CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2020; 80(05): 499-507
DOI: 10.1055/a-1091-8630
GebFra Science
Review/Übersicht
Georg Thieme Verlag KG Stuttgart · New York

HELLP Syndrome or Acute Fatty Liver of Pregnancy: A Differential Diagnostic Challenge

Common Features and DifferencesArticle in several languages: English | deutsch
Werner Rath
1  Medizinische Fakultät, Gynäkologie und Geburtshilfe, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany
,
Panagiotis Tsikouras
2  Democritus University of Thrace, Department of Obstetrics and Gynecology, Alexandroupolis, Greece
,
Patrick Stelzl
3  Frauenklinik, Universitätsklinikum Erlangen, Erlangen, Germany
› Author Affiliations
Further Information

Correspondence/Korrespondenzadresse

Univ.-Prof. Dr. med. Dr. h. c. Werner Rath
Medizinische Fakultät Gynäkologie und Geburtshilfe
Universitätsklinikum Schleswig-Holstein, Campus Kiel
Arnold-Heller Straße 3
24105 Kiel
Germany   

Publication History

received 06 November 2019
revised 15 December 2019

accepted 08 January 2020

Publication Date:
18 May 2020 (online)

 

Abstract

HELLP syndrome and the less common acute fatty liver of pregnancy (AFL) are unpredictable, life-threatening complications of pregnancy. The similarities in their clinical and laboratory presentations are often challenging for the obstetrician when making a differential diagnosis. Both diseases are characterised by microvesicular steatosis of varying degrees of severity. A specific risk profile does not exist for either of the entities. Genetic defects in mitochondrial fatty acid oxidation and multiple pregnancy are considered to be common predisposing factors. The diagnosis of AFL is based on a combination of clinical symptoms and laboratory findings. The Swansea criteria have been proposed as a diagnostic tool for orientation. HELLP syndrome is a laboratory diagnosis based on the triad of haemolysis, elevated aminotransferase levels and a platelet count < 100 G/l. Generalised malaise, nausea, vomiting and abdominal pain are common symptoms of both diseases, making early diagnosis difficult. Clinical differences include a lack of polydipsia/polyuria in HELLP syndrome, while jaundice is more common and more pronounced in AFL, there is a lower incidence of hypertension and proteinuria, and patients with AFL may develop encephalopathy with rapid progression to acute liver failure. In contrast, neurological symptoms such as severe headache and visual disturbances are more prominent in patients with HELLP syndrome. In terms of laboratory findings, AFL can be differentiated from HELLP syndrome by the presence of leucocytosis, hypoglycaemia, more pronounced hyperbilirubinemia, an initial lack of haemolysis and thrombocytopenia < 100 G/l, as well as lower antithrombin levels < 65% and prolonged prothrombin times. While HELLP syndrome has a fluctuating clinical course with rapid exacerbation within hours or transient remissions, AFL rapidly progresses to acute liver failure if the infant is not delivered immediately. The only causal treatment for both diseases is immediate delivery. Expectant management between 24 + 0 and 33 + 6 weeks of gestation is recommended for HELLP syndrome, but only in cases where the mother can be stabilised and there is no evidence of foetal compromise. The maternal mortality rate for HELLP syndrome in developed countries is approximately 1%, while the rate for AFL is 1.8 – 18%. Perinatal mortality rates are 7 – 20% and 15 – 20%, respectively. While data on the long-term impact of AFL on the health of mother and child is still insufficient, HELLP syndrome is associated with an increased risk of developing cardiovascular, metabolic and neurological diseases in later life.


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Introduction

Pregnancy-specific liver disorders include intrahepatic cholestasis of pregnancy (ICP), HELLP syndrome and acute fatty liver of pregnancy (AFL). ICP is the most common, with a geographically-dependent prevalence of between 0.3 and 5.6% [1], followed by HELLP syndrome with a prevalence of 0.5 – 0.9% [2] and AFL with a prevalence of 0.005 – 0.01% [3].

