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| CECIL |
| TEXT BOOK of MEDICINE |
Section XIII Diseases of the Liver, Gallbladder, and Bile Ducts
| 154 INHERITED AND METABOLIC HEPATIC DISORDERS Kris V. Kowdley • |
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■ INHERITED LIVER DISORDERS
■ Inherited Liver Disorders in Which the Metabolic Disorder Is Localized to the Liver (Table 154-1)
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■ Wilson's Disease
Definition
In Wilson's disease, a disorder of copper metabolism leads to progressive accumulation of copper in the liver and various other tissues with eventual tissue toxicity and end-organ damage. Copper accumulates within the liver because of failure to excrete copper in bile, which is the major method of elimination of copper from the body.
Epidemiology and Pathobiology
The Wilson disease gene, ATP7B, is on chromosome 13 and encodes an intracellular P-type adenosine triphosphatase located within the Golgi complex in hepatocytes. The frequency of ATP7B mutations ranges from 1 in 90 to 1 in 150, and estimates of the prevalence of Wilson's disease are between 1 in 30,000 and 1 in 60,000. More than 200 mutations of the ATP7B gene, including deletions, insertions, and missense or nonsense mutations, can cause phenotypic Wilson's disease, and the phenotypic pattern may vary among different genotypes. The usual presumed mode of inheritance is autosomal recessive, but some mutations may be present in heterozygous or homozygous forms, whereas others may be compound heterozygous forms.
Pathophysiology
Loss or deficiency of functional ATP7B results in reduced vesicular secretion of copper into bile and impaired incorporation of copper into ceruloplasmin. Consequently, copper accumulates in hepatocytes and extrahepatic sites, particularly in the central nervous system, kidneys, endocrine organs, heart, and musculoskeletal system. Over time, copper accumulation in the liver leads to chronic liver injury. Acute release of copper from the liver may result in a characteristic syndrome of acute fulminate liver failure (Chapter 158), Coombs-negative hemolytic anemia, and a Fanconi syndrome type of renal tubular defect (Chapter 123).
Clinical Manifestations
The clinical features of Wilson's disease are varied and may include liver disease, neurologic or psychiatric abnormalities, renal disease, osteoporosis, osteoarthritis, chondrocalcinosis, cardiac disease, hemolytic anemia, and endocrine abnormalities such as infertility, amenorrhea, and hypoparathyroidism. The age at diagnosis ranges from 5 years to older than 80 years, with the diagnosis made in about 50% of patients by 15 years of age.
Most patients with Wilson's disease demonstrate evidence of liver disease that may range from nonspecific changes such as microvesicular and macrovesicular steatosis to chronic active hepatitis, fibrosis, fulminant hepatitis, and cirrhosis with portal hypertension. Chronic hepatitis, the most common manifestation of hepatic Wilson's disease, may be difficult to differentiate from chronic hepatitis of other causes (Chapter 152), so Wilson's disease should be included in the differential diagnosis of any patient with chronic liver disease. Fulminant hepatitis is frequently associated with Coombs-negative hemolytic anemia, as well as with low serum alkaline phosphatase and uric acid levels. Liver cancer is uncommon in patients with Wilson's disease.
Neuropsychiatric symptoms of Wilson's disease generally occur in the second decade of life and follow signs of liver disease. Motor disorders are typically observed and may include tremors, dysarthria, micrographia, drooling, and pseudobulbar palsy; dysphagia may result in weight loss. Psychiatric symptoms may range from anxiety to personality disorders to frank psychosis.
Diagnosis
The diagnosis of Wilson's disease requires a high level of clinical suspicion, usually because of the presence of hemolytic anemia or neurologic or neuropsychiatric disease in addition to the liver disease. The initial diagnostic test is the serum ceruloplasmin level, which is generally less than 20 mg/dL. Hypoproteinemia may result in reduced serum ceruloplasmin levels in the absence of Wilson's disease. Conversely, ceruloplasmin is an acute phase reactant that may be falsely elevated into the normal range in patients with Wilson's disease. Although the total serum copper level is low in parallel with the low ceruloplasmin level, the free serum copper level is elevated (>25 μg/dL). Similarly, urinary copper excretion usually exceeds 100 μg/24 hr in symptomatic patients, but it can be normal in asymptomatic individuals.
