Liver D isease Associated with Pregnancy*

Transcription

1 ANNALS O F CLIN ICAL AND LABORATORY SCIEN CE, Vol. 20, No. 4 Copyright 1990, Institute for Clinical Science, Inc. Liver D isease Associated with Pregnancy* ENDLA K. ANDAY, M.D. and ARNOLD C O H EN, M.D. University of Pennsylvania School o f Medicine, Departments o f Pediatrics and Obstetrics and Gynecology, Philadelphia, PA ABSTRACT Pregnancy is associated with altered liver function, particularly in serum enzymes. Anabolic steroids are responsible to some degree in mediating the physiologic and biochemical changes that occur during an uncomplicated pregnancy. However, several liver disorders are unique to pregnancy and include intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy, and hepatic dysfunction associated with pre-eclampsia and eclampsia. It is imperative for the clinician to diagnose these liver disorders in a timely m anner and to institute appropriate m anagem ent as maternal and fetal outcome are affected in an adverse m anner if these conditions are left untreated. Introduction Acute and chronic forms of liver disease occur during pregnancy, including a group of liver disorders unique to p reg nancy (table I). These may p resent special difficulties in diagnosis as the im plications for the fetus and m other depend on appropriate identification and m anagement. The purpose of this paper is to review the effects of pregnancy on liver function and to discuss diseases of the liver specifically related to pregnancy. Liver Function Changes in Norm al Pregnancy W hile no significant anatomical or histological changes occur in the liver dur * Address reprint requests to Endla K. Anday, M.D., Division of Neonatal-Perinatal Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA ing the course of a normal hum an pregnancy, s e v e ra l a lte ra tio n s in liv e r fu n ctio n hav e b e e n d o c u m e n te d as shown on Table II.6 Alterations in the synthesis, catabolism, and serum concentration of various plasm a proteins occur during gestation. Although a c ertain portion of th e decrease in total serum p ro te in and album in m ay be accounted for by simple dilution caused by an increased total blood volume, this m echanism cannot account for th e variable changes in the several globulin fractions. A lterations in serum enzym es also occur during the course of an uncomplicated pregnancy. O f note, total serum alkaline phosphatase rises minimally in the first trim ester to a two to four fold increase above normal values by term gestation. It has been shown that the placenta accounts for over 50 percent of the rise in alkaline phosphatase, with a further increase during labor.10 Levels of /90/ $00.90 Institute for Clinical Science, Inc.

2 2 3 4 ANDAY AND COHEN TABLE I Liver Disease Specifically Related to Pregnancy The role that anabolic steroids, estrogens and progestins play in m ediating th e physiologic and biochem ical alterations during an uncom plicated preg nancy is not entirely clear. Anabolic steroids, particularly those containing a methyl or ethyl group in the C-17 position, are known to cause cholestasis and result in an increased serum level of alkaline phosphatase, 5'-nucleotidase, GGTP, bile acids, and bilirubin. E strogens increase hepatic rough endoplasmic reticulum and accelerate the synthesis of p ro te in s. F u rth e r, e stro g e n ic com pounds can reduce lipoprotein lipase activity and accelerate hepatic triglyceride biosynthesis, leading to an elevation of serum lipids. Intrahepatic cholestasis of pregnancy (ICP) Acute fatty liver of pregnancy (AFLP) Eclampsia and spontaneous rupture of the liver serum gamma glutam yl-transpeptidase (GGTP), lactic d eh y d ro g en ase, and o rn ith in e tran scarb am y lase are also increased near term. However, serum aspartate am inotransferase (AST) and serum alanine aminotransferase (ALT) are only slightly increased near term with values usually within the range of normal.15 Substantial increases in serum triglyceride and serum cholesterol levels also occur during the last trim ester of pregnancy. Serum bilirubin may be slightly elevated in approximately five percent of otherwise norm al pregnancies w ith clinical jaundice occurring in approximately one in 