—  SPECIALTY CONFERENCE  —

Liver Pathology

Case 2 - Resolving Acute Fatty Liver of Pregnancy Complicated by HELLP Syndrome

Charles R. Lassman
UCLA Center for Health Sciences
Los Angeles, California


Click on each slide thumbnail image for an enlarged view
Clinical History
The patient is a 22 year old woman, G3P1, S/P C-section for full-term pregnancy, transferred to UCLA Medical center with deep jaundice and acute liver failure. There was no prior history of liver disease. She was approximately 38 weeks gravid when she noted ankle swelling and elevated blood pressure was detected. There was no pruritus and no alteration in mental status. She presented to a local Medical Center (1 week prior to transfer) with an approximately 1-week history of increasing jaundice. Upon admission, she was noted to be deeply jaundiced and anemic. The fetus was bradycardic. A STAT C-section was performed, and the baby was reported to be doing well post-delivery.

Following delivery, she developed hypotension and was transferred to the ICU for close monitoring. There, she was given PRBC's and FFP for anemia and coagulopathy. She remained afebrile. On post-operative day #1, she was noted to be somewhat lethargic. Her serum bilirubin continued to rise, though her transaminases remained low. She developed progressive thrombocytopenia to 43,000. She was started on IV antibiotics. Over the subsequent days, her coagulopathy progressed with increasing jaundice requiring supportive transfusions. Her renal function progressively worsened. She also developed increasing abdominal distention and discomfort. Paracentesis revealed bloody fluid without obvious infection. In view of her worsening clinical picture, she was transferred for a higher level of care. The clinical differential diagnosis included acute fatty liver of pregnancy and HELLP syndrome. Over the ensuing week, the coagulopathy worsened, renal function deteriorated, encephalopathy developed and the bilirubin continued to rise. The AST and ALT remained mildly elevated. The patient underwent orthotopic liver transplantation approximately 2 weeks following her initial presentation. A summary of lab values is shown below.

 OLT-14 days OLT-7days OLT - 1day
AST 51 81 87
ALT 38 32 41
Total bili 20.7 34.3 41.5
Alk phos 333 252 173
HCT 30.5   
PLTS 75   
WBC 11.7 30.6  


Case 2 - Figure 1 - Low power view of explanted liver.
Case 2 - Figure 2 - Portal tract.
Case 2 - Figure 3 - Medium power view of central vein and portal tracts.



Case 2 - Figure 4 - High power view of portal tracts showing cholangiolar cholestasis.
Case 2 - Figure 5 - High power view of portal tract.
Case 2 - Figure 6 - Medium power view of central vein.



Case 2 - Figure 7 - High power view showing canalicular cholestasis.
Case 2 - Figure 8 - High power view of portal tract.
Case 2 - Figure 9 - Low power view of reticulin stain.



Case 2 - Figure 10 - Portal structures on reticulin stain.
Case 2 - Figure 11 - Centrilobular area on reticulin stain.



Case 2 - Figure 12 - Low power, Masson stain.
Case 2 - Figure 13 - High power, Masson stain.


Major causes of hepatic dysfunction in late pregnancy
  • Acute fatty liver of pregnancy

  • Toxemia of pregnancy

  • HELLP syndrome

  • Acute viral hepatitis
Acute fatty liver of pregnancy is the most serious of the pregnancy related liver diseases. Without treatment the maternal and fetal mortality rate was as high as 80% [4, 5, 6, 11, 12, 13] . With increasing recognition, earlier diagnosis and recognition of more mild forms of the disease, the mortality rate for both mother and fetus has decreased to 5-50%, with one study reporting no deaths in 28 patients [6]. Prompt termination of pregnancy and improvements in supportive care for acute liver failure are thought to contribute to the improved outlook [5, 11] .

The most common clinical presentation is a prodromal illness characterized by pruritus severe vomiting and jaundice in the final 10 to 4 weeks of pregnancy in a primigravid female. Acute liver failure ensues with modest elevations of transaminases, bilirubin and doubling of prothrombin time. Many patients will have hypertension and proteinuria. Jaundice may develop following delivery [5].

Grossly the liver is yellow, and usually small. Microscopically hepatocytes are swollen and the cytoplasm is transformed by tiny fat vacuoles [5, 11, 13] . The vesicles of microvesicular steatosis may be too small to appreciate on routine stains; in this case, fat stains or electron microscopy may be necessary [11]. Microvesicular steatosis is most prominent in zone 3, usually involves zones 2 and 3, an is not infrequently panacinar. While hepatocellular necrosis is not generally prominent, hepatocellular loss can be demonstrated on the reticulin stain, and indirectly by Kupffer cell hypertrophy and reduced organ weight. Other less specific features include canalicular and hepatocellular cholestasis, and mild mixed portal infiltrates with lymphocytes, eosinophils and plasma cells. Serial biopsies in patients who have survived have demonstrated rapid resolution of microvesicular steatosis within days of delivery with zone 3 hepatocytes being the last to resolve [11].

Toxemia of pregnancy includes preeclampsia and eclampsia and is characterized by hypertension, proteinuria and edema (preeclampsia) and when more severe includes disseminated intravascular coagulation (DIC) [5, 7, 12] . Fewer than 50% of patients will have clinical evidence of liver disease, and many of these patients will have normal biopsies. When jaundice occurs in toxemia it is usually not due to liver involvement but instead is due to hemolysis. The most characteristic findings are those of DIC with deposition of fibrin in sinusoids, and focal hepatocellular necrosis of varying degrees, often but not always periportal [1, 7] . Portal areas will have minimal infiltrates and arterioles (and larger arteries) may have evidence of DIC with swollen endothelial cells and mural insudates.

