Critical Care Obstetrics part 40 docx

Acute Renal Failure
379
fl exion and then compresses the bladder [19,20] . Other risk
factors for urinary obstruction in pregnancy include pyelonephri-
tis, renal calculi, ureteral narrowing, and low abdominal wall
compliance [21] .
Renal ultrasound is the fi rst step in the evaluation of possible
urinary tract obstruction, although results may be inconclusive
due to the physiologic dilation of the collecting system often seen
in pregnancy due to both the effects of progesterone and the
mechanical pressure of the gravid uterus. Thus, anterograde or
retrograde pyelography may be necessary for defi nitive diagnosis.
Relief of the obstruction may be accomplished by ureteral stent
placement, percutaneous nephrostomy, manual reduction of an
incarcerated uterus, or amnioreduction in the case of polyhy-
dramnios. If the fetus is signifi cantly premature, correcting
the obstruction should allow for a substantial delay in delivery
as well as recovery of renal function. If the patient is near term,
however, delivery may be indicated to remove both the mechani-
cal and hormonal causes of the obstruction. It should be noted
that the fetal mortality rate for reversible obstructive uropathy
with associated renal failure has been reported to be as high as
33% [22] .
Pyelonephritis
Pyelonephritis is an important cause of ARF during pregnancy.
As a result of the normal physiologic changes that accompany
pregnancy, the urinary collecting system is prone to dilation and
urinary stasis. In addition, there is an increased sensitivity to
bacterial endotoxin - induced tissue damage. These normal
changes result in an increased incidence in both upper and lower
tract infections. The incidence of pyelonephritis in pregnancy is

approximately 2% and it is one of the most common causes of
sepsis during pregnancy [23] . Presenting symptoms generally
include fever, fl ank pain, nausea, vomiting, and possibly urinary
frequency, dysuria, and urgency. The most common causative
organism is E. coli , which accounts for nearly 75% of cases [24] .
Other potential pathogens include Proteus mirabilis , Klebsiella
pneumoniae , group B streptococci, enterococci, and Pseudomonas
aeruginosa . Prompt and appropriate antibiotic treatment is gen-
erally very effective in treating pyelonephritis during pregnancy,
with improvement seen in the fi rst 24 – 48 hours. After resolution
of the initial infection, suppressive antibiotic treatment through-
out pregnancy should be considered as the recurrence rate is as
high as 20%.
Although pyelonephritis rarely results in a signifi cant decline
in renal function in non - pregnant patients, Gilstrap and col-
leagues demonstrated a substantial decrease in creatinine clear-
ance among gravidas with pyelonephritis, with a return to normal
or near - normal renal function in the majority of women re -
evaluated following antibiotic therapy [25,26] . As mentioned
previously, it has been postulated that this decline in renal func-
tion is related to an increased vascular sensitivity to bacterial
endotoxins and vasoactive mediator release in pregnancy [1] . It
ATN may occur in cases of rhabdomyolysis or massive hemolysis.
More commonly in pregnancy, however, ATN is ischemic in
nature, as a result of a hemodynamic insult with hypotension and
impaired renal perfusion. This is commonly due to a hemorrhage
during pregnancy, which may be the result of either placental
abruption or a postpartum hemorrhage which complicates
approximately 1% and 4 – 6% of pregnancies respectively [16] .
In those patients with pre - eclampsia who develop renal failure,

ATN appears to be the underlying renal lesion. Clinically, it may
be diffi cult to distinguish between severe prerenal azotemia and
ATN, although urinary indices and urinalysis may be helpful
(Table 28.2 ). Urinalysis typically reveals muddy brown granular
casts and renal tubular epithelial cells. In light of impaired renal
tubular function, laboratory evaluation reveals a high urinary
sodium excretion as well as urine that is neither concentrated nor
dilute. Acute tubular necrosis may be either oliguric (urine
output < 400 mL/day) or non - oliguric ( > 400 mL/day), depending
on the mechanism of injury and the severity. Treatment of ATN
is supportive and necessitates optimization of hemodynamics,
avoidance of potential nephrotoxin exposure, nutritional support
with careful monitoring of fl uids and electrolytes and, occasion-
ally, dialysis. Renal function typically recovers in 7 – 14 days with
appropriate treatment.
Urinary o bstruction
Although urinary obstruction is a relatively uncommon cause of
ARF in pregnancy, it is readily reversible and, therefore, must be
considered in the differential. Obstruction may occur at any level
of the urinary tract due to a wide variety of causes, many of which
are not unique to pregnancy (Table 28.6 ). Additionally, gravidas
with an abnormally confi gured or overdistended uterus, such as
those with uterine leiomyomata, polyhydramnios, or multiple
gestations, may be particularly susceptible. Ureteral compression
by the gravid uterus, with resultant ARF and hypertension, has
been reported [17] and large leiomyomata have even been
reported to cause ureteral obstruction in the fi rst trimester [18] .
Another cause unique to pregnancy is an incarcerated uterus,
which may cause urinary retention as the gravid uterus enlarges
but becomes trapped in the pelvis secondary to signifi cant retro-