A decreased serum ceruloplasmin level should raise suspicion for Wilson's disease but does not confirm the diagnosis. Liver biopsy to measure the hepatic copper concentration and measurement of total urinary copper excretion over a 24-hour period are considered confirmatory tests for the diagnosis of Wilson's disease. Hepatic copper concentrations greater than 250 μg/g dry weight (normal, <35 μg/g) are often found in untreated patients with Wilson's disease, but the hepatic copper concentration may also be elevated into the range associated with Wilson's disease in patients with chronic cholestatic disorders because copper is normally excreted through bile.
Treatment
Medical treatment is based on copper chelating agents, which bind copper and allow it to be excreted in urine. Trientine at a dose of 1.0 to 1.2 g/day has largely replaced d-penicillamine at a dose of 1.0 to 1.5 g/day as the initial copper chelator of choice because it is less toxic. Chelators are indicated in patients with evidence of significantly increased copper stores (i.e., ≥250 μg/g); lifelong therapy is frequently needed to achieve negative copper balance and to remove excess copper from parenchymal tissues. Zinc acetate at a dose of 50 mg three times daily is an alternative treatment option for patients in whom Wilson's disease is diagnosed early in the course of the disease, before the development of significant end-organ damage, or as maintenance therapy after negative copper balance has been achieved and storage sites have been depleted, as evidenced by a reduction in urinary copper excretion (i.e., <500 mg/24 hr) after initial cupruresis. Zinc inhibits the intentional absorption of copper via induction of metallothionein in the intestine. New agents being tested include ammonium tetrathiomolybdate, particularly for neurologic Wilson's disease.
Liver transplantation is indicated for fulminant hepatic failure, liver dysfunction unresponsive to chelation, or noncompliance with chelation therapy. Liver transplantation is curative in Wilson's disease because the primary site of the metabolic defect is in the liver. As serum ceruloplasmin and copper levels return to normal after liver transplantation, neuropsychiatric symptoms may improve, although this possibility is not a primary indication for liver transplantation.
■ α1-Antitrypsin Deficiency
Definition and Epidemiology
α1-Antitrypsin deficiency (Chapter 88) is an autosomal recessive disorder with a prevalence of 1 in 1550 to 2800 among populations of northern European descent. It has been estimated that approximately 116 million individuals carry the trait and that 1.1 million have clinically significant α1-antitrypsin deficiency.
Pathobiology
α1-Antitrypsin, a 52-kD glycoprotein, is secreted into blood by hepatocytes, phagocytes, and epithelial cells in the lungs. The protein is an inhibitor of serine proteases, primarily human neutrophil elastase. Absent or severely reduced α1-antitrypsin levels may result in emphysema as a result of degradation of connective tissue. The associated liver disease is a consequence of progressive accumulation of deformed, aggregated polymers of α1-antitrypsin in the endoplasmic reticulum of hepatocytes, as seen by periodic acid–Schiff staining of histologic specimens.
The more than 75 structural variants of α1-antitrypsin can be classified by their migration velocity on starch gel electrophoresis as F (fast), M (medium), S (slow), or Z (very slow). The most common phenotypes associated with normal α1-antitrypsin levels (85 to 215 mg/dL) are the M1 to M4 variants. The Z variant is the most common deficiency variant; patients homozygous for this mutation (designated PiZZ) have only 15% normal α1-antitrypsin levels with an increased risk for lung or liver disease. The S variant is also a common “deficient” variant with α1-antitrypsin levels less than 80 mg/dL. Null or QO variants have undetectable plasma levels of α1-antitrypsin and an increased risk for emphysema but not liver disease.
Clinical Manifestations
α1-Antitrypsin deficiency is the most common cause of inherited liver disease in neonates and children. In the newborn, liver disease may initially be manifested as jaundice at 4 to 8 weeks of age. Many such patients will have spontaneous resolution of jaundice and cholestasis and become asymptomatic by 1 year of age. Patients with persistent symptoms may demonstrate any feature of chronic liver disease or bleeding, including chronic active hepatitis, cryptogenic cirrhosis, or portal hypertension. The odds ratio for liver disease and hepatocellular carcinoma in adult homozygotes has been estimated to be 8.3 to 18.3 and 5.0, respectively.
