Advanced Therapy in Gastroenterology and Liver Disease - part 9 potx

Drug-Induced Liver Disease / 693 carbonated soda or antiemetic medication. A feeding tube may be needed in patients who cannot tolerate the medication orally. Oral N-acetylcysteine has no serious side effects, but the IV preparation may rarely cause an ana- p hylactic reaction. Other Therapies Apart from N-acetylcysteine treatment for acetaminophen poisoning, therapy for drug-induced liver injury is scant. A short course of high-dose corticosteroid may be used for severe drug-induced liver disease, especially in patients with systemic features of a hypersensitivity reaction. However, corticosteroids have not been proven to be of value in controlled trials. Nevertheless, we recommend a short course of corticosteroids when systemic features of immune hypersensitivity accompany acute hepatitis (eg, phenytoin skin rash and liver injury). In patients with prolonged drug-induced cholestatic liver disease, ursodeoxycholic acid treatment may be of use, although the efficacy is unproved. Prevention Because there is little specific therapy for drug-induced liver disease, prevention is of great importance. This process starts during drug development. It is important to moni- tor for ALT abnormality, as well as signs and symptoms of liver disease,during clinical studies with new drugs. Even after a drug receives approval from the US Food and Drug Administration, surveillance and report of suspected cases should continue to identify hepatotoxicity that may not have been apparent during the initial clinical studies. For patients who take drugs that are known to have hepa- totoxic potential,monitoring liver enzymes should be considered. Careful follow-up may identify emerging hepatotoxicity and, thus, prevent severe drug-induced liver disease. However, this approach is most rational for delayed-onset, idiosyncratic, drug-induced liver disease.When starting any drug, all patients should be educated about the signs and symptoms of liver disease and urged to report such symptoms to health care pro- fessionals immediately. This practice is particularly important for patients who take multiple medications because immune cross-sensitization has been known to occur among drugs in the same class, such as anticonvulsants, macrolides, or phe- nothiazines. If patients have a history of an immune hypersensitivity reaction to one drug, they may need to avoid other drugs from the same class. Supplemental Reading Ballet F. Hepatotoxicity in drug development: detection, significance and solutions. J Hepatol 1997;26 Suppl 2:26–36. Danan G, Benichou C. Causality assessment of adverse reactions t o drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug- induced liver injuries. J Clin Epidemiol 1993;46:1323–30. Degott C, Feldmann G, Larrey D, et al. Drug-induced prolonged c holestasis in adults: a histological semiquantitative study d emonstrating progressive ductopenia. Hepatology 1992;17:244–51. Farrell G. Liver disease caused by drugs, anesthetics, and toxins. In: Feldman M, Friedman LS, Sleisenger MH, editors. Sleisenger & Fordtran’s gastrointestinal and liver disease: pathophysiology, diagnosis, and management. 7th ed. Philadelphia: Saunders; 2002. Kaplowitz N. Drug-induced liver disorders: implications for drug development and regulation. Drug Saf 2001;24:483–90. Kaplowitz N, Aw TY, Simon FR, Stolz A. Drug-induced hepatotoxicity. Ann Intern Med 1986;104:826–39. Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991;303:1026–9. Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease. Clin Liver Dis 2002;6:755–74. Makin AJ, Wendon J, Williams R. A seven year experience of severe acetaminophen-induced hepatotoxicity (1987–1993). Gastroenterology 1995;109:1907–16. O’Grady J. Paracetamol-induced acute liver failure: prevention and management. J Hepatol 1997;26 Suppl 1:41–6. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137:947–54. Schiødt FV, Rohling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med 1997; 337:1112–7. S e eff LB, Cuccherini BA, Zimmerman HJ, et al. Acetaminophen hepatotoxicity in alcoholics: a therapeutic misadventure. Ann I nt e rn Med 1986;104:399–404. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. N Eng l J M ed 1988;319:1557–62. Stieger B, Fattinger K, Madon J, et al. Drug- and estrogen- ind uce d cholestasis through inhibition of the hepatocellular bile salt export pump (BSEP) of rat liver. Gastroenterology 2000;118:422–30. 694 CHAPTER 120 LIVER DISEASE AND PREGNANCY ANNE M. LARSON,MD Liver Disease During Pregnancy Cholelithiasis and gallstone disease are seen in 3 to 12% of pregnant women, with higher incidence in the second and third trimesters. Most women are asymptomatic, however, up to 50% will have recurrent pain and worsening symptoms as pregnancy advances. Asymptomatic cholelithiasis requires no treatment. Symptomatic disease should initially be managed conservatively, but up to 35% will fail medication management and require surgical intervention. If possible surgery should be delayed until the second trimester. Likewise, medical management during the third trimester is preferable with surgical intervention following delivery. Variable outcomes are seen in pregnant women with cirrhosis and portal hypertension. Significant hepatic decompensation (jaundice, ascites, and encephalopathy) can occur. Preexisting portal hypertension may be worsened by increased total blood volume, possibly increasing the risk of bleeding from esophageal varices. Pregnancy is generally uneventful in patients with chronic hepatitis B or C virus infections. Women with autoimmune hepatitis have had successful pregnancies and should continue to be treated with corticosteroids and/or azathioprine. Women w ith unt reated Wilson’s disease are generally anovulatory, but can undergo successful pregnancy with following cop- per chelation treatment. Penicillamine or trientine therapy Normal pregnancy induces physiologic, hormonal, and biochemical changes which are adaptive and do not represent significant pathology. These changes may cause confusion about the true status of the liver and the presence or absence of disease. Liver test abnormalities are seen in about 10% of all pregnancies and represent disorders commonly seen in the nongravid state (ie, viral hepatitis), disorders related to pregnancy, or disorders unique to