Table 28.6 Causes of urinary obstruction.
Upper tract Lower tract
Stones Stones
Blood clots Blood clots
Tumor Tumor
Sloughed papillae Neuropathic bladder
Ureteral stricture or ligation Urethral stricture
Retroperitoneal fi brosis
Extrinsic compression by tumor, gravid uterus
Chapter 28
380
of underlying chronic renal disease, presumably unmasked by
pregnancy and/or pre - eclampsia [5] .
HELLP s yndrome
HELLP is an acronym used to describe a constellation of fi ndings,
including h emolysis, e levated l iver enzymes, and l ow p latelets.
Nausea, epigastric or right upper quadrant pain, and tenderness
may be present at the time of diagnosis, as well as proteinuria and
renal dysfunction. Coagulation studies including fi brinogen, pro-
thrombin time, and partial thromboplastin time may be useful in
distinguishing this disorder from others associated with dissemi-
nated intravascular coagulation (DIC), in that they are often
normal in patients with HELLP syndrome in the absence of pla-
cental abruption.
HELLP syndrome has been described in 4 – 12% of patients
with severe pre - eclampsia [30] and is considered to represent
a variant of severe pre - eclampsia. However, in a small study
by Krane, in which patients with HELLP syndrome underwent
renal biopsy, less than half had the glomerular endotheliosis
classic for pre - eclampsia [31] . Sibai et al. observed acute renal

failure in 7.4% (32/435) of patients with HELLP syndrome, and
approximately one - third of these patients required hemodialysis
[32] . Evidence of disseminated intravascular coagulation was
present in 84% of these patients, and 44% had abruptio placen-
tae. HELLP syndrome associated with acute renal failure in this
study carried a maternal mortality rate of 13% and perinatal
mortality rate of 34%. The poor prognoses described by Sibai
likely refl ect the severity of disease seen in his patient
population.
Generally, treatment of HELLP syndrome consists of
expeditious delivery once the diagnosis is established, as well as
magnesium sulfate for seizure prophylaxis as discussed earlier,
with rapid recovery of renal function expected. In a group of 23
patients with HELLP syndrome who were normotensive prior to
pregnancy, no residual renal impairment was observed following
delivery. However, 40% of patients with chronic hypertension
and subsequent HELLP syndrome eventually required chronic
dialysis [32,33] .
Acute f atty l iver of p regnancy
Acute fatty liver of pregnancy is another uncommon cause of ARF
in pregnancy, with an incidence reported as between 1 in 6700
and 1 in 13 000 deliveries [34,35] . The disease exhibits a slight
predominance in nulliparas; it has been diagnosed as early as 24
weeks of gestation and as late at 7 days postpartum [4,35] , but
usually occurs in the last few weeks of gestation. Initial manifesta-
tions are non - specifi c, including nausea, vomiting, headache,
malaise, and abdominal pain. Laboratory evaluation reveals mild
elevation of serum transaminase levels, hyperbilirubinemia, and
leukocytosis as well as hypoglycemia. Renal failure develops in
is this sensitivity to endotoxin that may account for the greater

incidence of septic shock and adult respiratory distress syndrome
from pyelonephritis during pregnancy.
Pre - e clampsia
Among those causes of ARF unique to pregnancy, pre - eclampsia/
eclampsia accounts for the majority. One study of ARF in preg-
nancy performed in Uruguay, which included patients from 1976
to 1994, reported that pre - eclampsia was the cause of ARF in
approximately 47% of cases [27] . Another retrospective study
conducted at an inner - city hospital in Georgia described pre -
eclampsia in more than one - third of 21 cases of ARF diagnosed
at their institution from 1986 to 1996 [7] .
Classically, pre - eclampsia is defi ned as the development of
hypertension, proteinuria, and edema after the 20th week of ges-
tation. (It should be noted, however, that severe pre - eclampsia
may occur earlier than 20 weeks in the presence of gestational
trophoblastic disease, also called a molar pregnancy.) Elevated
liver enzymes, coagulation abnormalities, and microangiopathic
hemolytic anemia may be seen in severe pre - eclampsia as well.
The diagnosis is established clinically and rarely confi rmed by
renal biopsy.
Pathologically, pre - eclampsia is characterized by swollen glo-
merular capillary endothelial cells or glomerular endotheliosis,
with resultant capillary obstruction and glomerular ischemia
[28] . Importantly, the extent of the morphologic lesion does
not necessarily correspond to the degree of renal functional
impairment [4] . In addition, the presence of subtle volume
depletion and enhanced sensitivity of the renal vasculature to
vasoconstriction may contribute to superimposed ATN, which
many believe to be the lesion associated with signifi cant ARF in
pre - eclampsia.