1,500 gestations.6 However, a significant rise in serum biliru b in level should alert the clinician to consider eith er liver or hematologic disease. S e x H o r m o n e E f f e c t s o n L iv e r F u n c t io n Intrahepatic Cholestasis of Pregnancy This syndrome, consisting of pruritis and mild jaundice occurring in the last trim ester of pregnancy, was originally d e s c rib e d by T h o rlin g in S w ed ish w om en.19 In trah ep atic cholestasis of pregnancy (ICP) is second only to viral hepatitis in causing jau n d ice during pregnancy and accounts for approximately 20 percent of all cases of clinical jaundice.6 The frequency of ICP varies in different racial groups and may com plicate as many as 2.4 p ercen t of p reg nancies in Scandinavian and C hilean w om en.14 Approximately 50 percent of w om en may suffer from IC P in subsequent pregnancies. Although th e m echanism of cholestasis is uncertain, substantia l e v id e n c e su g g e sts an u n u su a l sen sitiv ity to e stro g en ic stero id s is im portant in the pathogenesis of ICP. This is suggested by the observation that individuals with this syndrome develop similar clinical symptoms and biochem i cal changes while taking oral contracep- T A B L E II Alterations in Liver Function Tests in Normal Pregnancy Elevated Lactic dehydrogenase Alkaline phosphatase and globulins Cholesterol and lipids Sulfobromophthalein (BSP) retention Fibrinogen Ceruloplasmin Transferrin Bilirubin Decreased Protein Albumin Gamma globulin Period of Maximum Change (Trimester) Second Second Second

3 LIVER DISEASE ASSOCIATED WITH PREGNANCY tive medications containing estrogens.9 G enetic factors may also be involved as a fam ilial occurrence of IC P has been shown and provides evidence that the inheritance is M endelian dominant. An occasional but major complication of ICP on the m other is postpartum hem orrhage, presum ably owing to a prolongation of prothrom bin time as a result of vitamin K deficiency. There also seems to be an increased risk of prem ature labor (60 percent) and perinatal mortality owing to prem aturity.13,18 C l in ic a l F e a t u r e s The characteristic feature of ICP is onset of pruritis at the beginning of the third trim ester followed in one to two weeks by the onset of m ild jaundice, dark u rin e, and light colored stools, Rarely, the pruritis may present as early as the sixth week of pregnancy.10 There is an increased incidence of emesis in early pregnancy in wom en w ith IC P, thus suggestin g th e existence of an underlying metabolic disorder throughout pregnancy.7 Pruritis can involve any area of the body and is more severe at night. The insomnia owing to itching can lead to irritability and fatigue. Shortly after delivery, the p ru ritis resolves within 24 hours, with jaundice resolving subsequently. B io c h e m ic a l C h a n g e s Although the physical exam is unremarkable in ICP, the laboratory findings are c o n siste n t w ith cholestasis w ith m arked elevation of serum alkaline phosphatase (7 to 10 fold), and 5'-nucleotidase. Total serum bilirubin is usually less than five mg per 100 ml and rarely above 10 mg p er 100 ml, with the major fraction being conjugated. Serum bile acid levels are markedly increased (10 to 100 fold) with a rise in cholic as well as in chenodeoxycholic and deoxycholic acids. Presumably, the pruritis in IC P is secondary to the deposition of bile acids in the skin. Serum amino transferases are usually only m oderately elevated with values of AST and ALT com parable to those seen in uncom plicated preg n an cies. Occasionally, prothrom bin tim e may be prolonged because of m alabsorption of Vitamin K when jaundice appears early in pregnancy. H is t o l o g ic F e a t u r e s Histologically, the liver in ICP shows characteristic features of cholestasis with canalicular bile plugs which are m ost p ro m in en t around the cen tral veins. M ild Kupffer cell proliferation and p eriodic-acid Schiff (PAS)-positive granules are seen in macrophages. However, the architecture of the liver remains intact, and the portal areas are normal.5 There is little evidence of parenchym al necrosis, although in some areas enlarged and irregular m itochondria may be seen in parenchym al cells. M a n a g e m e n t Generally, therapy of ICP is directed at treating the pruritis coagulopathy and observing for onset of prem ature labor. The drug of choice for lowering serum and skin bile acid levels is cholestyramine with doses as high as 20 g per day occasionally re q u ire d for relief. P ro throm bin time should be m onitored as cholestyram ine adds to th e m alabsorption of vitamin K already present in cholestasis. Vitamin K in a dose of 10 mg orally per day may prevent the abnormality of prothrom bin time. Acute Fatty Liver of Pregnancy Acute fatty liver of pregnancy (AFLP) is a potentially fatal, uncomm on disorder