Diagnosis
α1-Antitrypsin deficiency should be included in the differential diagnosis of any patient with unexplained chronic liver disease or hepatocellular carcinoma. The key initial diagnostic test is a low serum α1-antitrypsin level (<85 mg/dL), although the value may be increased into the normal range as an acute phase reactant or be decreased because of hypoproteinemia in patients with other causes of liver dysfunction. Confirmation of the diagnosis requires demonstration of an abnormal α1-antitrypsin phenotype (such as PiZZ) and evidence of periodic acid–Schiff–positive, diastase-resistant globules on liver biopsy.
Treatment
No specific medical therapy is available for the liver disease of α1-antitrypsin deficiency. Because it is now believed that phenotypic expression of α1-antitrypsin deficiency requires both increased accumulation and decreased degradation of the abnormal protein, patients should avoid alcohol or other hepatotoxins that may reduce clearance of the abnormal protein. Treatment is otherwise aimed at management of the complications of chronic liver disease. Liver transplantation (Chapter 158) should be offered to patients with decompensated liver disease. α1-Antitrypsin deficiency is the most common inherited liver disease for which liver transplantation is performed in children.
■ Glycogen Storage Diseases
The hepatic glycogen storage diseases (Chapter 219) include a rare group of inherited enzymatic disorders in which the metabolism of glycogen to glucose is impaired. Consequently, excess glycogen accumulates in the liver, heart, muscle, kidney, and other organs, where it leads to organ dysfunction. The three major glycogen storage diseases that lead to liver disease are types I, III, and IV, each of which is inherited in an autosomal recessive pattern and is associated with specific enzymatic deficiencies.
■ Type I (Von Gierke's Disease)
Definition and Pathobiology
This disorder (Chapter 219) results from a deficiency in glucose-6-phosphatase, an enzyme expressed in the hepatic microsomal system and also in the renal tubular epithelium, pancreas, and intestine. Loss-of-function mutations in the gene encoding glucose-6-phosphatase reduce the activity of this enzyme, thereby resulting in accumulation of glycogen in multiple organs.
Clinical Manifestations
The disease may be manifested in infancy and rarely in adulthood with hypoglycemia, lactic acidosis, hyperlipidemia, and hyperuricemia. Clinical features include failure to thrive, growth retardation, and hypoglycemic seizures. Hepatomegaly, elevated serum bilirubin levels, and abnormal serum aminotransferase levels may be observed as a result of increased glycogen deposition. Children may be disposed to the development of hepatocellular adenomas with a high risk for subsequent malignant transformation. Other complications include renal disease, renal stones, and osteoporosis. The diagnosis is confirmed by demonstrating decreased or absent activity of glucose-6-phosphatase.
Treatment
Treatment is aimed at preventing hypoglycemia with multiple daytime carbohydrate feedings and enteral glucose administration. Diagnosis early in life can prevent irreversible complications and preserve growth and development. Liver transplantation, which has been performed in patients with progressive liver disease or neoplasms, corrects the underlying metabolic defect.
■ Type III
Type III glycogen storage disease is caused by a deficiency in amylo-1,6-glucosidase, an enzyme responsible for structural modification of glycogen. In contrast to other forms of glycogen storage disease, the phenotypic manifestations are less severe because of the availability of alternative methods of gluconeogenesis. However, significant end-organ damage may develop in the liver, musculoskeletal system, and heart. Medical management should focus on dietary protein intake as a source of gluconeogenic amino acids. There are anecdotal reports of successful liver transplantation for type III glycogen storage disease.
■ Type IV (Andersen's Disease)
Glycogen storage disease type IV (Chapter 219) is related to deficiency in another structural enzyme, α-1,4-α-1,6-glucosyltransferase, which results in accumulation of glycogen molecules similar to amylopectin. Type IV glycogen storage disease may be complicated by advanced liver disease, neurologic disease, cardiomyopathy, and skeletal muscle abnormalities. Liver transplantation is indicated for decompensated liver disease, but cardiac complications may reduce survival after liver transplantation.
■ Amyloidosis
Definition
Amyloidosis describes abnormal deposition of the fibrillar amyloid protein in various tissues (Chapter 296).