Treatment of severe pre - eclampsia and the associated renal
failure ultimately depends on delivery of the infant and seizure
prophylaxis with magnesium sulfate during the delivery and for
at least 24 hours postpartum. This is accomplished regardless of
the gestational age of the fetus, though consultation with a mater-
nal - fetal medicine specialist is recommended with a premature
fetus to determine if it is possible to delay delivery long enough
to administer corticosteroids in an attempt to improve fetal lung
maturity. It is important to monitor fl uid administration closely
while magnesium sulfate is given as patients with impaired renal
function will not clear the medication as well and dose reductions
may be necessary.
Recovery of renal function is usually seen within days to weeks
after delivery with isolated pre - eclampsia, although up to 20%
may have some degree of residual impairment [29] . In contrast,
when patients with chronic hypertension and underlying renal
disease experience ARF in pregnancy, approximately 80% will
require long - term renal replacement therapy [15] . Histologic
evaluation in those patients with persistent renal impairment,
proteinuria, or hypertension postpartum has revealed evidence
Acute Renal Failure
381
those receiving such treatment. Additional therapeutic interven-
tions varied, including aspirin, dipyridamole, and corticosteroids.
Greater than 50% of all patients had evidence of renal dysfunc-
tion, although those with severe ARF or anuria were excluded
from the Canadian multicenter trial.
Delivery in cases of TTP/HUS is not necessarily indicated,
especially at very early gestational ages, which is why care
must be taken to differentiate this disease from severe

pre - eclampsia.
Nine of the 76 women seen at Johns Hopkins presented in their
third trimester of pregnancy, although there was no comment as
to the degree of renal impairment in this subset of patients. A
recent report of three patients with postpartum HUS at the
Rhode Island hospital who were treated with frequent plasma
exchange and prednisone reported survival in all three patients
[41] . Additionally, Hayward and colleagues described nine preg-
nant women presenting between the fi rst trimester of gestation
and 1 month postpartum with TTP - HUS [42] . Of these 21
women from three institutions, all but one survived, and none
required renal replacement therapy. With respect to future preg-
nancies, one recent report cites only an 18% recurrence risk in
subsequent pregnancies in patients with a history of postpartum
TTP/HUS [43] .
Postpartum r enal f ailure
Idiopathic postpartum renal failure, also referred to as postpar-
tum HUS, is a unique cause of pregnancy - associated ARF that
typically develops in the puerperium following an uncomplicated
pregnancy and delivery. Women may present up to several
months following delivery with severe hypertension, microangio-
pathic hemolytic anemia, and oliguric renal failure, often with
congestive heart failure and CNS manifestations. A prodromal
fl u - like illness or initiation of oral contraceptives may be associ-
ated with postpartum renal failure as well as with idiopathic HUS,
suggesting a toxic or hormonal infl uence.
Pathologically, the disease is often indistinguishable from the
thrombotic microangiopathies, idiopathic HUS and TTP, with
arteriolar injury, fi brin deposition, and microvascular (arteriolar
and glomerular capillary) thrombosis. The major pathologic

involvement is renal, as opposed to CNS involvement seen in
TTP. The pathogenesis of the thrombotic microangiopathies
remains unclear, although intravascular coagulation, disordered
platelet aggregation, endothelial damage, and alterations in pros-
taglandins have been suggested [44] . Therapies have been chosen
in an attempt to intervene in one or more of these processes,
including plasma exchange, plasma infusion, antiplatelet agents,
and anticoagulation. In addition, acute and long - term dialytic
support is often necessary, with approximately 12 – 15% of
patients developing end - stage renal disease. The maternal mortal-
ity rate was estimated at between 46% and 55% in the 1980s
[45,46] but appears to be improving with the use of plasma
exchange and other treatments.
the majority of cases and, left untreated, patients may progress to
fulminant hepatic failure with jaundice, encephalopathy, dis-
seminated intravascular coagulopathy, gastrointestinal hemor-
rhage, and death. Maternal and fetal mortality rates as high as
85% were seen in the past, although with earlier diagnosis and
treatment a recent analysis of 28 consecutive cases reported no
maternal deaths [35] .
Diagnosis of fatty liver may be established by liver biopsy
revealing microvesicular fatty infi ltration. Computed tomogra-
phy (CT) may reveal decreased hepatic attenuation. A report by
Usta and colleagues described their experience with 13 patients
(14 cases) of AFLP over an 8 - year period, all of whom had ARF
on presentation [36] . They reported 100% maternal survival,
with 13% perinatal mortality . Although nine of 14 cases were
initially diagnosed as pre - eclampsia, the diagnosis of AFLP was
subsequently confi rmed either by liver biopsy (10/14), CT of the
liver (2/14), or clinically. One patient experienced a recurrence

