Gut, 1968, 9, 489-493

Acute fatty liver of pregnancyR. A. JOSKE, D. J. McCULLY, AND F. L. MASTAGLIA

From the Departments of Medicine and Pathology,University of Western Australia

Acute fatty liver of pregnancy was established asan entity by Sheehan (1940) under the name 'ob-stetric acute yellow atrophy'. He reviewed theearlier literature and distinguished three types ofacute hepatic failure in pregnancy.The first of these was 'true acute yellow atrophy',

and corresponds to the disease now called massivehepatic necrosis. It may occur in pregnant or non-pregnant patients, and is characterized patholo-gically by massive parenchymal cell necrosis withoutfatty change in liver cells. It is generally ascribed,although without proof, to a fulminating acutevirus hepatitis.

Sheehan's second entity was delayed chloroformpoisoning. The pathological change in this was ofliver cell necrosis occurring in isolated cells, or asmid-zonal or centrilobular necrosis. Affected cellshad a swollen, non-fatty cytoplasm and pyknoticnucleus, and fatty change was slight or absent.However, this lesion is now of historic rather thanclinical interest.The third type of liver change Sheehan termed

'obstetric acute yellow atrophy'. This was clinicallysimilar to massive hepatic necrosis but occurredonly late in pregnancy at 36 to 40 weeks and wasfrequently associated with toxaemic manifestationssuch as hypertension and proteinuria. It progressedrapidly, leading to maternal death within two weeks.The histological appearances were characteristic.There was 'an entire absence of necrobiosis', butan intense fatty change affecting all cells of thelobule, except for a sharply defined rim of normalcells adjacent to the portal tracts. This fatty changeoccurred diffusely thoughout the cytoplasm, givingit a ballooned, vacuolated appearance. The distri-bution of the affected cells and the diffuse fattychange throughout the cytoplasm clearly distin-guished the condition from the occasional fatdroplets seen in centrilobular cells followinghyperemesis of late pregnancy (Sheehan, 1939).Portal tracts were normal and bile thrombi rare orabsent. This obstetric acute yellow atrophy is nowgenerally called acute fatty liver of pregnancy.It remains probably the gravest form of liverdisease in pregnancy.

In recent years, some authors have included fattyliver associated with tetracycline therapy duringpregnancy in the general group of acute fatty liverof pregnancy (Kunelis, Peters, and Edmondson,1965). It does, however, occur in non-pregnantpatients, and may be associated with other drugs ofthe tetracycline series (Saint and Joske, 1953;Klatskin, 1963). Despite its clinical and pathologicalsimilarities to acute fatty liver of pregnancy, itshould, therefore, be regarded as a separate entitywith a different aetiology and pathogenesis.True acute fatty liver of pregnancy is a rare

condition. Ober and LeCompte (1955) reported 14cases including three of their own in 1955, and in1966 Haemmerli extended the collective experienceto 40 cases. The clinical picture is of a rapidlyprogressive parenchymal cell failure which is clini-cally indistinguishable from that of acute massivenecrosis. It has been reported in patients ranging inage from 16 to 42 years, and in 37 of the 40 cases itoccurred during the first pregnancy. The prognosisis grave: of the 40 cases collected by Haemmerli, onlysix mothers and five children have survived.The pathological appearances in all cases cor-

respond to those described by Sheehan (1940). Theyare potentially reversible, for in one survivor fol-lowed up by serial liver biopsies, normal histolo-gical appearances were ultimately restored (Whitacreand Fang, 1942).The present paper reports a further case of acute

fatty liver of pregnancy, which is of interest becauseof some unusual features, in particular steadyprogression of the lesion despite delivery of a livingchild, haemolytic anaemia, and the finding at ne-cropsy of massive mid-zonal hepatic necrosis.