pregnancy. Normal Changes during Pregnancy Anatomic Changes The enlarging uterus rotates the liver superiorly and pos- teriorly, however, the liver’s size and gross appearance do not change. Nonspecific histologic changes include hepatocyte variability, cytoplasmic granularity, centrilobular fat vacuoles, and a minimal increase in Kupffer cells. Despite increases in global maternal blood volume of 20 to 70%, and a 30 to 50% increase in maternal cardiac output, liver blood flow remains unchanged. Laboratory Studies The major liver test changes during pregnancy are outlined in Table 120-1. Increases in alkaline phosphatase levels represent an influx of the placental isoenzyme. Decreases in serum γ-glutamyl transpeptidase (GGT) are secondary to impaired hepatic release. Maternal hemodilution and decreased hepatic synthesis lead to a relative decrease in serum albumin. Decreased hepatic synthesis of antithrombin III and increased synthesis of fibrinogen lead to the prothrombotic state seen in pregnancy. There is a marked increased hepatic synthesis of lipoproteins, cholesterol, and triglycerides. Increased concentrations of cholesterol found in the bile. Physical Examination Spider angiomata occur in 60 to 70% of women, with pal- mar erythema in as many as 63% of white women and 39% of black women. These changes are likely due to the hyper- estrogenemia seen during pregnancy and disappear in the majority of women by about 7 weeks postpartum. The liver is normally not palpable. TABLE 120-1. Normal Changes During Pregnancy Serum Test Usual Change Albumin Decreased (mean value 3 g/dL) AST Normal ALT Normal Alkaline phosphatase Two- to fourfold increase GGT Normal or slight decrease Bilirubin Slight decrease 5’-nucleotidase Slight incr ease Pr othrombin time Normal Ferritin Decreased Ceruloplasmin Decreased Cholesterol/Triglycerides Marked increase Bile acids No change ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = γ-glutamyl transpeptidase. Liver Disease and Pregnancy / 695 should be continued in this setting because discontinuation can lead to fulminant liver failure (the potential effects of these medications on the fetus should be discussed with the patient). Alcoholic women with significant liver disease m ay be anovulatory and thus infertile. Pregnancy-Associated Liver Disorders Hyperemesis Gravidarum Nausea and vomiting occur in up to 90% of all pregnancies. Hyperemesis gravidarum (HG) has a prevalence of 0.35 to 1%, and is characterized by severe, persistent nausea and vomiting during the first trimester. Intractable vomiting requires aggressive support, including, at times, parenteral nutrition. Risk associations include increased body weight, multiple gestations, hyperemesis in a prior pregnancy, and nulliparity. Up to half of women hospitalized for HG have liver enzyme abnormalities, generally occurring within the first 1 to 3 weeks following onset of vomiting. Aminotransferase levels may be as high as 2 to 3 times normal, but rarely above 1000 IU/L. The more severe the vomiting, the higher the elevation. Mild elevations in bilirubin (rarely above 4 mg/dL) and jaundice, occasionally with pruritus, occur. Alkaline phosphatase levels are usually elevated beyond those seen with normal pregnancy. The etiology of the hepatic abnormalities is unknown, but it is a relatively benign process. Liver abnormalities r esolve rapidly with resolution of emesis. HG was at one time a lethal disease, however, with early diagnosis and aggressive support, both maternal and fetal mortality is now negligible. Intrahepatic Cholestasis of Pregnancy Intrahepatic cholestasis of pregnancy (IHCP) is heralded by the development of pruritus, liver enzyme abnormalities, and occasionally jaundice. Most cases occur within the third trimester of pregnancy (Table 120-2). The worldwide incidence varies; ICHP occurs in less than 1 to 2% of all pregnancies in the United States, Asia,Australia, and Europe, but in Bolivia, Chile, and Scandinavia, the incidence is as high as 14%, with rates of 24% in the Araucanian Indians of Chile. There is a greater prevalence among woman from the Indian subcontinent and the disease is rare in black patients. IHCP recurs in 60 to 70% of subsequent pregnancies and is 5 times more frequent in women with multiple gestation. The etiology of ICHP is uncertain and is probably multifactorial. Seasonal variations suggest environmental influ- TABLE 120-2. Features of Liver Disease of Pregnancy IHCP AFLP HELLP Maternal age of onset (years) Any 26 (range, 16 to 39) 25 (range 14 to 40) Gestational age of onset (weeks) 29 (range, 7 to 40) 36 (range, 26 to 40) 33 (range, 22 to 40) 70%: 3rd trimester 100%: 3rd trimester 60%: 3rd trimester 30%: before 3rd - 30%: postpartum trimester 13: 5% 1st/2nd trimester Parity Any 42 to 70% 52-81% Fivefold incr ease Primagravida Primagravida with twin pregnancy 60 to 76% male fetus - - 10 to 15% twin pregnancy - Incidence (in all pr egnancies) 1 to 24 % 1 in 7,000 to 15,000 0.17 to 0.85% Recurrence 60 to 70% Rare 2 to 3% Malaise - 100% 100% Nausea/Vomiting 5 to 75% > 70% up to 90% Abdominal Pain 9 to 24 % ~ 60% ≥ 80% Headache – 40% 25% Incr eased alkaline phosphatase ~67% 100% – Increased bilirubin 25% ≥ 95% 47 to 62% Incr eased AST/AL T 20 to 60% ≥95% ≥95% Incr eased PT ≤ 20% ≥ 90% ≤ 15% Hypertension Rare 30 to 40% > 90% Preeclampsia Rare ≥ 50% ≥ 80% Maternal mortality Low 15 to 50% up to 8% Fetal mortality 1 to 2% 40 to 50% 8 to 37% Adapted from Larson AM. Liver disease in pregnancy. Clin Perspectives Gastroenterol 2001; 4:351(17). AFLP = acute fatty liver of pr egnancy; AL T = alanine aminotransferase; AST = aspar tate aminotransferase; HELLP = hemolysis, ele - vated liver enzymes, and low platelets syndr ome; ICPH = intrahepatic cholestasis of pr egnancy; PT = pr othr ombin time. 696 / Advanced Therapy in Gastroenterology and Liver Disease ences. Genetic components are suggested given that female relatives of patients with IHCP often develop IHCP and it is seen in successive generations (30 to 50% report a positive family history). Further support for this is the high r ecurrence rate in subsequent pregnancies. Nearly half of the women who develop IHCP will also develop jaundice when using oral contraceptives, suggesting that the genetic defect is in estrogen processing. Estrogen concentrations peak in the third trimester of pregnancy, perhaps