HELLP syndrome or Hemolysis, Elevated Liver tests, and Low Platelets is seen in a small percentage of patients with preeclampsia/eclampsia. It may occur a few days following delivery. There is not complete agreement as to whether HELLP is a mild form of DIC or a subtype of toxemia. The histology is variable ranging from normal, to mild portal and lobular hepatitis to focal necrosis. Hepatic infarction has been reported [3, 5, 14, 15]

Gross and microscopic description
The liver weighed 1400 grams, was tan/brown without obvious hemorrhage, was vaguely micronodular on sectioning and dark green upon fixation. Microscopic sections show mild perturbation of lobular architecture by marked periportal regeneration. Portal areas are expanded and contain mild predominantly lymphocytic infiltrates. There is an extensive ductal reaction at the interface with numerous metaplastic appearing ductal structures with gaping lumens containing bile. Zone 1 hepatocytes demonstrate marked regenerative activity with minimal macro and microvesicular steatosis. Zone 2 and 3 hepatocytes demonstrate moderate macrovesicular steatosis occasional cells with microvesicular droplets, occasional ballooning, rare necrosis and marked cholestasis with canalicular dilation and rosette formation. There is patchy zone three hepatocellular drop out, hemorrhage and there is extensive Kupffer cell hypertrophy.

Differential diagnosis
The distinction between AFLP and toxemia is complicated by overlapping clinical findings, and the evolution or resolution of histologic findings. Because a significant proportion of patients with AFLP develop toxemia and DIC, histologic findings suggestive of toxemia and DIC do not exclude a diagnosis of AFLP. As biopsy studies have demonstrated rapid resolution of microvesicular steatosis after parturition, the absence of diffuse microvesicular steatosis does not rule out AFLP. In Rolfes and Ishak's 1985 report of 35 cases of AFLP, three types of steatosis were reported: ballooning cells with droplets too small to be appreciated by light microscopy; microvesicles and macrovesicles. Ballooning in this context is thought to represent the earliest manifestation of microvesicular steatosis, and macrovesicular steatosis is thought to result form coalescence of microvesicles over time.

This patient presented with hypertension and peripheral edema and following delivery developed hemolysis with low platelets consistent with HELLP syndrome and possibly toxemia. Histology demonstrated minimal microvesicular steatosis and moderate macrovesicular steatosis, mostly in acinar zone 3. Zone three necrosis/dropout was accompanied by portal tract changes often seen in ischemia. Periportal fibrin was not appreciated, nor was there extensive periportal hemorrhage. The findings of zone three dropout and of periportal ductal reaction argue for an element of ischemia most likely secondary to DIC.

Some investigators believe that fatty liver of pregnancy may be part of the spectrum toxemic disease. In one series [9], microvesicular steatosis was found in 41 of 41 biopsies performed in preeclamptic patients. Furthermore, periportal sinusoidal fibrin has been reported in AFLP [4, 10] . This finding should not however be surprising as a significant number of patients with AFLP develop toxemia.

Diagnosis:
Resolving acute fatty liver of pregnancy complicated by HELLP syndrome.

References

  1. Arias F, Manchilla-Jimenez R. Hepatic fibrinogen deposits in preeclampsia. Immunofluorescent evidence. N Engl J Med, 1976; 295-578-582.

  2. Barron WM. The syndrome of pre-eclampsia. Gastroenterol Clin North Am, 1992; 21:851-872.

  3. Barton JR, Sibai BM. Care of the pregnancy complicated by HELLP syndrome. Gastroenterol Clin North Am, 1992; 21:937-950.

  4. Burroughs AK, Seong NH, Dojcinov DM et al. Idiopathic acute fatty liver of pregnancy in twelve patients. Q J Med, 1982; 204-481-497.

  5. Burt AD, Portmann BC, MacSween RNM. Liver pathology associated with diseases and other organs or systems. in Liver Pathology, 4th Edition, 2002; 16:827-883.

  6. Castro MA, Fasset JM, Reynolds RB, Shaw KJ, Goodwin TM. Reversible peripartum liver failure: a new perspective on the diagnosis, treatment, and cause of acute fatty liver of pregnancy based on 28 consecutive cases. Am J Obstet Gynecol, 1999; 181:389-396.

  7. Knox TA, Olans LB. Liver disease in pregnancy. N Engl J Med, 1996; 22:569-576.

  8. Monga M, Katz AR. Acute fatty liver in the second trimester. Obstet Gynecol, 1999; 93:811-813.

  9. Minakama H, Oka, N, Sako T, Tamada T, Yasuda T, Hirota N, Preeclampsia: A microvesicular fat disease of the Liver? Am J Obstet Gynecol Jun;40(6):754-60.

  10. Pockros PJ, Peters RL, Reynolds TB. Idiopathic fatty liver of pregnancy: findings in ten cases. Medicine, 1984; 63:1-11.

  11. Rolfes DB, and Ishak KG. Acute Fatty Liver of Pregnancy: A clinicopathologic study of 35 cases. Hepatology, 1985; 5:1149-1158.

  12. Rolfes DB, Ishak KG. Liver disease in pregnancy. Histopathology, 1986 10:555-570.

  13. Sheehan HL. The pathology of hyperemesis and vomiting of late pregnancy. J Obstet Gynacecol, 1940; 46:658-699.

  14. Sibai BM, Taslimi MM, El-Nazer A et al. Maternal-perinatal outcome associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia-eclampsia. Am J Obstet Gynecol, 1986; 155:501-509.

  15. Stone JH. HELLP syndrome: Hemolysis, elevated liver enzymes, and low platelets. JAMA, 1998; 280:559-562.