CASE REPORT

A primipara aged 21 years had a normal pregnancyuntil the thirty-seventh week, when she developed oedemaof both legs to the knees and was noted by her husbandto be jaundiced. There was no history of jaundice or ofexposure to hepatitis or hepatotoxic drugs or chemicals.Two days later (day 3) she was admitted to hospital,where she was found to have a blood pressure of 150/100 mm Hg (previously 135/50 mm Hg), and protein-

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490 R. A. Joske, D. J. McCully, and F. L. Mastaglia

TABLE ISUMMARY OF LABORATORY DATA

Day 7 Day 9Investigation

Haemoglobin (g/100 ml)Haematocrit ( %)Reticulocyte count (per 100 red cells)Nucleated red cells (per 100 red cells)White blood cell count (per cu mm)Differential count (%)

NeutrophilsLymphocytesMonocytesEosinophilsMetamyelocytesMyelocytes

Platelet count (per cu mm)Serum haptoglobins (mg/100 ml)Serum bilirubin (mg/100 ml)Serum alkaline phosphatase(King-Armstrong units)

Serum glutamic oxalo-acetic transaminase (Karmen units)Serum glutamic pyruvic transaminase (Karmen units)Blood ammonia nitrogen (isg/100 ml)Plasma urea (mg/100 ml)Serum protein electrophoresis (grams/100 ml) Albumin

al-Globulina2-GlobulinR -Globuliny -Globulin

Thymol turbidityPlasma electrolytes (m-equiv/1)

SodiumPotassiumBicarbonateChloride

uria. She was treated with bed rest and chlorothiazide500 mg daily, and on day 6 was delivered of a normal maleinfant. Labour was spontaneous and delivery uncompli-cated until 11 hours after delivery when she sustained ahaemorrhage of 600 ml per vaginam and vomited alteredblood. Her systolic blood pressure fell to 40 mm Hg andshe received 2 pints of plasma and 1 of blood over thenext four hours, with restoration of her blood pres-sure. The intravenous infusion was then continued withdextrose and saline solutions, 2 litres daily. Her con-dition showed little change and on day 9 the serumbilirubin level was 12 mg %.She was admitted to the Royal Perth Hospital on

day 9. At this time, she was disorientated in time andplace. Pulse was 120 per minute and blood pressure140/85 mm Hg. There was moderate jaundice andpitting oedema of all extremities. The cervical venouspressure was not raised, and the heart and chest showedno abnormal signs. Neither liver nor spleen was palpable.Neurological examination showed that the limbs were

hypotonic with some muscular twitching. The reflexeswere symmetrical and brisk and the plantar responsesflexor. The genitalia showed the usual signs of a recentdelivery. There were no signs of chronic liver diseasesuch as spider naevi or palmar erythema.

Serial haematological studies and liver function testsare shown in Table I. A chest radiograph and vaginalswab were normal. The urine contained protein andculture grew coliform organisms. The blood film showedanisocytosis, burr cells, and fragmented cells, withnormoblasts and occasional macronormoblasts with

Howell-Jolly bodies; there was toxic granulation ofneutrophils. Direct and indirect Coombs tests werenegative. Blood cultures and a cervical smear grew no

pathogens.Treatment was begun with kanamycin 3.0 g daily and

ampicillin 2-0 g daily by intragastric tube and methicillin4.0 g daily by injection. A transfusion of 1 pint of bloodwas given followed by dextrose and saline solution. Onday 10 she was stuporose, with neck retraction, hyper-tonia, and augmented tendon reflexes. Spider naeviappeared over the arms and chest. The liver remainedimpalpable. The following day she developed clonicmovements of the limbs which were controlled only bythe use of phenobarbital, paraldehyde, and magnesiumsulphate by injection. Hydrocortisone was also given byinjection, 400 mg daily. Other treatment, includingfurther blood transfusion, was contined.Her progress was steadily downhill and chest infection

required tracheostomy on day 12. Her urinary output wasmaintained and exceeded 1,800 ml daily. The bloodammonia nitrogen level continued to rise, and she deve-loped hyperpyrexia (40.5°C) and died on the following day.Necropsy was performed nine-and-a-half hours after

death. The body was that of a well-nourished, deeplyjaundiced, young female (weighing 49 kg and measuring160 cm in length). The face, hands and legs were oedem-atous. Bilateral pale yellow pleural effusions were presentmeasuring 350 ml and 100 ml. The right and left lungsweighed 480 g and 360 g respectively; both showed basalcollapse and minimal oedema. The state of the genitalorgans was consistent with the post-partum state. The

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Acute fatty liver ofpregnancy

FIG. 1. Section of liver showing massive centrilobularand midzonal fatty change and necrosis. Haematoxylinand eosin x 29 5.