Clinical Manifestations
Amyloidosis may result in nonspecific signs and symptoms, but typical findings include macroglossia, heart failure, arrhythmias, hepato-splenomegaly, carpal tunnel syndrome, peripheral neuropathy, renal failure, and nephrotic-range proteinuria. Liver involvement occurs in about 60% of patients with systemic amyloidosis. Hepatic amyloidosis may be accompanied by abdominal pain and is commonly associated with a palpable, firm, and enlarged liver. Decompensated liver disease characterized by severe cholestasis and massive hepatic amyloid deposition is an uncommon late complication.
Diagnosis
Laboratory tests typically reveal an elevated serum alkaline phosphatase level (86%), hypoalbuminemia, proteinuria, and a monoclonal protein spike in serum or urine (89%). The diagnosis of amyloidosis is confirmed by demonstration of apple-green birefringence on polarization microscopy after Congo red staining of the affected tissue.
For patients with secondary or AA amyloidosis, treatment of the primary disorder is indicated. For primary or AL amyloidosis, no treatment is curative, but melphalan, colchicine, and corticosteroids can improve survival (Chapter 296). Liver transplantation can be successful in patients with acute liver failure secondary to amyloidosis.
■ Familial Amyloidotic Polyneuropathy
Definition and Pathobiology
Familial amyloidotic polyneuropathy is a unique form of hereditary amyloidosis associated with the accumulation of amyloidogenic transthyretin (TTR, the most common type), gelsolin, or apolipoprotein A-I. It is an autosomal dominant disorder with variable penetrance, even in patients with the same mutation in the TTR gene. TTR is primarily synthesized in the liver and is bound to thyroxine or to a retinol binding protein in plasma. More than 100 mutations in the gene encoding TTR, which is located at 18q12.1, can create an abnormally folded TTR, thereby resulting in accumulation of fibrillar amyloid deposits.
Clinical Manifestations
The clinical manifestations, which are related to deposition of abnormal amyloid fibril in various parenchymal tissues, include sensorimotor and autonomic polyneuropathy, ocular disease, cerebral angiopathy, gastrointestinal dysmotility, cardiomyopathy, renal dysfunction, and hematologic sequelae.
Treatment
Familial amyloidotic polyneuropathy may be fatal. However, liver transplantation can correct the underlying metabolic defect and may prevent progressive neuromuscular disease, with reported overall survival rates of 82% at 1 year and 60% at 5 years. Therefore, liver transplantation has been recommended early in the course of disease, before the development of neurologic, cardiac, renal, or gastrointestinal disease.
■ Inherited Disorders in Which the Metabolic Disorder Is Extrahepatic
■ Hereditary Hemochromatosis
Definition
Hemochromatosis (Chapter 231) is a syndrome of end-organ damage caused by excessive deposition of iron in various tissues. At the present time, four types of primary iron overload disorders have been described, including HLA-linked hereditary hemochromatosis, one of the most common genetic disorders in the white population.
Pathobiology
HLA-linked hereditary hemochromatosis, or HFE-associated hemochromatosis (type 1), is the most common form. The normal HFE protein is a transmembrane protein localized to the basolateral aspect of the villus cell in the small intestine. HFE binds transferrin and appears to play a role in internalization of the transferrin–transferrin receptor complex. The C282Y-mutated HFE protein is trapped intracellularly and thus does not bind transferrin. Furthermore, hepatic release of hepcidin, a circulating peptide that has antimicrobial properties and inhibits iron absorption in the duodenum, appears to be inappropriately low in type 1 hereditary hemochromatosis. However, despite these observations, it remains unclear how the mutant HFE protein disrupts normal regulation of iron metabolism.
The other types of hereditary hemochromatosis are distinctly uncommon. Juvenile hemochromatosis, called type 2 hereditary hemochromatosis, may be associated with mutations in the hemojuvelin gene (HJV), which is located on chromosome 1 and encodes a glycosylphosphatidylinositol-linked membrane protein, or with mutations in HAMP, a gene located on chromosome 19 that encodes hepcidin. Type 3 hereditary hemochromatosis is associated with mutations in transferrin receptor 2 (TFR2), which is highly expressed in hepatocytes and thought to play a role in signaling the liver regarding body iron stores. Type 4 hereditary hemochromatosis is an autosomal dominant condition associated with mutations in ferroportin, a protein thought to be responsible for transporting iron out of cells.