of AFLP in a subsequent pregnancy. Although CT revealing
hepatic density below the normal range of 50 – 70 Hounsfi eld
units has been reported as suggestive of AFLP, Usta ’ s study dem-
onstrated a high false - negative rate with only two of 10 abnormal
scans, including nine biopsy - proven cases [36] . Contributing to
the diagnostic dilemma in these women is the frequent occur-
rence of hypertension, edema, and proteinuria suggestive of pre -
eclampsia, although renal pathology has failed to reveal evidence
of glomerular endotheliosis. As is the case with severe pre -
eclampsia, expeditious delivery is warranted, with prompt
improvement in both hepatic and renal failure noted in nearly all
cases [34,35] .
Thrombotic t hrombocytopenic
p urpura/ h emolytic u remic s yndrome
Thrombotic thrombocytopenic purpura/hemolytic uremic syn-
drome (TTP/HUS) is an uncommon disorder during pregnancy
with an incidence of approximately 1 in 25 000 births [37] . It is
characterized by the classic pentad of thrombocytopenia, hemo-
lytic anemia, fever, neurologic abnormalities, and some degree of
renal dysfunction. During pregnancy, the disorder tends to
present earlier than pre - eclampsia, with a median gestational age
of onset of 23 weeks [38] . The underlying pathophysiology of the
disorder is apparently due to intravascular thrombi that result in
fragmentation of red blood cells, platelet consumption, and
varying degrees of systemic ischemia.
Although treatment guidelines are not well established, plasma
exchange is recommended due to an apparent benefi t in survival
in a small number of patients. Due to the continuum of disease,
both HUS and TTP have been considered together in most clini-
cal trials. The Canadian Apheresis Study Group and a group at

Johns Hopkins University examined therapeutic outcomes in
TTP and TTP/HUS, respectively [39,40] . Both reported the supe-
riority of plasma exchange therapy in terms of clinical response
and survival, with mortality rates of 22% and 9% respectively, in
Chapter 28
382
tion recovers. Close attention to fl uid balance is critical because
either superimposed volume depletion or fl uid overload may
exacerbate ARF or necessitate earlier dialytic intervention. In
addition, magnesium sulfate administration in cases of pre -
eclampsia may also increase the patient ’ s risk for fl uid overload
or toxicity from the medication and should be monitored closely.
Correction of the metabolic acidosis seen with ARF may require
bicarbonate therapy or dialysis, if it remains refractory to medical
therapy or occurs in the setting of congestive heart failure.
Prevention of hyperphosphatemia includes dietary phosphate
restriction and non - absorbable or calcium - containing phosphate
binders given with meals. Dietary potassium restriction also is
imperative to avoid potentially life - threatening hyperkalemia. A
cation - exchange resin, such as kayexalate, can be used for mild
hyperkalemia or until dialysis is available. For hyperkalemia with
associated electrocardiographic changes, acute therapy includes
intravenous calcium gluconate to stabilize the cardiac membrane,
infusion of glucose and insulin or inhaled β - agonists to
transiently shift potassium intracellularly, and acute dialysis.
Additional conservative measures include avoiding further neph-
rotoxic exposure and hypotension, control of hypertension, and
medication dose adjustment according to the degree of renal
impairment.
In patients with severe metabolic abnormalities that are unre-

sponsive to conservative medical management, volume overload
and pulmonary congestion that cannot be corrected with diuret-
ics, or signs and symptoms of uremia including pericarditis and
encephalopathy, dialysis is indicated.
As discussed previously, if the underlying etiology is deter-
mined to be severe pre - eclampsia, then delivery may be indicated,
even at very early gestational ages as there is no other way to
prevent progression of the disease.
Prognosis
The prognosis for return of renal function depends on multiple
variables, including baseline renal status, duration of renal failure,
Bilateral r enal c ortical n ecrosis
Acute, bilateral renal cortical necrosis is a pathologic entity con-
sisting of partial or complete destruction of the renal cortex, with
sparing of the medulla. While not unique to pregnancy, this rare
and catastrophic form of ARF occurs most commonly in preg-
nancy, with obstetric causes accounting for 50 – 70% of cases [47] .
Although BRCN represents less than 2% of cases of ARF in the
non - pregnant population, it has been reported to account for
10 – 38% of obstetric cases of renal failure, perhaps secondary to
the hypercoagulable state and altered vascular sensitivity of preg-
nancy [31,48] . Patients typically present between 30 and 35 weeks
of gestation in association with profound shock and renal hypo-
perfusion, such as that seen with abruptio placentae, placenta
previa, and other causes of obstetric hemorrhage. Acute BRCN has
also been observed early in pregnancy associated with septic abor-
tion. Abruption placentae, with either overt or concealed hemor-
rhage, appears to be the most common antecedent event [47] .
Patients with BRCN present with severe and prolonged
oliguria or anuria (urine output < 50 mL/day), fl ank pain, gross