explaining the onset of illness during this time. Serum bile acids are also markedly increased (10 to 100 times normal), suggesting decreased hepatic capac- ity to either process or transport them. Both estrogens and monohydroxy bile acids are conjugated within the liver. It has been postulated that a genetic defect in sulfotransferase activity leads to the accumulation of toxic metabolites via glucuronidation. Mutations have been described in the MDR3 gene, which encodes for a biliary canalicular phos- pholipid translocater. MDR3 has been associated with familial forms of intrahepatic cholestasis and in women with IHCP associated with an elevated GGT. Exogenous progesterone administration or impaired secretion of progesterone metabolites has also been implicated as a trigger for IHCP in predisposed women. Nearly all affected women report intense pruritus, which typically involves the palms and soles, but may be diffuse. Pruritus is often worse at night and becomes progressively severe as the pregnancy progresses. It may precede abnormalities in liver tests. There appears to be no correlation between serum levels of bile acids and the severity of pruritus. Pruritus gravidarum, clinical jaundice within 1 to 4 weeks after onset of pruritus, develops in 10 to 60% of patients. The skin appears normal but patients may have excoriations secondary to scratching. Systemic symptoms are generally mild (see Table 120-2). Elevation in bilirubin correlates with jaundice and is rarely greater than 5 to 6 mg/dL. GGT levels are normal to minimally elevated. Prolonged prothrombin time (PT) generally reflects the vitamin K deficiency resulting from impaired bile salt formation. Serum bile acids are often as high as 100 times normal (bile acid concentrations change little during normal pregnancy) and are the most sensitive marker for IHCP. They may be the only abnormality, however, absolute levels do not cor- relate with maternal symptoms, other liver tests, or with prognosis. Diagnosis is made clinically, based upon history, symptoms, and laboratory studies. Other causes of liver disease, such as viral hepatitis or gallstone disease, must be ruled out. Liver biopsy is rarely needed and histopathology reveals normal portal tracts, and bland cholestasis, with bile plugs predominating in zone 3. Maternal management of IHCP is symptomatic and the most common approach is early delivery (generally 37 to 38 weeks). Oral vitamin K should be started at the time of diagnosis and, when given before delivery, can minimize postpartum hemorrhage. Treating pruritus is more problematic. Antihistamines and benzodiazepines have been used with little success. Studies using phenobarbitol have been c ontradictory and it may cause neonatal respiratory depression. Dexamethasone (12 mg/d for 7 days with 3 day taper) has been shown to improve pruritus. Controlled trials have not been done, however, and there is a report of worsened liver function with dexamethasone use. Studies with S-adenosyl-methionine have shown conflicting results. In two randomized controlled trials, it significantly decreased pruritus (800 mg/d intravenously or 1,600 mg/d orally). In a third double blind randomized controlled trial, no improvement was seen. Pruritus has been successfully treated with cholestyramine at 8 to 16 g per day, although it is usually poorly tolerated. It must be used with caution as it may worsen maternal absorption of Vitamin K and maternal steatorrhea. Therapy with ursodeoxycholic acid (UDCA) at dosages of 15 mg/kg/d leads to a reduction in pruritus, a reduction in maternal serum bile acids and maternal aminotransferases, and a reduction in delivery of bile acids to the fetus. UDCA also appears to decrease negative maternal and fetal sequelae. UDCA can cross the placenta, but there have been no reports of fetal toxicity. Because UDCA appears safe to mother and fetus, it is reasonable to consider its use, keeping in mind that it is not approved for this indication in the United States. Larger randomized controlled trials are needed. Maternal prognosis is excellent with IHCP and there are usually no hepatic sequelae. Symptoms progress until delivery and then promptly disappear. Jaundice resolves rapidly and serum laboratory tests resolve over weeks to months. Acute liver failure does not occur. IHCP is associated with an increased incidence of primary postpartum hemorrhage (20 to 22%), likely due to vitamin K deficiency. The incidence of cholelithiasis is also increased. Fetal prognosis is less benign. Fetal morbidity and mortality are significantly increased. Premature labor (6 to 60%), meconium-stained amniotic fluid (26 to 58%), fetal distress (17 to 22%), and stillbirth (1 to 3%) are all seen. Early reports of fetal mortality were as high as 10 to 15%; however, with more aggressive management, this is improving (1.7 to 3.5%). Unfortunately, there are no antepartum tests, which predict fetal compromise. Acute F atty Liver of Pregnancy Acute fatty liver of pregnancy (AFLP) was first described in 1934 and is a rare, idiopathic, potentially fatal disease presenting in the third trimester of pregnancy. Incidence r anges from 1 of 7,000 to 1 of 16,000 deliveries and it con- stitutions 16 to 43% of severe liver disease seen during pregnancy. In its most severe form, it is manifest by fulminant he patic failure. Seen worldwide, there appears to be no ethnic or geographic variation. Liver biopsy provides the diagnostic gold standard, but it is problematic if coagulopathy is present, and is rarely needed (Figure 120-1). Fatty changes in pancreatic acinar cells and renal tubular epithelia have also been described a nd likely account for the findings of renal failure and pancreatitis in these patients. Upper gastrointestinal hemorrhage (in 30 to 40% of cases) occurs from a variety of causes. Renal dysfunction is generally mild to moderate, but 25% of patients develop severe renal failure and may require dialysis. Coagulopathy (elevated PT), decreased antithrombin III levels, and thrombocytopenia) probably represents both hepatic synthetic dysfunction and peripheral consumption. Frank disseminated intravascular coagulation (DIC) is common (up to 70%). Pancreatitis develops in up to 30% of patients. Severe hypoglycemia may be seen in 25 to 50% of patients and can occur at any stage in the disease. AFLP is a medical and obstetrical