Clinical Manifestations
Type 1 hereditary hemochromatosis is generally associated with the development of symptoms in middle age. Although men and women may inherit the mutation equally, phenotypic expression is milder in women and occurs later in their life. The clinical manifestation of type 1 hereditary hemochromatosis reflects the sequelae of iron deposition in multiple organs, including the liver, heart, pancreas, skin, joints, and anterior pituitary. The resulting classic complications may include cirrhosis and hepatocellular carcinoma, diabetes mellitus, cardiomyopathy, hyperpigmentation or “bronzing” of the skin, arthropathy of the metacarpophalangeal joints, and hypogonadotropic hypogonadism. However, most patients may be asymptomatic or have nonspecific symptoms such as weakness, lethargy, arthralgias, and abdominal pain. It should be emphasized that hepatic iron overload is also seen in alcoholic liver disease, which sometimes causes confusion between these two diagnoses. The development of cirrhosis is associated with an increased risk for hepatocellular carcinoma and reduced life expectancy.
Type II hereditary hemochromatosis is associated with severe phenotypic expression in the second and third decades of life. Men and women are affected equally, and cardiac manifestations predominate. Clinical features of iron overload associated with TFR2 mutations (type II hereditary hemochromatosis) are similar to those of HFE-associated hereditary hemochromatosis. The pattern of hepatic iron deposition and clinical features in type IV hereditary hemochromatosis are different from other forms of hereditary hemochromatosis. This disorder is characterized by hepatic iron deposition predominantly in reticuloendothelial cells, frequently normal serum transferrin iron saturation, and increased serum ferritin levels.
Diagnosis
Appropriate evaluation of suspected hereditary hemochromatosis should include a complete medical history, family history, and physical examination. The initial screening test is measurement of the serum transferrin iron saturation percentage; if the saturation is 45% or greater, a repeat fasting measurement should be obtained along with a serum ferritin level. If the repeat serum transferrin iron saturation is 45% or higher, HFE gene testing is appropriate, especially if the serum ferritin level is elevated (>200 ng/mL in women and >300 ng/mL in men). The majority of white patients (>85%) with typical phenotypic hereditary hemochromatosis are homozygous for the C282Y mutation. Compound heterozygosity for the C282Y and H63D mutations is found in approximately 5% of patients who have clinical evidence of hereditary hemochromatosis, although the severity of iron loading is less in these patients. In individuals heterozygous for the C282Y mutation, iron overload typically does not develop except in the presence of another disorder such as chronic hepatitis C infection or alcoholic liver disease. Therefore, only the C282Y homozygous and C282Y/H63D compound heterozygous genotypes are currently considered diagnostic of type 1 hereditary hemochromatosis. Patients with suspected hereditary hemochromatosis based on elevated serum transferrin iron saturation who have either of these two mutation patterns can be confirmed to have hereditary hemochromatosis.
The diagnosis of hereditary hemochromatosis by phenotypic criteria is problematic in the setting of advanced liver disease. Serum iron studies may lack specificity for iron overload in this population because serum transferrin is frequently low as a result of decreased hepatic function and because it is a negative acute phase reactant. Furthermore, many patients with alcohol- or hepatitis C–related end-stage liver disease have hepatic iron overload despite the absence of HFE mutations.
Liver biopsy, previously considered to be the “gold standard” for the diagnosis of hereditary hemochromatosis, shows increased stainable iron in hepatocytes and bile duct cells with a paucity of iron in Kupffer cells and a hepatic iron concentration usually greater than 4000 μg/g dry weight. Liver biopsy remains important to identify possible cirrhosis in patients who are homozygous for C282Y or are C282Y/H63D compound heterozygotes if liver enzymes are elevated or if the serum ferritin level is 1000 ng/mL or greater. Liver biopsy should also be considered both to clarify the diagnosis and to exclude cirrhosis in patients who have elevated serum transferrin iron saturation and ferritin levels but are neither homozygous C282Y nor C282Y/H63D compound heterozygotes. Noninvasive measurement of hepatic iron content with magnetic resonance imaging and susceptometry for estimation of iron content and fibrosis may substitute for liver biopsy in the future.