hematuria, and urinalysis demonstrating RBC and granular casts.
Diagnosis is established by renal arteriogram demonstrating
virtual absence of cortical blood fl ow (interlobular arteries),
despite patency of the renal arteries. Diagnosis may also be estab-
lished by ultrasonography, contrast - enhanced CT demonstrating
areas of cortical lucency, and MRI [49] . The prognosis for patients
with BRCN is extremely poor, again likely related to the severity
of illness, with one study of 15 cases during pregnancy reporting
a mortality rate of 93% [48] .
Management of a cute r enal f ailure
Management of ARF in pregnancy is similar to that in the non -
pregnant patient, including supportive therapy as well as dialysis.
General principles include treating the underlying cause, preven-
tion of further renal injury, and supportive care until renal func-
Table 28.7 Classifi cation of pregnancy - associated acute renal failure.
Pre - eclampsia HELLP syndrome Acute fatty Postpartum Pyelonephritis Bilateral renal
liver of pregnancy (HUS) renal failure
cortical necrosis
Proteinuria RUQ pain Elevated LFTs Occurring postpartum Positive urine culture Hemorrhage
Hypertension Proteinuria Hyperbilirubinemia MAHA Fever Hypotension/shock
Edema Hemolysis Coagulopathy Oliguria Oliguria/anuria
Elevated LFTs Oliguria Severe HTN Flank pain
Thrombocytopenia Nausea Prodromal illness Gross hematuria
Normal coags Abdominal pain Thrombocytopenia
Leukocytosis CNS involvement
HTN, hypertension; LFTs, liver function tests; MAHA, microangiopathic hemolytic anemia; RUQ, right upper quadrant.
Acute Renal Failure
383
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16 Ovelese Y , Ananth CV . Placental abruption . Obstet Gynecol 2006 ; 108 :
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23 Cunningham FG , Lucas MJ . Urinary tract infections complicating
pregnancy . Bailli è re ’ s Clin Obstet Gynaecol 1994 ; 8 : 353 – 373 .
24 Davison JM , Lindheimer MD . Renal disorders . In: Creasy RK , Resnick
R , eds. Maternal Fetal Medicine , 4th edn . Philadelphia : WB Saunders ,

1999 : 873 – 894 .
25 Whalley PJ , Cunningham FG , Martin FG . Transient renal dysfunction
associated with acute pyelonephritis of pregnancy . Obstet Gynecol
1975 ; 46 : 174 – 177 .
26 Gilstrap LC , Cunningham FG , Whalley PJ . Acute pyelonephritis
during pregnancy: an anterospective study . Obstet Gynecol 1981 ; 57 :
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27 Ventura JE , Villa M , Mizraji R , Ferreiros R . Acute renal failure in
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29 Suzuki S , Gejyo F , Ogino S . Post - partum renal lesions in women
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30 Martin JN , Blake PG , Perry KG , et al. The natural history of HELLP
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31 Krane NK . Acute renal failure in pregnancy . Arch Intern Med 1988 ;
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32 Sibai BM , Ramadan MK . Acute renal failure in pregnancies compli-
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and the etiology of the ARF. For instance, if the patient had
normal renal function before ARF from an acute obstructive
process that is relieved in a timely manner, then a full recovery

should be expected. On the other hand, as previously discussed,
studies have demonstrated that, of patients with compromised
renal function who develop pre - eclampsia with ARF, up to 80%
may require long - term dialysis [15] .
Summary
Evaluation of the pregnant patient with ARF encompasses a
broad range of disorders, some of which are unique to pregnancy.
Prerenal azotemia, intrinsic renal disease, including ATN, GN,
and interstitial nephritis, and urinary obstruction should be con-
sidered based on clinical presentation. Evaluation of ARF during
pregnancy is similar to that in the non - pregnant patient, includ-
ing urinalysis and urinary diagnostic indices, and in some cases,
renal biopsy. In addition, diseases unique to pregnancy and those
more common during pregnancy must be considered, including
pre - eclampsia, HELLP syndrome, AFLP, postpartum renal
failure, and BRCN (Table 28.7 ). Treatment may necessitate
prompt delivery of the infant, even at early gestational ages when
issues of prematurity may exist.
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40 Rock GH , Shumak KH , Buskard NA , et al. Comparison of plasma

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385
Critical Care Obstetrics, 5th edition. Edited by M. Belfort, G. Saade,
M. Foley, J. Phelan and G. Dildy. © 2010 Blackwell Publishing Ltd.
29
Acute Fatty Liver of Pregnancy
T. Flint Porter
Department of Obstetrics and Gynecology, University of Utah Health Science UT, and Maternal - Fetal Medicine, Urban Central
Region, Intermountain Healthcare, Salt Lake City, UT, USA
Introduction
Acute fatty liver of pregnancy (AFLP) is a rare, yet potentially
fatal complication of late pregnancy. Also known as acute fatty
metamorphosis or acute yellow atrophy, the incidence ranges
between 1 in 7000 and 1 in 15 000 depending on the population
studied [1 – 3] . Older published series reported maternal and peri-
natal mortality rates as high as 75 and 85%, respectively [4] .
However, more recent experience suggests that both morbidity
and mortality can be reduced by early recognition and prompt
treatment [1,2,5] .
Epidemiology
The majority of cases of AFLP occur during the third trimester
[1,5,6] , usually between 30 and 38 weeks of gestation [3] ; some
do not become clinically evident until after delivery [7] . Rare
mid - trimester cases have also been reported [8,9] . There are no
clear epidemiologically distinct risk factors for AFLP. Neither
maternal age nor ethnicity appears to affect risk. Most affected