4 2 3 6 ANDAY AND COHEN that may complicate the last trim ester of pregnancy.3,20 It was first recognized in and is e stim a ted to occur in roughly 1 p e r 13,000 d eliv eries. It usually occurs after th e 35th w eek of pregnancy but has been noted as early as the 30th week and most often affects prim iparas, p articu la rly th ose carrying tw ins or m ale fetuses. T he cause of AFLP is unknown, but it clearly is not an infectious process. Increased levels of fatty acids have been found in the livers of patients, suggesting a toxic effect of these compounds. M arked abnormalities of the structure of the mitochondria, as well as abnormalities in the urea cycle enzym es su g g est a re se m b la n c e to Reye s syndrome. However, in contrast to the findings in Reye s syndrome, the mitochondrial matrix does not expand in fatty liver of pregnancy, nor does it becom e thickened, flocculent, or granular.21 C l in ic a l F e a t u r e s The syndrome is characterized by the sudden onset of nausea, severe recurrent vomiting followed by abdominal pain, and h ead ach e.16 T he abdom inal pain may be epigastric, suggesting a w orsening of reflux esophagitis that commonly occurs in pregnancy. Jaundice follows shortly, as well as bleeding from punctu re sites and h e m a te m e sis. M any p atien ts have m ild h y p erten sio n and peripheral edem a, suggestive of p re eclampsia. The abdomen may be tender, but the liver is small and not palpable. Seizures and frank coma are later, more ominous manifestations. Spontaneous labor frequently occurs with the delivery of a dead fetus. Following delivery, there is significant im provem ent in the patient s status. L a b o r a to r y C h a n g e s Early diagnosis of acute fatty liver of pregnancy is critical as it leads to prompt treatm ent, improving both m aternal and fetal survival. Liver am inotransferase levels should be m easured immediately in any woman in the third trim ester of pregnancy who has the symptoms noted previously. E levated serum am inotransferase, at levels in the range o f300 to 500 units per ml, should prom pt further laboratory evaluation. The peripheral blood smear shows throm bocytopenia and norm oblasts, as w ell as b u r r cells, fragm en te d re d cells, and H ow ell-jolly bodies, in d icatin g m icroangiopathic hem olysis.1,2 T h ere is evidence of dissem inated intravascular coagulopathy as fibrinogen levels are below the norm al values for pregnancy and fibrin split products are present. Prothrom bin tim e is markedly prolonged at greater than 25 seconds. Serum bilirubin is usually less than 10 mg per dl b ut alkaline phosphatase is markedly elevated. O ther abnorm al laboratory values include, an elevated blood ammonia level, decreased blood glucose level, increased white cell count, often above 20 X 109 p er L, an increased blood urea nitrogen, uric acid and creatinine levels. The m aternal mortality rate is extremely high, varying betw een 65 to 90 percent with fetal mortality somewhat less. H is t o l o g ic C h a n g e s The liver is small and pale on gross examination in AFLP. Microscopically, hepatocytes, particularly those in the pericentral area, are swollen and pale with centrally located nuclei. The pale, vacuolated appearance of hepatocytes is due to the fat-filled microvesicles which can be d em o n strated using fat stains such as oil red O on fresh-frozen biopsy specim ens. T he portal triad is unaffected, but bile throm bi are often seen in the central areas.4,6 Lobular disarray is commonly seen, as well as patchy hepatocellular necrosis, lo b u lar inflam m a tion, and reticulin condensation.