emergency. It is often difficult to distinguish from toxic or viral hepatitis. Patients may progress to fulminant liver failure and death or require liver transplantation. No specific therapy is available. Patients should promptly be admitted to an experienced liver failure unit, since it is impossible to predict which patients will progress to liver failure. The patient should be medically stabilized and delivery attempted as soon as rea- sonably possible; ALFP never resolves before delivery. Aggressive maternal supportive care is required and fresh frozen plasma or cryoprecipitate may be necessary prior to delivery. Blood glucose levels should be followed frequently. Likewise, PT must frequently be checked as this helps to assess the severity of disease. With early diagnosis and management, severity of disease and need for liver transplantation can be minimized. Maternal mortality has been reported as high as 70%, but can be improved to 10 to 20% with early delivery and intensive clinical support. Fetal death occurs in 42 to 90% FIGURE 120-1. Acute fatty liver of pregnancy. The zone 3 centrilobular hepatocytes ar e swollen with micr ovesicular fat globules. Sinusoidal compression can be seen but signs of hepatic necrosis and inflammation are often subtle. Hepatic necrosis is a minor feature. Courtesy of Carolyn A Riely, MD. Liver Disease and Pregnancy / 697 The average maternal age at onset is 26 years (range, 16 to 39 years) with gestational age of onset at about 36 weeks (range, 22 to 40 weeks). AFLP can rarely occur earlier in pregnancy or shortly postpartum. Primagravidas with male g estations comprise most cases (see Table 120-2). Recurrence with subsequent pregnancies, once thought to be uncommon, is increasingly being reported. AFLP has little or no association with the hormonal changes of pregnancy. Its etiology is unknown, but may stem from decreases in fetal mitochondrial fatty acid β- oxidation by the enzyme long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD). Cholestatic liver disease with microvesicular steatosis is often seen in patients with LCHAD deficiency and an association between LCHAD and AFLP has been described. In many cases, the defect appears to reside in the α-subunit of a trifunctional protein gene, which includes LCHAD activity. This may lead to poor fetal processing of triglycerides and free fatty acids, which are toxic to the maternal hepatocytes. Testing for the genetic variants of the LCHAD enzyme is available. When the deficiency is present, recurrent disease can be seen in subsequent pregnancies. Not all investigations have con- firmed this specific association and other genetic variants, such as a defect in short-chain acyl-coenzyme A dehydrogenase, have been associated with AFLP. Asymptomatic elevations in liver tests may be the only abnormality, but the majority of severe cases present with malaise, fatigue, anorexia, headache, nausea, and vomiting (see Table 120-2). Right upper quadrant or epigastric pain may mimic acute cholecystitis or reflux esophagitis. Within 1 to 2 weeks of onset of symptoms, and within days following clinical jaundice, the disease may rapidly worsen, leading to acute liver failure, with hepatic encephalopathy, ascites, edema, and renal insufficiency. Hallmarks of preeclampsia (hypertension, proteinuria) are seen in over 50% of cases. Serum aminotransferases are generally less than 1,000 IU/L and do not reflect severity of liver dysfunction. Hyperbilirubinemia averages 10 to 15 mg/dL, but levels up to 30 to 40 mg/dL have been reported. In the setting of eclampsia and preeclampsia, hyperbilirubinemia is pre- dominantly unconjugated and hemolysis is present. Increases in alkaline phosphatase are difficult to interpret because they overlap the normal values seen late in pregnancy. A left-shifted leukocytosis and some degree of thrombocytopenia are nearly universal. Clinical and laboratory findings suggest the diagnosis of AFLP. The differential diagnosis includes acute viral hepatitis, acute toxic or drug-induced hepatitis, preeclampsia-related liver disease (including hemolysis, elevated liver enzymes, and low platelets syndrome [HELLP]), and biliary tract disorders. Imaging studies are useful in assessing the biliary tree. Virologic markers and history can help to rule out viral and toxic hepatitis. 698 / Advanced Therapy in Gastroenterology and Liver Disease of cases with only minimal improvement with early delivery (36%). After delivery, affected women improve slowly; full recovery often takes up to a month. There are no hepatic sequelae. Infants who survive should be tested for L CHAD deficiency and other fatty acid transport and mitochondrial oxidation disorders. Toxemia and Preeclampsia/Eclampsia Pregnancy-induced hypertension (toxemia) is seen late in pregnancy and remains a major medical challenge. Five to 10% of pregnant women with toxemia may develop preeclampsia (hypertension plus proteinuria and nonde- pendent edema). Preeclampsia generally occurs during the second and third trimesters, and is most frequent in young primagravidas. Risk factors associated with preeclampsia include nulliparity, a positive family history, preeclampsia in a prior pregnancy, obesity, chronic hypertension or renal disease, diabetes mellitus, a multiple gestation pregnancy, low socioeconomic status, and cigarette smoking. The cause of preeclampsia is unknown. Laboratory abnormalities are nonspecific. Hepatic involvement is seen in 10 to 30% of women with preeclampsia. Mild elevations of serum transaminases and, rarely, an increase in indirect bilirubin can be seen in the absence of HELLP syndrome. Histologically, periportal fibrin deposition and hemorrhage with hepatocellular necrosis are seen (Figure 120-2). Preeclampsia can also have a similar histological pattern to AFLP (both may develop microvesicular steatosis). The clinical course may be mild or rapidly progressive. Onset of seizures signals development of true eclampsia (usually young primagravidas), accounting for approxi- mately 8% of all maternal deaths. Control of the hypertension is associated with reduced morbidity and mortality in b oth the mothe r and the fetus. Definitive therapy requires delivery. HELLP Syndrome The HELLP syndrome is a severe, life-threatening form of preeclampsia reported as early as 1922. The acronym HELLP was coined by Weinstein in 