women are in their fi rst pregnancy [7] though AFLP has been
diagnosed in multiparous women with otherwise normal obstet-
ric histories. Recurrence in subsequent pregnancy has also been
reported [10,12] . Additional suggested risk factors include the
presence of a male fetus [13] , and multiple gestation [7,14] .
Pathogenesis
The pathogenesis of AFLP has not been fully elucidated but
abnormalities in mitochondrial fatty acid oxidation likely play an
important role. Fatty acid oxidation (FAO) is the major source
of energy for skeletal and heart muscle, a process that occurs
primarily in the liver during conditions of prolonged fasting,
illness, and increased muscular activity [3] . Hepatic FAO also
plays an essential role in intermediary liver metabolism and syn-
thesizes alternative sources of energy for the brain when blood
glucose levels are low [13] .
Mitochondrial FAO functions via a protein complex known as
mitochondrial trifunction protein (MTP). It is composed of three
enzymes, one of which is long - chain 3 - hydroxyacyl - CoA dehy-
drogenase (LCHAD). Human defects in MTP have emerged as
an important group of metabolic errors because of their serious
clinical implications (Figure 29.1 ). They are recessively inherited
and result in either isolated LCHAD defi ciency or dramatically
reduced functionality of all three of the MTP enzymes. Most
reported cases involve children with isolated LCHAD defi ciency
who present within the fi rst few hours to months of life with
non - ketotic hypoglycemia and hepatic encephalopathy, which
progresses to coma and death if untreated [15,16] . Cardiomyopathy,
slowly progressing peripheral neuropathy, skeletal myopathy, or
sudden, unexpected death are also reported [17,18] .
Schoeman [11] and colleagues were the fi rst group to suggest

an association between recurrent maternal AFLP and a fetal fatty
acid oxidation disorder in two siblings, both whom died at 6
months of age [16] . Other reports of a potential causative rela-
tionship followed [15,19 – 22] . In one series of 12 affected preg-
nancies, several offspring delivered of mothers with AFLP were
diagnosed postnatally with a homozygous form of LCHAD
[19,23] . Parental heterozygosity was subsequently confi rmed.
LCHAD defi ciency was later reported in three families in associa-
tion with pregnancies complicated by AFLP [20] . Ibdah [15]
reported that 80% of mothers who delivered babies with con-
fi rmed MTP defects developed either AFLP or HELLP during
their pregnancy. Three of them had a history of AFLP in a previ-
ous pregnancy. In a subsequent prospective study, the same
group [24,25] found that in approximately 1 in 5 pregnancies
complicated by AFLP, the fetus is LCHAD - defi cient. These fi nd-
ings support the potentially life - saving role of screening for MTP
defects in children born to women with AFLP. Prenatal diagnosis
Chapter 29
386
ops and leads to oliguria and acute tubular necrosis [1] . In turn,
damage to the proximal renal tubules results in decreased sensi-
tivity to vasopressin and transient diabetes insipidus [27,28] .
Laboratory evidence of renal dysfunction is evident early in the
disease with increased serum creatinine levels. Uric acid and
blood urea nitrogen concentrations are also elevated, and with
the onset of jaundice, urobilinogen appears in the urine. Serum
electrolytes may refl ect metabolic acidosis and plasma glucose is
often below 60 mg/dL suggesting reduced hepatic glycogenolysis
[29] . It is not uncommon for mild hypoglycemia to be masked
in subsequent pregnancies has also been performed using chori-

onic villus sampling in an effort to identify at - risk pregnancies
[26] .
Clinical p resentation
The clinical presentation of AFLP is non - specifi c and most com-
monly includes nausea, vomiting, anorexia, tachycardia, and
abdominal pain (Table 29.1 ) [1,3,5,7] . Symptoms may develop
suddenly or over a 2 – 3 week period. Though liver size is usually
normal or small, 50% of women with AFLP are jaundiced and
complain of right upper quadrant or epigastric pain. Fever, head-
ache, and pruritus are not uncommon [1,3] . Symptoms of pre -
eclampsia are present in 50% of women with AFLP including
hypertension, proteinuria, and edema [7] . Some women present
with isolated obstetric complaints including contractions,
decreased fetal movement, and vaginal bleeding [1] .
Systemic complications of AFLP are due to fulminant hepatic
failure and include encephalopathy, acute renal failure, infection,
pancreatitis, gastrointestinal hemorrhage, coagulopathy, and at
least mild hypoglycemia. Neurological dysfunction begins early
and should immediately alert the physician to the possibility of
AFLP. Symptoms may rapidly progress from restlessness, confu-
sion, and disorientation, to asterixis, seizures, psychosis, and ulti-
mately coma [1,3,5] . Other systemic effects include respiratory
failure, sometimes requiring assisted ventilation [5] , ascites
[7] , and gastrointestinal bleeding from gastric ulceration and
Mallory – Weiss syndrome [2,7] .
Renal insuffi ciency associated with AFLP is due to fatty infi ltra-
tion of the kidneys [1] . Hepatorenal syndrome eventually devel-
3-ketoacyl-CoA thiolase
CoA
3-ketoacyl-CoA

Acetyl-CoA Acyl-CoA
2,3-enoyl-CoA
R
3-hydroxyacyl-CoA
dehydrogenase
LCHAD
deficiency
block
Trifunctional
protein defrciency
block
Acyl-CoA dehydrogenase
FAD
FADH
2
3-hydroxyacyl-CoA
Enoyl-CoA hydratase
NADH + H
+
NAD
+
OH
C
O
S CoACCH
2
H
2
O
O