ICP is defined as a reversible form of reduced bile secretion with cholestasis. HELLP syndrome is considered a severe manifestation of pre-eclampsia (not a disease in its own right) and presents with a typical triad of laboratory findings consisting of haemolysis, pathologically elevated aminotransferases and a platelet count of < 100 G/l [4]. As hypertension and proteinuria are not present in up to 15% of cases with HELLP syndrome [5], the AWMF guideline 015/018 published in 2019 [6] defines HELLP syndrome as a constellation of laboratory findings typically occurring in pregnancy, often associated with pre-eclampsia. AFL is characterised by acute liver disfunction with progression to fulminant liver failure caused by pronounced, centrilobular, microvesicular steatosis [7].

As its main symptoms are excruciating pruritus (typically worst in the palms and soles) in the late 2nd and the 3rd trimester of pregnancy and elevated bile acid levels (≥ 11 µmol/l), it is usually easy to distinguish ICP from HELLP syndrome and AFL. However, the similarities in clinical and laboratory findings between HELLP syndrome and AFL can pose a significant challenge when making a differential diagnosis and may lead to delays in obtaining the correct diagnosis. As both diseases are acute, life-threatening complications of pregnancy, rapid diagnosis followed by immediate treatment is of decisive prognostic importance. The common features and differences in these two entities are therefore described below.


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Predisposing Factors

There is no specific risk profile for either of the two diseases. It is still unknown whether pre-existing liver disease increases the risk [5], [8].

HELLP syndrome in a previous pregnancy is considered a predisposing factor for the occurrence of HELLP syndrome in a subsequent pregnancy [2], this does not apply to AFL (individual cases, [9]).

According to epidemiological studies [10], nulliparity is a predisposing factor for AFL; in hypertensive diseases of pregnancy, nulliparity is a predisposing factor for pre-eclampsia but not for HELLP syndrome [11].

Multiple pregnancy is significantly more common in both disorders compared to uncomplicated singleton pregnancies: prevalence of HELLP syndrome: 0.2% of singleton pregnancies, 0.9 – 1.4% of twin pregnancies, 2.1 – 10.5% with triplets; percentage of all HELLP syndromes: 10.3 – 15.5% (overview in [7]). The prevalence of twin pregnancies in cases with AFL is 7.1 – 28.6%, which is also significantly higher [7], [10], [12].

Male foetal gender, confirmed in 70% of cases, is a predisposing factor for AFL [12].

Being underweight (BMI < 20) is considered a predisposing factor for AFL (increasing the risk 1.4-fold, [10], [12]), while obesity (BMI ≥ 30) tends to be a predisposing factor for pre-eclampsia/HELLP syndrome.

In 20 – 40% of cases with AFL, patients have concomitant pre-eclampsia, and in up to 20% of cases patients have concomitant HELLP syndrome [13], [14].

Autosomal recessive disorders of mitochondrial fatty acid beta-oxidation affecting the mother and the child may be important in this context, particularly deficiencies in mitochondrial trifunctional protein (MTP) and its alpha subunit long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD, overview in [15]). Foetal LCHAD deficiency was confirmed in around 20% of cases with AFL [10], most commonly the mutation 1528 G → C in exon 15 [16]. LCHAD catalyses the penultimate step in the mitochondrial beta-oxidation of long-chain fatty acids. Decreased maternal and placental fatty acid catabolism leads to an accumulation of 3-hydroxy fatty acid intermediates in the maternal circulation, leading to hepatotoxicity; 50 – 70% of mothers with LCHAD-deficient foetuses develop a maternal liver disorder including AFL [17]. Infants with homozygous LCHAD deficiency have a 38% mortality rate within 3 months of the diagnosis due to severe hypoglycaemia and liver failure [18]. Testing for LCHAD deficiency is part of neonatal screening in Germany.

But there is also an association with pre-eclampsia and HELLP syndrome. Heterozygous mothers of LCHAD-deficient infants have a 77% risk of developing AFL or HELLP syndrome [19].


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Clinical Symptoms, Complications and Course

Both disorders predominantly present between the 28th–36th week of gestation (median time of presentation for HELLP syndrome is week 34 of gestation; [5], median time of presentation for AFL is week 36 of gestation [10], [12]), rarely before week 22. In 7 – 30% of cases, HELLP syndrome occurs up to 48 (72) hours post partum [20]. In the largest prospective study to date, the diagnosis of AFL was made postnatally in 15 out of 57 cases [10].