liver was smaller than normal, weighing 1,068 g and thecapsule was slightly wrinkled. On section, the parenchymawas firm and diffusely yellow. The gall bladder was normaland there was no evidence of extrahepatic biliary obstruc-tion. Other viscera were macroscopically normal.The most striking feature in sections of the liver

stained with haematoxylin and eosin was the presence ofextensive liver cell necrosis with sparing of the periportalzones (Fig.1). In the necrotic zones many of the hepaticcell outlines were preserved, revealing that some cellswere swollen and vacuolated while others were shrunkenand eosinophilic (Figs. 2 and 3). The nuclei were faintlystaining in the former cells and an Oil Red 0 fat stainconfirmed the presence of lipid in their cytoplasm. TheGordon and Sweet reticulin stain confirmed collapsewith condensation of the supporting connective tissuefibres in the necrotic areas. There were a number ofintracanalicular bile plugs in the midzonal and cen-trilobular areas. Inflammatory cellular infiltrate wasextremely sparse and consisted of a few lymphocytes andplasma cells seen mainly in the necrotic areas. In the peri-portal zone of normal looking liver cells, there wasearly regeneration in the form of ductular cell proli-feration (Fig. 4). The glomeruli of the kidneys showedminimal basement membrane thickening consistent withthe changes described in toxaemia of pregnancy. Thebone marrow was hypercellular with a degree of ery-throid hyperplasia and megakaryocytes were present innormal numbers.The most prominent feature in the brain was the

presence of many protoplasmic astrocytes throughoutthe grey and white matter. These astrocytes were of theAlzheimer II variety and only their large round or ovalvesicular nuclei with a loose chromatin pattern could beseen. A periodic acid Schiff (PAS) stain demonstrated thepresence of multiple small PAS-positive inclusions withinthe nuclei ofthese cells. Although present in all parts of thebrain, these protoplasmic astrocytes were most numerousin the region of the subthalamic nucleus, the putamen,Ammon's horn, and the dentate nucleus. There were alsodegenerative changes in the neurons, involving parti-cularly those of Sommer's sector in Ammon's horn andalso those of the deeper layers of the cortical grey matter.The neuronal changes consisted of shrinkage and cyto-plasmic eosinophilia, changes suggestive of anoxicencephalopathy. The Purkinjie cells of the cerebellumwere well preserved and there was only a mild proli-feration of Bergmann's layer of astrocytes in the cere-bellum.

Attempts to isolate virus from postmortem specimensof liver and kidney were unsuccessful.

DISCUSSION

The diagnosis of acute fatty liver of pregnancy inthis patient is based on clinical and pathologicalfindings. The clinical picture of a rapidly progres-sive parenchymal failure accompanied by mani-festations of toxaemia in the last month of preg-nancy in a primipara is characteristic of the disease.The laboratory findings are also typical: hyper-bilirubinaemia with an increase in serum alkalinephosphatase but no increase in y-globulin andnegative flocculation tests. Azotaemia is present inabout half the cases and is generally ascribed tooligaemia. The terminal decrease in plasma urea isalso a usual finding and is probably the result ofdecreased hepatic synthesis of urea. The intenseleucocytosis is also common, recorded figuresvarying from 19,200 to 32,000 per cubic millimetre(Haemmerli, 1966). However, a haemolytic anaemiaof the degree seen in this patient is unusual and doesnot appear to have been recorded previously. Itsexplanation is unknown.The pathological findings in the present case are

also unusual. The diagnosis of acute fatty liver ofpregnancy is supported by the diffuse cytoplasmicfatty change in hepatocytes, the rim of normal cellsadjacent to portal tracts, and the minimal in-flammatory infiltrate in the liver. The massive mid-zonal necrosis seen here has not, however, beenreported previously, and its explanation is uncertain.The patient received no hepatotoxic drugs before theonset of her illness, and there was no known ex-posure to hepatitis A virus. Lesions such as thoseproduced by tetracycline toxicity are thus excluded.It may reflect the relatively long survival period ofseven days after delivery, which is the longest re-

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492 R. A. Joske, D. J. McCully, and F. L. Mastaglia

W..~~ ~ ~ ~ ~ ~ A ~.^ - ~~~~~~~~~~~~~~~~FIG. 3.FIG. 2.