RSCoACCH
3
CH
2
O
RSCoACCHCH
O
C
O
S CoACH
3
RC
O
CoA
S
R CH S CoACCH
2
O
Acyl-CoA
Figure 29.1 The biochemistry of mitochondrial
trifunctional protein (MTP) defi ciencies.
Mitochondrial fatty acid β - oxidation spiral where the
MTP catalyzes long chain fatty acids substrates (see
box). In isolated LCHAD defi ciency, the pathway is
blocked after the enoyl Co - A hydratase reaction and
before the 3 - hydroxyacyl Co - A dehydrogenase
reaction, causing the accumulation of medium - and
long - chain 3 - hydroxy fatty acids and their
metabolites. In complete MTP defi ciency, the
pathway is blocked after the acyl Co - A

dehydrogenase reaction and before the enoyl Co - A
dehydrogenase reaction causing the accumulation of
straight - chain fatty acids and their metabolites.
Adapted from Ibdah JA. Acute fatty liver of
pregnancy: an update on pathogenesis and clinical
implications.
World J Gastroenterol
2006; 12(46):
7397 – 7404 [2] .
Table 29.1 Signs and symptoms of acute fatty liver of pregnancy.

Symptoms

Nausea, vomiting Almost always
Malaise Always
Abdominal pain Almost always, may be variable in position
and severity

Physical signs

Hypertension Almost always
Edema Almost always
Proteinuria Variable
Jaundice Always
Elevated liver transaminases Always
Hypoglycemia Always, may be masked by administration of
glucose - containing intravenous fl uids
Coagulopathy Common
Diabetes insipidus Common
Encephalopathy Common, may correlate with ammonia levels

Acute Fatty Liver of Pregnancy
387
by the administration of dextrose solutions which often routinely
occurs at the time of admission.
Virtually all women with AFLP have laboratory evidence of
coagulopathy and at least 50% require replacement of blood
components [1,2,5,30] . Impaired hepatic synthesis of coagulation
factors leads to prolongation of prothrombin time (PT) and acti-
vated partial thromboplastin time (aPTT). Hypofi brinogenemia,
profound antithrombin III defi ciency, and thrombocytopenia are
common. Factor VIII levels most accurately refl ect the extent of
coagulopathy and their return toward normal signals recovery.
Coagulopathy may worsen in the postpartum period, most likely
secondary to low antithrombin III levels [31] .
Serum transaminase concentrations are typically mildly
increased, usually between 100 and 1000 U/L. Bilirubin levels are
variable but generally exceed 5 mg/dL. Alkaline phosphatase is
elevated but is not helpful in making the diagnosis because of
placental production. Serum albumin is usually low. Ammonia
levels are elevated, due to decreased utilization by urea cycle liver
enzymes and may predict the degree of altered sensorium.
Elevated amylase and lipase should raise suspicions of concomi-
tant pancreatitis [32] . Liver function tests usually return to
normal 4 – 8 weeks after delivery [4] .
The gold standard used for confi rmation of AFLP remains the
liver biopsy. However, it is rarely necessary when other clinical
and laboratory parameters are consistent with the diagnosis.
Microscopic examination of fresh specimens stained with special
fat stains, most commonly oil red, demonstrate hepatocellular
cytoplasm distended by numerous fi ne vacuoles giving the cells a

distinct foamy appearance (Figure 29.2 ). The myriad of tiny
vacuoles are separated from each other by thin eosinophilic cyto-
plasmic strands and do not coalesce to form a single large vacuole.
In contrast to the cytoplasm, the cell nucleus is located centrally
and is normal in size and appearance.
Histologic changes are most prominent in the central portion
of the lobule with a thin rim of normal hepatocytes at the periph-
ery. The lobular architecture is usually preserved and, with rare
exceptions, necrosis and infl ammation are absent [33] . This is
distinct from the periportal fi brin deposition and hemorrhagic
necrosis reported in pre - eclampsia (Figure 29.3 ). Characteristic
histologic changes may be present up to 3 weeks after the onset
of jaundice.
Diagnosis
A high index of suspicion based on clinical presentation corre-
lated with correct interpretation of laboratory testing is usually
suffi cient to make the diagnosis of AFLP [1,7] . Liver biopsy is
usually not necessary or even possible because of coagulopathy.
Most common among the differential diagnoses are pre -
eclampsia/HELLP syndrome, viral hepatitis, and cholestasis
(Table 29.2 ). Women with AFLP or pre - eclampsia/HELLP may
have elevated serum transaminases, thrombocytopenia or coagu-
lation defects. However, liver failure and jaundice are rare in
(a)
(b)
Figure 29.2 (a) Acute fatty liver of pregnancy (H & E stain; magnifi cation 200 × ).
Note diffuse fatty infi ltration and absence of necrosis and infl ammation.
(b) Higher magnifi cation demonstrates the fi ne cytoplasmic vacuoles and
centrally placed nuclei (H & E stain; magnifi cation 1000 × ). (Courtesy of Dr Patricia
Latham, University of Maryland Hospital.)