HELLP syndrome is characterised by a classic triad of laboratory findings, consisting of haemolysis, elevated aminotransferase levels and thrombocytopenia < 100 G/l; this is considered diagnostic proof of disease. Currently, a diagnosis of AFL is made based on clinical symptoms and laboratory findings (previously: liver biopsy). The Swansea criteria provide a diagnostic orientation [21] and are summarised in [Table 1]. After excluding other liver function disorders (particularly HELLP syndrome), at least 6 of the criteria must be present. In a study of 24 patients, the sensitivity of this method was reported to be 100%, the specificity was 57%, the positive predictive value was 85% and the negative predictive value was 100% [22]. However, the Swansea criteria are still a matter of controversial debate [10], [12], [15]. Firm evidence that taking these criteria into account will result in earlier diagnoses of AFL is still lacking [15]; around 40% of pregnant women with AFL (later confirmed by liver biopsy) in accordance with the Swansea criteria also met the criteria for HELLP syndrome [22].

Table 1 Swansea criteria for the diagnosis of acute fatty liver of pregnancy [21].

Clinical symptoms

1. Nausea, vomiting

2. Abdominal pain

3. Polydipsia/polyuria

4. Encephalopathy

Diagnosis of exclusion (e.g. HELLP syndrome):

At least 6 criteria must be present!

Ultrasound

5. Ascites or “bright” liver

Laboratory findings

6. Serum creatinine ↑ (> 150 µmol/l)

7. Leucocytosis > 11 000/µl

8. Aminotransferases ↑ (> 42 U/l)

9. Bilirubin ↑ (> 14 µmol/l)

10. Hypoglycaemia (< 4 mmol/l)

11. Uric acid ↑ (> 340 µmol/l)

12. Ammonia ↑ (> 47 µmol/l)

13. Coagulopathy (PT > 14 s or aPTT > 34 s)

14. Liver biopsy: microvesicular steatosis

The common clinical symptoms at the beginning of both disorders such as general malaise, nausea, vomiting, and abdominal pain are rather unspecific. In HELLP syndrome, upper abdominal pain/epigastric pain is considered clinically indicative, while in AFL abdominal pain is not unambiguously localised ([Table 2]). Polydipsia/polyuria is not present in HELLP syndrome; depending on the severity of HELLP syndrome, oliguria is more likely to be a presenting symptom as a sign of renal dysfunction. Hypertension and proteinuria are less common in AFL, occurring in 20 – 40% of cases with AFL, compared to a prevalence of 85% in patients with HELLP syndrome (overview in [7]), although 12 – 18% of cases with HELLP syndrome do not have hypertension, 14% do not have proteinuria, and neither hypertension nor proteinuria was found in up to 15% of these women [2], [5].

Table 2 Comparison of the prevalence of clinical symptoms and complications in acute fatty liver of pregnancy and HELLP syndrome (ranges obtained from individual studies: data from [7] and [23]).

Criteria

Acute fatty liver of pregnancy

HELLP syndrome

DIC: disseminated intravascular coagulation

General malaise

78%

100%

Nausea/vomiting

50 – 82%

29 – 84%

Abdominal pain

32 – 70%

40 – 90%

Polydipsia/polyuria

11 – 82%

Jaundice/dark urine

29 – 100%

5%

Encephalopathy

9 – 91%

neurolog. symptoms: 33 – 61% e.g. headache

Hypertension/proteinuria

20 – 40%

85%

Acute kidney failure

14 – 90%

1.2 – 8%

Coagulopathy

36 – 87% (DIC: 10 – 48%)

DIC 21% (2 – 39%)

Lung oedema

5 – 30%

6 – 8%

Gastrointestinal bleeding

5 – 36%

rare

Liver haematoma

individual cases

0.9 – 1.6 – (2)%

The presentation of encephalopathy caused by elevated ammonia levels in the blood ranges from initial sleep disturbances/slight confusion to strong disorientation, flapping tremor and comatose state. In contrast, neurological symptoms such as strong headache (33 – 61%) and visual disturbances (10 – 20% of cases) predominate in HELLP syndrome [5], [23].

With an incidence of 27 – 38,6% [10], [12], ascites is more common in AFL than in HELLP syndrome where the reported incidence ranges from 4 – 11% [2]; subcapsular liver haematoma is more common in HELLP syndrome (0.9 – 1.6%) than AFL (individual cases). Liver rupture occurs in around 1% of cases with HELLP syndrome [20], while it has only been reported in individual cases with AFL [24], [25].