Treatment
Iron reduction therapy by phlebotomy, which is the mainstay of treatment, is safe, easy, and inexpensive and should not be delayed until the development of symptoms. Weekly phlebotomy of 500 mL of whole blood is generally well tolerated. Phlebotomy is continued until iron depletion is confirmed by mild anemia and a ferritin concentration lower than 50 ng/mL, a process that may take up to 2 years. Maintenance phlebotomy is then continued throughout the patient's life, typically via removal of 1 to 2 units of blood three to four times a year to maintain a serum ferritin level of less than 50 ng/mL. Patients should likewise be counseled to avoid vitamin C supplements, which can increase the absorption of iron. Phlebotomy should also be offered to patients with evidence of cirrhosis because it probably improves quality of life and may decrease complications of portal hypertension. Fatigue, elevated liver enzymes, and hepatomegaly may improve after phlebotomy is undertaken. Cardiac function may improve if treatment is begun before the development of dilated cardiomyopathy. However, joint symptoms may not respond to therapy.
Although HFE-associated hereditary hemochromatosis is an uncommon indication for liver transplantation (Chapter 158), liver transplantation is the only effective treatment for patients with decompensated cirrhosis or hepatocellular carcinoma. However, survival after liver transplantation is adversely affected by the risk for cardiac and infectious complications.
■ Erythropoietic Protoporphyria
Definition and Pathobiology
The porphyrias (Chapter 229) are characterized by genetic or acquired abnormalities in enzymes involved in heme biosynthesis. A deficiency in ferrochelatase, which is responsible for the final step in heme synthesis, results in erythropoietic or erythrohepatic protoporphyria. Erythrohepatic protoporphyria has an autosomal dominant pattern of inheritance with variable penetrance. In a subset of patients, protoporphyrin accumulates in hepatocytes and bile duct cells after biliary canalicular excretion is overwhelmed by the excess protoporphyrin produced in the bone marrow.
Clinical Manifestations
The most common symptom is photosensitivity secondary to accumulation of protoporphyrin in skin and associated vasculature, a process that can lead to pruritus and an acute cutaneous erythematous reaction (see Fig. 465-11). Occasionally, burning and itching can occur in the absence of skin damage or may be associated with petechiae and purpuric lesions. Continued sun exposure leads to the formation of bullous skin lesions, cholestasis, and nodular cirrhosis. Pigmented gallstones can form as a consequence of hemolysis.
Diagnosis
Liver disease should be suspected in patients with elevated serum liver enzymes and markedly high erythrocyte protoporphyrin levels (<1500 μg/dL). Liver biopsy may reveal increased deposition of protoporphyrin.
Treatment
Therapies used to treat this disorder include high-dose oral β-carotene supplementation, erythrocyte transfusion, intravenous heme administration, oral charcoal, oral cholestyramine, or oral chenodeoxycholic acid. Progressive liver disease, cirrhosis, and hepatic failure may require liver transplantation, which has been reported to have good outcomes, although great care must be taken to avoid cholestasis, such as from the formation of biliary strictures, because the ferrochelatase deficiency is unchanged and the excess production of protoporphyrin in bone marrow and elevated levels of protoporphyrin in erythrocytes and feces persist after liver replacement.
■ Inherited Diseases with a Systemic Metabolic Disorder and Significant Liver Involvement
■ Cystic Fibrosis
Definition and Epidemiology
Cystic fibrosis (Chapter 89) is a relatively common genetic disease in white individuals, with an incidence of 1 in 3000 newborns. The disease, which is inherited in an autosomal recessive pattern, is the result of a mutation in the gene on chromosome 7 that encodes the cystic fibrosis transmembrane regulator (CFTR) and regulates an apical cyclic adenosine monophosphate–dependent chloride channel that is ubiquitous in cells lining the epithelia of various tissues, including the bronchial tree, pancreatic ducts, bile ducts, sweat ducts, intestinal tract, and vas deferens. A large number of mutations result in variable penetrance and expressivity. The prevalence of cystic fibrosis–associated liver disease ranges from a low of 2% to a high of 68% in children and adolescents. However, it is likely that the prevalence of liver disease is increasing, given the improvements in management and longer life expectancy. Liver disease is now the second leading cause of death in patients with cystic fibrosis.