1982 to describe preeclampsia associated with microthrombi, thrombocytopenia, and coagulopathy. HELLP syndrome has an incidence of 0.11 to 0.85% of all live births and occurs in 20 to 25% of women with preeclampsia. Ethnic variations exist; risk is higher in white and Chinese populations (relative risk of 2.2) when compared to East Indian populations and is higher in black Americans when compared to white Americans. Patients are usually young primagravidas (see Table 120-2). The pathophysiology of preeclampsia and HELLP syndrome are unknown. They may represent a single disease spectrum, with the HELLP syndrome the most severe form of preeclampsia. An imbalance between endothelial vasodi- latative (ie, nitric oxide) and vasoconstrictive (ie, endothe- lin) substances probably occurs and increased vascular tone leads to increased platelet adhesion and aggregation. Thrombin-induced activation of intravascular coagulation s ubsequently occurs and can rapidly progress to disseminated intravascular coagulation (DIC ~20%). The resultant severe coagulopathy leads to fatal hemorrhagic complications and multiorgan failure. These changes may be more common in preeclampsia than in HELLP syndrome. Clinically, onset may be without warning. Nonspecific symptoms of nausea, vomiting, and malaise are seen in up to 90% of women (see Table 120-2). Abdominal pain precedes biochemical abnormalities in as many as 20 to 40% and visual changes (15 to 30%) have been reported. Hypertension may be absent in as many as 20% of cases and 5 to 15% of patients have little to no proteinuria. Thus, about 15 to 20% of women presenting with HELLP syndrome have no signs of preeclampsia.HELLP syndrome also appears to be associated with eclampsia, although reports of incidence are conflicting. Generalized edema (50 to 77% of cases) and development of ascites (8 to 10% of cases) carries an increased risk of con- gestive heart failure and adult respiratory distress syndrome. Pulmonary edema (6%) and acute renal failure may develop and, in association with ascites, often coexist with DIC. Transient nephrogenic diabetes insipidus has been reported. Gestational thrombocytopenia is seen in 4 to 8% of uncomplicated pregnancies, whereas thrombocytopenia in preeclampsia ranges from 15 to 50%. Those who develop gestational thrombocytopenia are sevenfold more likely to develop HELLP. Platelet levels in HELLP syndrome are frequently less than 100,000/ µL, and there is a positive correlation between the extent of platelet decline and the severity of liver abnormalities. Elevations of serum aminotransferases FIGURE 120-2. Eclampsia/ hemolysis, elevated liver enzymes, and low platelets syndrome (HELLP). Periportal fibrin deposition, hemorrhage, and hepatocellular necrosis seen in severe eclampsia. The classic histologic picture of HELLP is one of periportal or focal parenchymal necrosis, hyaline deposits, and vascular micr othr ombi. In some cases, fi brin exudate has been reported similar to that seen in eclampsia. Courtesy of Carolyn A Riely, MD. prolonging the gestation. Optimal dosages for maternal therapy have yet to be determined. In one trial, intravenous dexamethasone (10 mg twice daily) was superior to intramuscular betamethasone (12 mg once daily) in the sta- b ilization of maternal blood pressure, urinary output, and liver studies. This group recommended initiation of treatment in all patients with Class 1 and 2 HELLP (see Table 120-3), with discontinuation upon resolution of symptoms. Corticosteroids given postpartum have also been shown to accelerate maternal recovery and lower maternal morbidity. Laboratory studies may actually worsen after delivery. Haptoglobin and LDH levels generally normalize within 24 to 48 hours postpartum. Liver enzymes return to normal within 3 to 5 days. Platelets begin to recover within 23 to 29 hours postpartum, with normalization within 6 to 11 days. Failure of the platelets to recover within the first 96 hours postpartum is an indication of a severe declining postpartum course. Plasamapheresis may be needed in this setting, however, it’s use remains controversial. Hepatic infarction is usually associated severe right upper quadrant pain, fever, and significantly elevated serum aminotransferases (1,000 IU/L or higher). Hepatic infarction and unruptured hepatic hematoma can be managed expectantly and generally resolve without sequelae. Hepatic rupture may develop in a small percentage of women (~1%) leading to massive hemoperitoneum and shock requiring early intervention by a skilled surgeon and may be an indication for liver transplantation. HELLP syndrome may lead to fulminant hepatic failure, requiring intensive care management at a specialized liver failure unit. Those patients who survive generally have no hepatic sequelae. Overall, maternal mortality may be as high as 8%. Maternal outcome following hepatic infarction is generally favorable. When hepatic hematoma with rupture occurs, it is responsible for maternal mortality of up to 50% and fetal mortality of 60 to 70%. The risk of recurrent HELLP is about 2 to 37%, but has been reported to be as high as 61% if the prior pregnancy ended before 32 weeks. Fetal mortality is high (8 to 37%) and is associated with placental insufficiency, fetal hypoxia, and intrauterine Table 120-3 Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome Classification Systems Mississippi System Tennessee System Class 1—platelets < 50,000/mm 3 Complete Syndrome Class 2—platelets 50,000 to 100,000/mm 3 AST and/or ALT > 40 IU/L Class 3—platelets 100,000 to 150,000/mm 3 Platelets < 100,000/mm 3 hemolysis plus elevated liver enzymes LDH > 600 IU/L LDH > 600 IU/L AST > 70 IU/L Incomplete Syndr ome any one or two of the above ALT = alanine aminotransferase; AST = aspartate aminotransferase; LDH = lactate dehydrogenase. Liver Disease and Pregnancy / 699 precede platelet drop off in HELLP syndrome. Leukocytosis also correlates with the severity of disease. Measurement of serum haptoglobin is the most sensitive measure of hemolysis and it will be significantly r educed in 95 to 97% of cases. Elevations in serum bilirubin do not occur in all patients and are therefore a less reli- able measure of hemolysis (see Table 120-2). Other less specific measures include schistocytes and burr cells on peripheral blood smear (54 to 86%) and elevated serum lactate dehydrogenase