FIG. 2. Section of liver. Some of thel hepatocytes are shrunken with

densely staining eosinophiliccytoplasm, whilst others are swollenwith a vucuoluted cytoplasm. Oil Red0 confirms the lipid nature of the

. vacuoles. A few lymphocytes arepresent. Haematoxylin and eosin

FIG. 3. Section of liver. Thehepatocytes in the centrilobularzone contain many small cytoplasmicvacuoles. Haematoxylin and eosinx 475.

FIG. 4. Section of liver showingsurviving hepatocytes in the periportal

a:.!. _ region and early regeneration.Haematoxylin and eosin X 475.

FIG. 4.

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Acute fatty liver ofpregnancy 493

corded (Moore, 1966), in which case it represents amore advanced stage of the disease than has pre-viously been reported.The case offers no further information as to the

aetiology of acute fatty liver of pregnancy. Thehepatic lesions are not specific, occurring also intetracycline toxicity (Kunelis et al, 1965) and therecently described syndrome of encephalopathy anddegeneration of the viscera in children (Reye,Morgan, and Baral, 1963). Isolations of reo- and cox-sackie virus have been reported in this latter case,but were unsuccessful in the present case. Thehistological appearances in the liver also differfrom those we have found in human hepatitis due toreovirus (Joske, Keall, Leak, Stanley, and Walters,1964). The most probable explanation must be thatfatty liver of pregnancy is related to the toxaemiasof pregnancy, but is of unknown aetiology. Thefrequency of toxaemic manifestations in acutefatty liver of pregnancy would support this theory.The final point worthy of mention is that the infant

survived, making only the sixth surviving child inacute fatty liver of pregnancy. Haemmerli (1966)considers caesarian section indicated because theonly two reported survivals of both mother andchild followed caesarian section. One child survivedwhen the disease developed after a normal delivery,and three children after spontaneous delivery soonafter the onset of symptoms. In all these lattercases the mother died.

SUMMARY

A further case of acute fatty liver of pregnancy is

reported, making the 41st acceptable case in theliterature. Unusual features were steady progressionof the disease after natural delivery of a living child,severe haemolytic anaemia, and the finding atnecropsy of massive midzonal hepatic necrosis.

We wish to thank Drs J. B. Blackwell and B. A.Kakulas for their assistance with the examination of thepathological material. Mr B. Brown prepared the photo-micrographs.

REFERENCES

Haemmerli, U. P. (1966). Jaundice during pregnancy. With specialemphasis on recurrent jaundice during pregnancy and itsdifferential diagnosis. Acta med. scand., suppl. 444.

Joske, R. A., Keall, D. D., Leak, P. J., Stanley, N. F., and WaltersM. N. 1. (1964). Hepatitis-encephalitis in humans with reovirusinfection. Arch. intern. Med., 113, 811-816.

Klatskin, G. (1963). Toxic and drug-induced hepatitis. In Diseases ofthe Liver, edited by L. Schiff, 2nd ed., pp. 453-538. Lippincott,Philadelphia. Pitman, London.

Kunelis, C. T., Peters, J. L., and Edmondson, H. A. (1965). Fattyliver of pregnancy and its relationship to tetracyline therapy.Amer. J. Med., 38, 359-377.

Moore, H. C. (1956). Acute fatty liver of pregnancy. J. Obstet. Gynaec.Brit. Emp., 63, 189-198.

Ober, W. B., and LeCompte, P. M. (1955). Acute fatty metamor-phosis of the liver associated with pregnancy. A distinctivelesion. Amer. J. Med., 19, 743-758.

Reye, R. D. K., Morgan, G., and Baral, 3. (1963). Encephalopathyand fatty degeneration of the viscera. A disease entity inchildhood. Lancet, 2, 749-752.

Saint, E. G., and Joske, R. A. (1953). A note on fatty change in theliver complicating aureomycin therapy. Med. J. Aust., 1,222-224.

Sheehan, H. L. (1939). The pathology of hyperemesis and vomiting oflate pregnancy. J. Obstet. Gynaec. Brit. Emp., 46, 685-699.

(1940). The pathology of acute yellow atrophy and delayedchloroform poisoning. Ibid., 47, 49-62.

Whitacre, F. E., and Fang, L. Y. (1942). Fatty degeneration of theliver in pregnancy. Report of a case with recovery: chemical andhistologic studies. J. Amer. med. Ass., 118, 1358-1364.

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