5 LIVER DISEASE ASSOCIATED WITH PREGNANCY 237 M a n a g e m e n t Prom pt diagnosis is essential to appropriate therapy. O nce the diagnosis of AFLP is suspected, the patient should be managed with fluid and electrolyte solutions and m aintenance of norm al serum glucose. F resh frozen plasm a should be used to correct the clotting abnormalities and blood transfusion for controlling hemorrhage. As soon as the m o th e r s clinical condition has stab i lized, the infant should be delivered either by induction or cesarian section. Patients who survive have a rapid norm alization of liver function tests, and those who have undergone subsequent pregnancies have not suffered a rec u r rence of this disorder. Pre-Eclam psia and Eclampsia In approxim ately 50 percent of pregnancies classified as eclam psia or p re eclam psia, th e re is evidence of liver involvement as part of the general vascular disorder.6 If disseminated intravascular coagulation accom panies the p re eclampsia or eclampsia (approximately 10 percent of cases), liver injury is comm on and know n by th e m neum onic H ELLP syndrome (hemolysis, elevated liver enzym es, low platelets).811 C l in ic a l F e a t u r e s Following the onset of hypertension and proteinuria, patients will present in the last trim ester of pregnancy with nausea, vom iting, as well as m oderate to severe epigastric pain and occasionally jaundice. In addition to the physical findings common to pre-eclam psia and eclampsia, patients will exhibit tender hepatomegaly. B io c h e m ic a l C h a n g e s Changes in liver function associated w ith p re -e c la m p s ia and ecla m p sia include a m arkedly elev ated alkaline phosphatase and rise in AST to levels as high as 1,000 IU per ml. There is good correlation betw een the degree of abnormal liver function and clinical course. The bilirubin elevation that accompanies this disorder is usually mild at levels < 6 mg p er dl. Hemolysis which accompanies the dissem inated intravascular coagulation is a major contributing factor of the jaundice. H is t o l o g ic C h a n g e s M icroscopically, the changes in the liver of patients with pre-eclam psia or eclampsia differ from those of fatty liver of pregnancy. Characteristically, there are fibrin throm bi in the hepatic sinusoids associated with surrounding focal necrosis of the hepatocytes. Diffuse hemorrhagic necrosis, as well as centri- Iobular necrosis, is seen in severe cases, particularly w hen shock occurs. M a n a g e m e n t As the predisposing condition of this disorder is pre-eclampsia or eclampsia of pregnancy, tre a tm e n t should be first d ire c te d at stabilizing this disorder. W here there is disseminated intravascular coagulation, prompt delivery of the fetus is recommended. By 12 to 24 hours following delivery, there is reversal of hypertension and liver derangem ent. Summary A careful physical exam ination and perform ance of liver function tests are essential in evaluating the p reg n an t p atient who presents w ith sym ptom s that include gastrointestinal complaints, pruritis, abdom inal pain, edem a, and icterus. M easurements of excretory and synthetic functions of the liver should include determ ination of serum total protein, album in and globulin; direct