In the study by Chen et al. [12] the rate of acute pancreatitis, which is associated with an unfavourable prognosis, was 13.6% in patients with AFL, while the rate of acute pancreatitis in severe pre-eclampsia/HELLP syndrome reported in the observational study by Sang et al. [26] was 1.2%.

Gastrointestinal bleeding is more common in patients with AFL ([Table 2]); it only occurs in individual cases with HELLP syndrome as an initial manifestation of the disease caused by pronounced coagulopathy [27].

The incidence of lung oedema varies depending on the respective disease ([Table 2]). Coagulopathy (prolonged prothrombin time and aPTT) is present in up to 87% of cases with AFL [10]. With progressive liver failure, coagulopathy in women with AFL is a consequence of reduced synthesis of coagulation factors produced in the liver. Manifest coagulopathy with disseminated intravascular coagulation (Quick, PT, aPTT) in patients with HELLP syndrome is rare and is the result of pronounced DIC/disseminated intravascular coagulation in patients with severe disease progression. Thrombocytopenia caused by the sequestration of platelets in the peripheral circulation due to microangiopathy is always present.


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Laboratory Investigations and Diagnostic Procedures

HELLP syndrome is a microangiopathic haemolytic anaemia. Haemolysis accompanied by decreased haptoglobin levels is found in 95 – 97% of cases, increased total bilirubin levels in 47 – 62% and fragmented erythrocytes in peripheral blood smear in 54 – 88% of patients [2], [5], [23]. Despite the presence of anaemia, haemoglobin levels may still be within normal ranges due to haemoconcentration (reduced plasma volume).

Signs of haemolysis are rare in manifestations of AFL and usually only occur in the context of multi-organ failure.

Hyperbilirubinemia is more common and more pronounced with AFL (elevated direct conjugated bilirubin levels due to intrahepatic cholestasis) than in HELLP syndrome where indirect, unconjugated bilirubin levels are elevated due to haemolysis (overview in [28]).

Although determining the haptoglobin levels (acute-phase protein synthesised in the liver) might be useful for diagnostic differentiation of the two entities, there exist currently no studies on haptoglobin levels in AFL.

Aminotransferase levels are elevated in both disorders, although this increase is usually more pronounced in AFL than in HELLP syndrome.

Hypoglycaemia and leucocytosis are typical signs of AFL which do not occur with HELLP syndrome.

Thrombocytopenia < 100 G/l is a necessary criterion of HELLP syndrome; it is usually not detected as a manifestation of AFL but develops as a secondary symptom in the context of DIC. In non-bleeding pregnant women, a lack of thrombocytopenia combined with reduced antithrombin < 65% indicates AFL; the reduction in antithrombin levels is significantly less pronounced in HELLP syndrome [7].

Increased serum creatinine is more common and more pronounced in AFL than in HELLP syndrome.

Prolonged clotting times (INR, PT, aPTT) occur significantly more often in AFL than in HELLP syndrome (see above). Increased ammonia levels and elevated lactic and amino acid levels in blood indicating mitochondrial damage are typical for AFL [29].

Liver ultrasound should be a standard procedure in patients with HELLP syndrome to exclude subcapsular liver haematoma/liver rupture. In patients with AFL, changes found on ultrasound such as brightness or fatty infiltrations of the liver are unspecific and do not point at a specific diagnosis (overview in [15]).

Liver biopsy: Formerly the gold standard for the diagnosis of AFL, it is now only carried out in unclear cases where the clinical and laboratory findings do not permit diagnosis [15], [30]. As there is a significant risk of bleeding in cases with coagulopathy, biopsies in such cases should not be carried out percutaneously but should use a transjugular approach [15]. Liver biopsy is not indicated in HELLP syndrome. Microvesicular steatosis is a morphological sign in both AFL and HELLP syndrome [31], [32], although in contrast to AFL, fibrin deposition in the liver sinusoids is found in HELLP syndrome [33].

Overall, the morphological findings of a liver biopsy are inappropriate for obtaining a differential diagnosis [7], [15].


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Course of Disease

In up to 46% of cases, HELLP syndrome manifests as episodic exacerbations and transient remissions [34], but the syndrome can become acute within hours, with a risk of life-threatening complications and the development of DIC [5].