Figure 29.3 Liver section from a patient who died of complications of
pre - eclampsia (H & E stain; magnifi cation 40 × ). Note extensive hepatocellular
infl ammation and necrosis. (Courtesy of Dr James Kelley, Madigan AMC.)
Chapter 29
388
lutely contraindicated. AFLP should not be considered an
indication for cesarean, even though expeditious delivery is
recommended. Indeed, most hemorrhagic complications in
women with AFLP occur as a result of surgical trauma [1] .
Attempts at induction of labor and vaginal delivery are appropri-
ate as long as adequate maternal supportive care and fetal surveil-
lance are possible. Even so, fetal compromise during labor is
common and cesarean delivery is often necessary [1] . Women
who are critically ill should not be subjected to long arduous
induction of labor. The ultimate decision regarding route of
delivery should be individualized, based on the maternal and fetal
conditions as well as the favorability of the cervical exam.
Anesthetic options in patients with AFLP are limited. General
anesthesia can further damage an already compromised liver and
regional anesthetic poses a risk of hemorrhage when coagulopa-
thy is present. If general anesthesia must be used, inhalation
agents with potential hepatotoxicity (e.g. halothane ) should be
avoided. Isofl urane is a logical choice since it has little or no
hepatotoxicity and may preserve liver blood fl ow [36,37] . Epidural
anesthesia is probably the best option under most circumstances
because it preserves hepatic blood fl ow without hepatotoxic
effects [37,38] . Recognition and treatment of thrombocytopenia
and coagulopathy is essential prior to neuraxial techniques.
Supportive c are
Supportive care of patients with AFLP should include careful

monitoring for evidence of progressive hepatic failure, hypogly-
cemia, and coagulopathy. This should occur in an intensive care
setting and in consultation with physicians well - versed in the care
of critically ill patients. Prevention of worsening hypoglycemia
and reduction of endogenous production of nitrogenous wastes
can be accomplished by providing approximately 2000 – 2500
calories per day, primarily in the form of glucose. Most patients
require solutions containing more than 5% dextrose, sometimes
as high as 25%, administered intravenously or through a naso-
pre - eclampsia/HELLP. Some authorities believe that AFLP and
pre - eclampsia may occur concomitantly [1] . The diagnosis of
viral hepatitis can be established quickly and with reasonable
certainty via specifi c serologic testing. In addition, serum trans-
aminase levels in women with hepatitis are usually elevated well
beyond those typically seen in AFLP. Women with cholestasis of
pregnancy are usually not as ill - appearing as those with AFLP,
pre - eclampsia, or viral hepatitis. While liver function tests are
abnormal in cholestasis of pregnancy, concentrations of bilirubin
and transaminase are usually much lower compared to those of
AFLP or viral hepatitis and signs and symptoms typical of pre -
eclampsia are rarely present.
Ultrasonography, CT, and MRI are often performed as part of
the diagnostic work - up for jaundice during pregnancy. Ultrasound
demonstrates echogenicities within the liver of women with AFLP
[7] . While non - specifi c, ultrasound may also identify subcapsular
hematoma, cholecystitis, and/or cholangitis. Both CT and MRI
may suggest AFLP based on lower density that occurs with fatty
infi ltration of the liver [34,35] . However, both have high false -
negative rates that limit their usefulness [30] . In clinical practice,
imaging studies are complementary but not necessary to make

the diagnosis of AFLP and their performance should not delay
appropriate treatment. Moreover, a normal study does not
exclude AFLP.
Treatment
Women suspected of having AFLP should be hospitalized in an
intensive care setting where comprehensive supportive care can
be given and preparations for delivery can be made. All published
series have reported improved maternal and perinatal outcome
when prompt delivery is accomplished [1,3 – 5,7] . Most women
begin to show clinical improvement and resolution of laboratory
abnormalities by the second day postpartum [5] . There are no
reported cases of AFLP resolving prior to delivery; Therefore,
once the diagnosis is established, expectant management is abso-
Table 29.2 Differential diagnosis of acute fatty liver of pregnancy.
Acute fatty liver of
pregnancy
Acute hepatitis Cholestasis of pregnancy Severe pre - eclampsia
Trimester Third Variable Third Third
Clinical manifestations Nausea, vomiting, malaise,
encephalopathy, abdominal
pain, coagulopathy
Malaise, nausea, vomiting, jaundice,
anorexia, encephalopathy
Pruritus, jaundice Hypertension, edema, proteinuria,
oliguria, CNS hyperexcitability
Bilirubin Elevated Elevated Elevated Normal or minimally elevated
Transaminases Minimally elevated Markedly elevated Minimally elevated Normal or minimal to moderate
increase
Alkaline phosphatase Usually normal for pregnancy Minimally elevated Moderately elevated Normal for pregnancy
Histology Fatty infi ltration, no infl ammation

or necrosis
Marked infl ammation and necrosis Biliary stasis, no infl ammation Infl ammation, necrosis, fi brin
deposition
Recurrence Reported No Yes Yes