6 2 3 8 ANDAY AND COHEN and total bilirubin; alkaline phosphatase or 5'-nucleotidase; ALT and AST; cholesterol; and prothrom bin time. A timely diagnosis of the major hepatic disorders associated with pregnancy will lead to appropriate m anagem ent, with improved health and survival in both the m other and fetus. References 1. Burroughs, A. K., Seo n g, N. H., D ojcinov, D. M., S c h e u e r, P. J., a n d Sh e r l o c k, S. V. P.: Idio p ath ic acu te fatty acid liv er o f p reg n an cy in 12 p atients. Q uart. J. M ed. 51:481-97, C a n o, R. I., D e l m a n, M. R., P it c h u m o n i, C. S., L e v, R., and Ro se n t h a l, W. S.: Acute fatty liver of pregnancy: Complication by dissem inated intravascular coagulation. J. Am. Med. Assoc. 231:159-61, C a se R e c o r d s o f t h e M a ssa c h u se t t s G e n eral H o spita l (C ase ). N. Engl. J. M ed. 304:216-24, D u m a, R. J., D o w l in g, E. A., A le x a n d e r, H. C., Sibrans, D., and D em psey, H.: Acute fatty liver of pregnancy. Ann. Intern. Med. 63:851, E n g s t r o m, J., H e l l s t r o m, J., P o s s e, N., and Sjo v a l l, J.: Recurrent cholestasis of pregnancy. Treatment with cholestyramine of one case with an unusually early onset. Acta Obstet. Gynecol. Scand. 49:29, H a e m m e r l i, U. P,: Jaundice during pregnancy, with special emphasis on recurrent jaundice during pregnancy and its differential diagnosis. Acta Med. Scand. J79(Suppl. 444):1, J o h n s o n, P., S a m s io e, G., and G u s t a f s o n, A.: Studies in cholestasis of pregnancy with special reference to clinical aspects and liver function tests. Acta Obstet. Gynecol. Scand. (Suppl.) 54:77, K il lia m, A. P., D il l a r d, S. H., Pa tton, R. C., a n d P e d e r s o n, P. R.: P r e g n a n c y - in d u c e d h ypertension com plicated by acute liver disease and disseminated intravascular coagulation. Am. J. Obstet. Gynecol. 123:823, K r e e k, M. J., and SLEISENGER, M. H.: Estrogen-induced cholestasis due to endogenous and exogenous hormones. Scand. J. Gastroenterol. 7(Suppl.):123, K r e js, G. J., and H a e m m e r l i, U. P.: Miscellaneous disorders, Part I. Jaundice during pregnancy. In Schiff, L., and Schiff, E. R. (eds.): Diseases of the Liver, 5th ed., Philadelphia, J.B. Lippincott Company, L o n g, R. G., S c h e u e r, P. J., and S h e r l o c k, S.: Pre-eclampsia presenting with deep jaundice. J. Clin. Pathol. 30:212, P o c k r o s, P. J., P e t e r s, R. L., and R e y n o l d s, T. B.: Idiopathic fatty liver of pregnancy: Findings in ten cases. Medicine (Baltimore) 63:1 11, R e i d, R., I vey, K. J., R e n c o r e t, R. H., et al.: Fetal complications of obstetric cholestasis. Br. Med. J. 1:870, R e y e s, H., G o n z a l e z, M. C., R ib a l t a, J., et al.: Prevalence of intrahepatic cholestasis. Chile. Ann. Intern. Med. 88:487, Sc h i f f e r, M. A., and D u n n, I.: Jaundice with hepatorenal failure associated with pregnancy or gynecologic procedures. O bstet. Gynecol. 39:241, S h e e h a n, H. L.: The pathology of acute yellow atrophy and delayed chloroform poisoning. J. Obstet. Gynaecol. Br. Commonw. 47:49, St a n d e r, H. J., and C a d d e n, J. F.: Acute yellow atrophy of the liver in pregnancy. Am. J. Obstet. Gynecol. 28:61-9, St e e l, R., and Pa r k e r, M. L.: Jaundice in pregnancy. Med. J. Aust. 1:461, T h o r l in g, L.: Jaundice in pregnancy. A clinical study. Acta Med. Scand. (Suppl.) 302:131, Va r n e r, M., and R in d e r k n e c h t, N. K.: Acute fatty metamorphosis of pregnancy: A maternal mortality and literature review. J. Reprod. Med. 24:177-80, W e b e r, F. L. J r., S n o d g r a s s, P. J., P o w e l l, D. E., R a o, P., H u f f m a n, S. L., and B rady, P. G.: Abnormalities of hepatic mitochondrial urea-cycle enzyme activities and hepatic ultrastructure in acute fatty liver of pregnancy. J. Lab. Clin. Med. 94:27-41, 1979