levels. The definitive diagnosis of HELLP syndrome requires clinical suspicion as well as timely and appropriate laboratory screening. The differential diagnosis includes other causes of hematologic and/or liver abnormalities, such as AFLP,appen- dicitis, viral hepatitis, gallbladder disease,gastroenteritis, ulcer disease, idiopathic thrombocytopenia purpura, hemolytic- uremic syndrome, or thrombotic thrombocytopenic purpura. Microangiopathic hemolytic anemia, thrombocytopenia, and elevated serum aminotransferase activity are essentially always seen in the HELLP syndrome.Liver biopsy is rarely needed to establish the diagnosis, and women with the HELLP syndrome may not have evidence of hepatic synthetic dysfunction (see Figure 120-2). The clinical course of HELLP syndrome is unpredictable. Maternal complications occur in up to 65% of cases, including DIC (4 to 38%), placental abruption (10 to 16%), acute renal failure (1 to 8%), severe ascites (5 to 8%), pulmonary edema (2 to 10%), cerebral edema (1%), adult respiratory distress syndrome (ARDS, 1%), and hepatic infarction or rupture (1%). Eclampsia with maternal seizures can be seen. Events associated with maternal death include cerebral hemorrhage, cardiopulmonary arrest, DIC,ARDS,hepatic hemorrhage, and hypoxic ischemic encephalopathy. Several authors have attempted to define and classify HELLP syndrome based upon laboratory parameters (Table 120-3). These classifications have been used to predict the rapidity of recovery, risk of recurrence, perinatal outcome, and need for plasmapheresis. Intensive care in a tertiary care setting if appropriate remains critical to the management of HELLP syndrome. Medical stabilization and careful maternal monitoring are crucial. Ultimately, prolongation of the pregnancy would improve fetal outcome. Complete bed rest is indicated and complete reversal of symptoms with conservative treatment has been reported in individual cases. The development of DIC requires immediate delivery following correction of coagulopathy. Aggressive treatment of severe hypertension and antiseizure prophylaxis with magnesium sulfate are indicated.It may not be possible to prolong the pregnancy, and immediate delivery may be necessary. The baby should be delivered in an obstetric intensive care unit (fetal management is beyond the scope of this chapter and will not be discussed). Corticosteroids ha ve shown significant benefit in stabi- lizing maternal status, inducing fetal lung maturation, and 700 / Advanced Therapy in Gastroenterology and Liver Disease growth restriction. Prematurity at delivery also complicates fetal survival. In babies who survive, outcome is similar to children of similar gestational age. Summary Pregnancy-induced liver diseases carry a significant morbidity and mortality for both mother and fetus. Fortunately, with early recognition and aggressive management, survival rates have improved. A multidisciplinary approach and high level intensive care are crucial to enhanced patient outcome. Supplemental Reading Abell TL, Riely CA. Hyperemesis gravidarum. Gastroenterol Clin North Am 1992;21:835–9. Audibert F, Friedman SA, Frangieh AY, Sibai BM. Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Am J Obstet Gynecol 1996;175:460–4. Bacq Y. Acute fatty liver of pregnancy. Semin Perinatol 1998; 22:134–40. Bacq Y, Zarka O, Brechot JF, et al. Liver function tests in normal pregnancy: a prospective study of 103 pregnant women and 103 matched controls. Hepatology 1996;23:1030–4. Goodwin TM. Nausea and vomiting of pregnancy: an obstetric syn- d rome.Am J Obstet Gynecol 2002;185(5 Suppl Understanding): S 184-9. Ibdah JA, Yang Z,Bennett MJ. Liver disease in pregnancy and fetal fatty acid oxidation defects. Mol Genet Metab 2000;71:182–9. Kenyon AP, Piercy CN, Girling J, et al. Obstetric cholestasis, out- c ome with active management: a series of 70 cases. BJOG 2002;109:282–8. Lammert F, Marschall HU, Matern S. Intrahepatic cholestasis of pregnancy. Curr Treat Options Gastroenterol 2003;6:123–32. M agann EF, Martin JN Jr. Twelve steps to optimal management of HELLP syndrome. Clin Obstet Gynecol 1999;42:532–50. Mattar F, Sibai BM. Preeclampsia: clinical characteristics and pathogenesis. Clin Liver Dis 1999;3:15–29. Palmer DG, Eads J. Intrahepatic cholestasis of pregnancy: a critical review. J Perinat Neonatal Nurs 2000;14:39–51. Rahman TM, Wendon J. Severe hepatic dysfunction in pregnancy. QJM 2002;95:343–57. Rath W, Faridi A, Dudenhausen JW. HELLP syndrome. J Perinat Med 2000; 28:249–60. Reyes H. Acute fatty liver of pregnancy: a cryptic disease threatening mother and child. Clinics in Liver Disease 1999;3:69–81. Tsang IS, Katz VL,Wells SD. Maternal and fetal outcomes in hyperemesis gravidarum. Int J Gynaecol Obstet 1996;55:231–5. Yates MR, Baron TH. Biliary tract disease in pregnancy. Clin Liver Dis 1999;3:131–46. 701 CHAPTER 121 PRIMARY BILIARY CIRRHOSIS JORDAN J. FELD,MD,AND E. JENNY HEATHCOTE,MD that the disease progresses steadily from early stage to cirrhosis (about one stage per 2 years), this is not the case for all patients. In fact, there is evidence that sampling error is common in PBC. Early-stage lesions may be seen in one part of a biopsy, whereas fibrosis and/or cirrhosis are noted in other areas of the same specimen. That being said, in patients with preserved liver synthetic function (normal albumin, normal international normalized ratio, no ascites), aside from liver biopsy, there is no other means to prognosticate. Early-stage disease on biopsy, with adequate core size, is still predictive of a better outcome than the finding of significant fibrosis or cirrhosis. In addition, recent data suggest that the presence of a lymphoplasma- cytic interface hepatitis portends rapidly progressive disease, and more rapidly progressive bile duct loss has been reported to precipitate liver failure even in the absence of cirrhosis. Therefore, we tend to biopsy patients at diagnosis largely for prognostic reasons unless they are over the age of 70 years or have significant other comorbid illnesses, making it unlikely that PBC will alter their life expectancy. Naturally, in cases in which the diagnosis is not crystal clear, a biopsy is imperative to confirm features typical of PBC. Some Caveats Along with AMAs, patients will typically have evidence of anicteric cholestasis with mild elevation of the serum