antiviral therapy can be used to prevent recurrence of HBV infection when administered prior to transplantation; to treat hepatitis B that recurs after transplantation, including in patients who break through HBIg prophylaxis; and to reverse the course of otherwise fatal fibrosing cholestatic hepatitis. Clinical trials have shown that lamivudine antiviral therapy reduces the level of HBV replication substantially, sometimes even resulting in clearance of hepatitis B surface antigen (HBsAg); reduces alanine aminotransferase (ALT) levels; and improves histologic features of necrosis and inflammation.


InternalMed_Harrison

InternalMed_Harrison. sometimes even resulting in clearance of hepatitis B surface antigen (HBsAg); reduces alanine aminotransferase (ALT) levels; and improves histologic features of necrosis and inflammation. Long-term use of lamivudine is safe and effective, but after several months, a proportion of patients become resistant to lamivudine, resulting from YMDD (tyrosine-methionine-aspartate-aspartate) mutations in the HBV polymerase motif (Chap. 362). In approximately one-half of such resistant patients, hepatic deterioration may ensue. Fortunately, adefovir and tenofovir disoproxil fumarate are available as well and can be used to treat lamivudine-associated YMDD variants, effectively “rescuing” patients experiencing hepatic decompensation after lamivudine breakthrough. Currently, most liver transplantation centers combine HBIg plus lamivudine, adefovir, entecavir, or tenofovir disoproxil fumarate. In low-risk patients with no detectable hepatitis B viremia at the time of transplantation, a number of


InternalMed_Harrison

InternalMed_Harrison. centers combine HBIg plus lamivudine, adefovir, entecavir, or tenofovir disoproxil fumarate. In low-risk patients with no detectable hepatitis B viremia at the time of transplantation, a number of clinical trials have suggested that antiviral prophylaxis can suffice, without HBIg or with a finite duration of HBIg, to prevent recurrent HBV infection of the allograft. Antiviral prophylactic approaches applied to patients undergoing liver transplantation for chronic hepatitis B are being used as well for patients without hepatitis B who receive organs from donors with antibody to hepatitis B core antigen (anti-HBc). Patients who undergo liver transplantation for chronic hepatitis B plus D are less likely to experience recurrent liver injury than patients undergoing liver transplantation for hepatitis B alone; still, such co-infected patients would also be offered standard posttransplantation prophylactic therapy for hepatitis B.


InternalMed_Harrison

InternalMed_Harrison. Accounting for up to 40% of all liver transplantation procedures, the most common indication for liver transplantation is end-stage liver disease resulting from chronic hepatitis C. Recurrence of HCV infection after liver transplantation can be documented in almost every patient. The clinical consequences of recurrent hepatitis C are limited during the first 5 years after transplantation. Nonetheless, despite the relative clinical benignity of recurrent hepatitis C in the early years after liver transplantation, and despite the negligible impact on patient survival during these early years, histologic studies have documented the presence of moderate to severe chronic hepatitis in more than one-half of all patients and cirrhosis in ~20% at 5 years. Allograft cirrhosis is even more common, occurring in up to two-thirds of patients at 5 years, if moderate hepatitis is detected in a 1-year liver biopsy. Not surprisingly, then, for patients undergoing liver transplantation for hepatitis C,


InternalMed_Harrison

InternalMed_Harrison. in up to two-thirds of patients at 5 years, if moderate hepatitis is detected in a 1-year liver biopsy. Not surprisingly, then, for patients undergoing liver transplantation for hepatitis C, allograft and patient survival are diminished substantially between 5 and 10 years after transplantation.


InternalMed_Harrison

InternalMed_Harrison. In a proportion of patients, even during the early posttransplantation period, recurrent hepatitis C may be sufficiently severe biochemically and histologically to merit antiviral therapy. Treatment with pegylated IFN can suppress HCV-associated liver injury but rarely leads to sustained benefit. Sustained virologic responses are the exception, and reduced tolerability is often dose-limiting. Preemptive combination antiviral therapy with pegylated IFN and the nucleoside analogue ribavirin immediately after transplantation does not appear to provide any advantage over therapy introduced after clinical hepatitis has occurred. Similarly, although IFN-based antiviral therapy is not recommended for patients with decompensated liver disease, some centers have experimented with pretransplantation antiviral therapy in an attempt to eradicate HCV replication prior to transplantation; preliminary results are promising, but IFN treatment of patients with end-stage liver disease can lead to


InternalMed_Harrison

InternalMed_Harrison. antiviral therapy in an attempt to eradicate HCV replication prior to transplantation; preliminary results are promising, but IFN treatment of patients with end-stage liver disease can lead to worsening of hepatic decompensation, and HCV infection has recurred after transplantation in some of these recipients. Trials of hepatitis C immune globulin preparations to prevent recurrent hepatitis C after liver transplantation have not been successful. Similarly, a trial of a high-dose monoclonal antibody to the HCV E2 envelope glycoprotein delayed but did not prevent reappearance of viremia.


InternalMed_Harrison

InternalMed_Harrison. Although the current standard-of-care treatment of allograft hepatitis C is pegylated IFN and ribavirin, in a number of studies, the safety and efficacy of the addition of the approved HCV protease inhibitors telaprevir or boceprevir to pegylated IFN and ribavirin in genotype 1–infected patients with recurrent hepatitis C have been examined. Because of the profound inhibitory effects of the HCV protease inhibitors on the metabolism of the calcineurin inhibitors (increasing cyclosporine levels almost 5-fold and tacrolimus levels 70-fold), calcineurin inhibitor doses must be reduced to safe levels in these patients. In one multicenter study, treatment with a telapreviror boceprevir-based triple-drug regimen (with pegylated IFN and ribavirin) achieved rates of HCV clearance similar to those achieved in patients with chronic hepatitis C who had not undergone transplantation. Unfortunately, tolerability of these protease inhibitor–based regimens remains problematic in this population,