Pathobiology
The pathophysiology of liver disease is related to the lack of CFTR in bile duct epithelial cells, which results in obstruction of bile ducts by inspissated bile with a high protein content. Consequently, intrahepatic cholestasis and extrahepatic bile duct obstruction lead to jaundice and cirrhosis. The histologic features are consistent with a biliary tract disease and may be evidenced by periductular inflammation in addition to focal or diffuse biliary cirrhosis. Liver disease is associated with a history of meconium ileus and pancreatic insufficiency.
Clinical Manifestation and Diagnosis
Cystic fibrosis–associated liver disease may become apparent within the first decade of life, but the prevalence of liver disease increases over time into the teenage years and early adulthood. Ultimately, liver disease develops in up to 40% of patients, and advanced liver disease may develop in 2 to 8%. Once cirrhosis is established, portal hypertension and its complications may ensue, including hepatosplenomegaly, ascites, variceal bleeding, and liver failure. The presence of portal hypertension is a marker for worse prognosis, with a mean survival of 4.5 years after diagnosis.
Treatment
Treatment should focus on nutrition, especially fat-soluble vitamins, essential fatty acids, and mineral deficiencies, as in patients with pancreatic insufficiency of other causes (Chapter 147). High-dose ursodeoxycholic acid (20 to 30 mg/kg/day) appears to improve biochemical parameters but has not been shown to improve clinical outcomes.
Liver transplantation has been used successfully to treat advanced liver disease. Candidates for liver-only transplantation should have stable lung function with a forced vital capacity of 75% of the predicted value or greater and a forced expiratory volume in 1 second of 70% or greater. Outcome after liver transplantation in patients with cystic fibrosis is comparable to other indications, with long-term survival rates of up to 75%. Combined lung-liver or heart-lung-liver transplantation should be considered in patients with severe pulmonary disease, hypercapnia, recurrent lung infections, colonization with multidrug-resistant organisms, diminished pulmonary reserve, hepatopulmonary syndrome, or severe pulmonary hypertension. A transjugular intrahepatic portosystemic shunt or a surgical portosystemic shunt can be used to manage severe variceal hemorrhage in patients with otherwise compensated liver disease or those who are not candidates for liver transplantation.
■ NONINHERITED METABOLIC HEPATIC DISORDERS
■ Liver Diseases of Pregnancy
Liver diseases unique to pregnancy include hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, HELLP syndrome (h emolysis, e levated l iver enzymes, and l ow p latelet count), and acute fatty liver of pregnancy (Table 154-2).
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■ Hyperemesis Gravidarum
The symptoms of this condition, the pathogenesis of which is unknown, include severe nausea and vomiting in the first trimester and rarely after 20 weeks of gestation. The incidence is 0.35 to 0.8%. Up to 50% of patients have abnormal liver enzymes, although the degree of elevation is mild to moderate. Treatment is supportive with hydration and antiemetics.
■ Intrahepatic Cholestasis of Pregnancy
Intrahepatic cholestasis is generally observed in the second trimester of pregnancy. The etiopathology is likely to be due to increased sensitivity to the cholestatic effects of estrogen in a genetically predisposed individual. Mutations in the gene encoding a biliary canalicular phospholipid transporter may account for some cases.
Clinical Manifestations and Diagnosis
The clinical features, which include severe pruritus and jaundice in the mother, may result in prematurity and an increased risk for fetal demise. Elevated serum bile acid levels are the hallmark of the diagnosis; increased serum bilirubin and aminotransferase levels are frequent. Jaundice develops in a large proportion of patients a few weeks after the onset of itching. Liver biopsy may reveal primarily a cholestatic reaction with bile plugs in zone 3 and a paucity of periportal inflammation or necrosis. However, liver biopsy is not usually needed for diagnosis.
Treatment
Symptoms may be treated with antihistamines or cholestyramine, but severe disease may require early delivery. The syndrome may recur with future pregnancies.
■ HELLP Syndrome
HELLP syndrome is most commonly observed in the third trimester of pregnancy. It is usually diagnosed at 32 to 34 weeks' gestation. Associated conditions include preeclampsia, which is diagnosed by the triad of hypertension, proteinuria, and edema.