aminotransferases on routine liver biochemistry.Aspartate aminotransferase and alanine aminotransferase greater than four- to five-fold normal should prompt considera- tion of an alternative or concomitant diagnosis. Similarly, patients who present with jaundice that subsequently resolves spontaneously are unlikely to have PBC. In such patients, investigations to exclude biliary obstruction, drug or alcohol toxicity, and viral hepatitis must be carried out. A small proportion of patients with PBC will also have evidence of autoimmune hepatitis (AIH)—so-called PBC- AIH o verlap syndrome. Identification of such individuals is important because it may affect clinical management. Although no specific diagnostic criteria have been estab- lishe d for overlap syndrome, other suggestive features include IgG elevation (> 2 × upper limit of normal ), positive smooth muscle and/or antinuclear antibodies, and, most imp ortantly, interface hepatitis on liver biopsy. Primary biliary cirrhosis (PBC) is a chronic inflammatory disease of the interlobular and septal intrahepatic bile ducts. Destruction of these small ducts leads to ductopenia and retention of bile in hepatocytes. Cholestasis causes hepatocyte damage, which promotes progressive fibrosis and e ventual cirrhosis. Ultimately, liver failure and death ensue unless liver transplantation is available. Diagnosis Antimitochondrial Antibodies The identification of antimitochondrial antibodies (AMAs) as the serologic hallmark of PBC greatly improved the diagnostic sensitivity and specificity of this disease. These nonorgan-, nonspecies-specific antibodies are directed at the 2-oxoacid dehydrogenase enzymes located on the inner mitochondrial membrane. Using sensitive enzyme-linked immunosorbent assay or immunoblotting, AMAs can be detected in 95% of patients with histologic and clinical features of PBC, and they are rarely associated with any other clinical condition. They may occasionally be found in oth- erwise clear-cut autoimmune hepatitis but, fortunately, are not seen with any other chronic cholestatic liver diseases. Along with AMAs, other laboratory features of PBC include elevation of serum alkaline phosphatase and γ-glutamyl transpeptidase, a pattern typical of anicteric cholestasis, an elevated immunoglobulin (Ig)M, and high total cholesterol. Liver Biopsy Because of the high degree of specificity of AMAs, some authors have questioned the need for liver biopsy in all patients w ith PBC. I n midd le-aged women with fatigue, pruritus, cholestatic enzyme pattern, high IgM, and posi- t i v e AMAs, a liver biopsy is certainly not necessary to make a diagnosis of PBC. However, it does potentially provide so me utility in terms of prognostication. The staging system initially introduced by Scheuer in 1967 and further developed by Ludwig and colleagues in 1978 is still in common use. The histologic pattern is graded from I to IV, with stage I disease showing only portal inflammation with duct injury (+/ − granulomata) and stage IV disease represent- ing established cirrhosis. Although it has been suggested 702 / Advanced Therapy in Gastroenterology and Liver Disease Although corticosteroid therapy has been advocated for this group of patients, they appear to respond as well to ursodeoxycholic acid (UDCA) therapy as patients with PBC alone. I n a small number of patients, the clinical, biochemical, and histologic features of PBC will be present in the absence of AMA (even on repeated testing using highly sensitive methods). These patients tend to have circulating antinuclear antibody or smooth muscle antibodies, often in high titer. Before making a diagnosis of AMA-negative PBC, biliary tract imaging with magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography is imperative to exclude primary sclerosing cholangitis and/or biliary obstruction. Natural History As PBC is diagnosed at earlier and earlier stages of the disease, the natural history is becoming more clearly defined. It seems that there is likely a preclinical stage in which patients test AMA positive in serum but have normal liver biochemistry. Some of these patients will already have the histologic features of PBC on liver biopsy, and at 10-year follow-up, the majority develop cholestasis, many with symptomatic disease. Once biochemical cholestasis occurs, patients may be symptomatic or asymptomatic, and this appears to affect prognosis. The initial report on asymptomatic PBC suggested that over 10 years, 50% become symptomatic. Data from the controlled treatment trials of PBC suggest that about one-third of asymptomatic patients will develop symptoms within 5 years. The longest studies of natural history suggest that asymptomatic PBC tends to progress considerably more slowly than symptomatic PBC, with a mean survival of 8 years for symptomatic disease and 16 y ear s for asymptomatic disease. Because many patients do not present until later life and PBC is a slowly progressive disease, it is important to consider that PBC may not affect a given individual’s life expectancy. In fact, in a study from northern England, 54% of asymptomatic patients with PBC died of causes other than their liver disease. R ISK SCORES A number of risk scores have been developed to predict prognosis in PBC. None have found the severity of symptoms, titer or presence of AMA, or height of serum alkaline phosphatase or aminotransferases to be of prognostic value. In contrast, serum bilirubin has proven useful in all of the various risk scores. The most widely used risk score comes from the Mayo Clinic and, conveniently, does not require a liver biopsy to be performed for calculation. It takes into account age, serum albumin, prothrombin time, and the presence of fluid retention with or without diuretic use. The Mayo risk score has been shown to be valid in patients on UDCA therapy and those undergoing liver transplantation. Therapy M anagement of PBC can be divided into the following major components: (1) symptomatic/preventive therapy and (2) disease-modifying therapy (Table 121-1). Although much attention is focused on disease-modifying therapy, often preventive strategies and alleviation of symptoms are more important to patients. Symptomatic Therapy The most prevalent symptoms affecting patients with PBC are fatigue and pruritus. Both can be extremely debilitat- ing and significantly impact on