Clinical Manifestations and Prognosis
Patients may have no symptoms or may report nonspecific abdominal pain. Aminotransferase levels may exceed 1000 U/L. Coagulopathy may be present if the hemolysis is severe and associated with disseminated intravascular coagulation. The peripheral blood smear reveals schistocytes and burr cells, although the period of active hemolysis may be transient. Serum haptoglobin should be measured if the peripheral smear is not consistent with hemolysis. Thrombocytopenia with a platelet count lower than 100,000 is typical, but low platelet counts are not pathognomonic for HELLP syndrome because thrombocytopenia is present in up to 8% of pregnant women.
Histopathologic analysis of liver tissue may demonstrate periportal hemorrhage and fibrin deposition. The differential diagnosis includes hemolytic-uremic syndrome (Chapter 179), thrombocytopenic purpura (Chapter 179), acute viral hepatitis (Chapter 151), and acute fatty liver of pregnancy.
The most serious complication of HELLP syndrome is the development of hepatic infarction, which may be accompanied by subcapsular hematoma or intraperitoneal hemorrhage. Clues to this complication include an acute onset of severe abdominal pain, fever, and a marked elevation in aminotransferase levels (>5000 U/L). Immediate surgical intervention may be required in such cases, and the risk for mortality is increased.
Treatment
Treatment of HELLP syndrome is primarily early delivery, which generally resolves the abnormalities. If the fetus has not yet reached 37 weeks' gestation, corticosteroids can be given to promote fetal lung development and may help stabilize the syndrome itself.1
■ Acute Fatty Liver of Pregnancy
Acute fatty liver of pregnancy is a rare complication, usually seen in the last trimester, with an incidence of 1 in 13,000 to 16,000. Primigravidas account for up to 70% of cases, and the average maternal age is the middle of the second decade. The etiology of acute fatty liver of pregnancy is unknown.
Clinical Manifestations and Diagnosis
Patients may be asymptomatic or may have right upper quadrant or epigastric pain that may mimic acute cholecystitis or reflux esophagitis. The disease may progress rapidly within days to acute liver failure with hepatic encephalopathy, ascites, edema, and renal insufficiency. Preeclampsia is present in more than 50% of patients.
Marked jaundice and hyperbilirubinemia are common, and the serum bilirubin level may rise to greater than 40 mg/dL. Extrahepatic complications include gastrointestinal bleeding and renal dysfunction, which may require dialysis. Pancreatitis may develop in up to 30% of patients, and severe hypoglycemia may be seen in 25 to 50%.
Liver biopsy, which confirms the diagnosis, reveals vacuolization of hepatocytes and pallor in the central zone regions; microvascular steatosis is characteristic. Fresh-frozen tissue should be used to stain for fat.
Treatment
Acute fatty liver of pregnancy should be considered a medical and obstetric emergency. Patients should be promptly admitted to a liver failure unit; urgent liver transplantation may be needed. Mortality rates may be up to 15% even with early delivery, and fetal demise is common.
■ Liver Disease with Parenteral Nutrition
Liver disease may develop in up 40% of adult patients who receive chronic nutritional supplementation with long-term total parenteral nutrition (TPN; Chapter 236) for intestinal failure. The liver disease associated with TPN is quite variable and may include fatty infiltration (steatosis), biliary calculous disease (microlithiasis and macrolithiasis), and intrahepatic cholestasis with variable degrees of fibrosis. Fortunately, progressive liver disease with cirrhosis and its attendant complications are uncommon. Parenteral carbohydrates, which are converted to triglycerides, presumably contribute to the hepatic steatosis. Increased administration of lipid emulsions and possibly deficiencies of certain choline or other nutrients may also contribute to the steatosis. Other contributing factors include reduced bile flow, decreased intestinal secretion of gastrointestinal hormones, and cholestasis. A short residual functional small bowel may contribute to impaired enterohepatic circulation of bile salts.
Prevention and Treatment
Strategies to reduce the likelihood and severity of hepatic involvement associated with the use of TPN include attention to adequate vitamin supplementation, administration of adequate choline,2 balancing the lipid and carbohydrate content of TPN solutions,3 and the use of enteral nutrition whenever possible. Ursodeoxycholic acid therapy may be helpful to avoid cholestasis and promote bile flow.
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