patients’ quality of life. F ATIGUE Unfortunately, to date, no good therapy exists to manage fatigue in patients with PBC. There are many anecdotal reports that UDCA improves fatigue, and pilot studies of methotrexate (MTX) suggested that it may be effective for this purpose as well. Although targeted therapy may not markedly affect fatigue in PBC, it is important to ensure that there are no other contributing factors. Hypothyroidism is commonly associated with PBC and should be excluded. Fatigue is extremely common in the general population and is often multifactorial. It is important to take a good sleep history and to identify and correct any bad habits that may be worsening fatigue. Some common problems include TABLE 121-1. Strategies for Prevention and Management of Primary Biliary Cirrhosis Symptoms and Complications Problem Management Strategy Fatigue Ensure no contributing factors, exclude hypothyroidism Pruritis Cholestyramine 1 pkt before and after breakfast Rifampicin 150 mg bid Naltr exone 50 mg od (use cautiously) Ultraviolet light exposure Sialoadenitis/Sjögr en’ s Artificial teardrops syndrome Water, sugarless gum, pills with ++ water Regular dental follow-up Pilocarpine Osteoporosis All—calcium 1,500 mg/d + vitamin D 800 IU/d If osteoporosis—bisphosphonates Hor mone r eplacement therapy (use cautiously) Calcitonin Hepatocellular carcinoma Ultrasound screening every 6 mo for cirrhotics Esophageal varices Scr een once platelets < 200,000/ µ L β-Blocker/band ligation therapy as needed Hypercholesterolemia Not assisted with heart disease Cholestyramine (first line) “Statins” safe (if needed) bid = twice daily; od = once daily. [...]... jaundiced Serum tumor markers, including carcinoembryonic antigen, cancer antigen (CA) 1 9- 9 , and CA 1255, may be elevated The diagnosis of intrahep- 718 / Advanced Therapy in Gastroenterology and Liver Disease atic cholangiocellular carcinomas is then established with a needle biopsy specimen of a dominant liver mass showing AC in the absence of an alternative primary lesion The clinical presentation of the... vitamins when deficient are listed in Table 12 2-3 Cutaneous Sequelae of Cholestasis Hyperpigmentation The skin of patients with cholestasis may darken Hyperpigmentation is a classic finding in patients with PBC The pigment is melanin The etiology of the hyper- 714 / Advanced Therapy in Gastroenterology and Liver Disease Sokol RJ Fat-soluble vitamins and their importance in patients with cholestatic liver. .. Follow-up after liver transplantation for protoporphyric liver disease Liver Transpl Surg 199 6;2:2 69 75 Bonkovsky HL, Healey JF, Lourie AN, et al Intravenous hemealbumin in acute intermittent porphyria: evidence for repletion of hepatic hemoproteins and regulatory heme pools Am J Gastro 199 1;86:1050–6 Moore MR, Hift RJ Drugs in the acute porphyrias—toxicogenetic diseases Cell Mol Biol 199 7;43: 89 94 Mustajoki... Cholangiocarcinoma: current concepts and insights Hepatology 2003;37 :96 1 9 Graziadei IW, Wiesner RH, Marotta PJ, et al Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis Hepatology 199 9;30:1121–7 Patel T Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States Hepatology 2000; 33:1353–7 Peters RL, Craig JR, editors Liver. .. can lead to liver injury, neurologic and psychiatric signs and symptoms, liver failure, and death In patients with fulminant liver failure due to Wilson’s disease or in those with advanced liver disease unresponsive to medical treatment, liver transplantation can be lifesaving and curative The age of symptomatic clinical presentation of Wilson’s disease varies widely, but patients present mainly with... et al, 199 6) It is now known that the HFE protein binds with β2-microglobulin (β2M), which together interact with transferrin receptor-1, thereby affecting cellular iron transport Mutations in the HFE gene alter the cellular trafficking of HFE protein and the interaction with β2M, resulting in inappropriate iron absorption The exact cellular mechanism(s) by which this occurs are currently being investigated... and other liver diseases Ann Intern Med 199 9;130 :95 3–62 Bacon BR, Sadiq SA Hereditary hemochromatosis: presentation and diagnosis in the 199 0s Am J Gastroenterol 199 7 ;92 :784 9 Beutler E, Felitti VJ, Koziol JA, et al Penetrance of 845G-A (C282Y) HFE hereditary haemochromatosis mutation in the USA Lancet 2002;3 59: 211–8 Feder JN, Gnirke A, Thomas W, et al A novel MHC class I-like gene is mutated in patients... vitamin from liver stores Enhanced urinary clearance of retinol due to deficiency in transhyretin, a thyroxine binding globulin to which retinol binding globulin is bound in the circulation, may also occur Deficiency in vitamin A usually manifests itself as impaired dark adaptation, of which patients may not be aware; accordingly, opthalmological referral is necessary for a complete examination in patients... Wilson’s disease Normal in the absence of Wilson’s disease and in many patients early on Findings in Wilson’s disease with neurologic or psychiatric symptoms include atrophy, alterations in basal ganglia, subcortical white matter, midbrain, and pons Abnormalities can be present in some asymptomatic patients Haplotype: same as proband indicates Wilson’s disease present, different in carriers and unaffected... somatostatin infusion, endoscopic band ligation, and portosystemic shunting, or liver transplantation Encephalopathy is present in the acute fulminant setting, or in patients with end-stage liver disease In this latter group, encephalopathy may exacerbate neuropsychological symptoms due to the Wilson’s disease, and should be considered and treated separately For Wilson’s disease patients with liver disease, . of severe acetaminophen-induced hepatotoxicity ( 198 7– 199 3). Gastroenterology 199 5;1 09: 190 7–16. O’Grady J. Paracetamol-induced acute liver failure: prevention and management. J Hepatol 199 7;26 Suppl. HELLP syndrome. J Perinat Med 2000; 28:2 49 60. Reyes H. Acute fatty liver of pregnancy: a cryptic disease threatening mother and child. Clinics in Liver Disease 199 9;3: 69 81. Tsang IS, Katz. Imaging studies are useful in assessing the biliary tree. Virologic markers and history can help to rule out viral and toxic hepatitis. 698 / Advanced Therapy in Gastroenterology and Liver Disease of

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