To date, there are no reports of spontaneous remission of AFL prior to delivery of the infant [35]. The characteristic course is a progressive course to acute liver failure within 1 (2) weeks, which is characterised by increasing jaundice (this only occurs in 5% of cases with HELLP syndrome), hypoglycaemia, development of coagulopathy, ascites/pleural effusions, encephalopathy and acute kidney failure in up to 90% of affected women (up to 8% of patients with HELLP syndrome) ([Table 2]). In a recent study by Chen et al. (n = 44), the incidence of multi-organ failure in AFL was 38.6%; the reason cited was the delay in referring these pregnant women to a perinatal centre [12]. The latency period between making the diagnosis and delivery of the infant also has an impact on prognosis of women with acute HELLP syndrome [5], [36].

After the birth, clinical and laboratory findings usually return to normal ranges within 7 – 10 days in both diseases [5], [15]. However, in patients with AFL there is a significant negative correlation between hyperbilirubinemia, reduced total protein, thrombocytopenia and prolonged thrombin time [12], [37]. In patients with HELLP syndrome, no platelet increase within 98 hours is considered to indicate severe disease with a risk of multi-organ failure [38].


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Therapeutic Approach

As AFL und HELLP syndrome are incalculable life-threatening complications, patients should be treated in a perinatal centre with a neonatal intensive care unit.

Terminating the pregnancy is considered the only “causal” therapy for both disorders. With AFL, there is no spontaneous remission of disease prior to termination of the pregnancy [35]. In patients with HELLP syndrome, acute exacerbation or recurrent relapses without a definitive “cure” can also make it necessary to terminate the pregnancy. Given the course of AFL and its progression to acute liver failure irrespective of gestational age, rapid delivery is required [39]. The Italian Association for the Study of the Liver (AISF) supports terminating the pregnancy at the latest within one week from the manifestation of symptoms [3]. For patients with HELLP syndrome, conservative management in a perinatal centre is possible between GW 24 + 0 and GW 33 + 6 if the mother is stable and the foetus is not compromised [6]. It is important to monitor mother and foetus for any criteria requiring immediate termination of the pregnancy for foetal (e.g. pathological CTG/Doppler findings) or maternal indications (such as increasing renal failure, acute lung oedema, signs of DIC, placental abruption, persistent severe abdominal pain, sudden CNS symptoms or eclamptic seizure) [6]. After 34 + 0 weeks of gestation, immediate delivery is recommended for patients with HELLP syndrome [6].

For both entities, initial treatment consists of stabilising the mother: in patients with AFL this will include supportive measures such as increasing the fluid intake and correction of metabolic acidosis, electrolyte imbalance, hypoglycaemia and coagulopathy [35]; in patients with HELLP syndrome stabilisation includes the administration of antihypertensive drugs and anticonvulsant prophylaxis/treatment with magnesium sulphate; the administration of glucocorticoids for antenatal lung maturation before < 34 + 0 weeks of gestation is mandatory [6].

Plasmapheresis after the birth has been successfully carried out in individual cases with severe course of disease/life-threatening complications [40], [41], [42]. According to a meta-analysis by Wang et al. [43], delivery by Caesarean section significantly decreased maternal mortality in cases with AFL compared to vaginal delivery/induced labour, reducing maternal mortality by 44% (RR 0.56; 95% CI: 0.41 – 0.76) and also reducing perinatal mortality (RR 0.52; 95% CI: 0.38 – 0.71). Patients with acute HELLP syndrome, particularly cases with an unripe cervix remote from term, should be delivered by Caesarean section [5].

Liver transplantation may be a last resort for individual patients with AFL, particularly if their liver function continues to deteriorate, or for patients with encephalopathy and elevated lactic acid levels, concomitant sepsis or hypoxic/ischaemic liver damage [13]. For patients with HELLP syndrome, liver rupture with extensive organ damage may be an indication for liver transplantation [44].


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Prognosis

While in the 1980s, maternal mortality for AFL was still around 85%, advances in intensive care over the last 20 years, early diagnosis due to increased awareness of the disorders, and immediate delivery has reduced this rate since the beginning of the millennium to 10 – 15% [10], [45]. In the largest epidemiological study (n = 57), maternal mortality was only 1.8% [10], although the rate reported in another large study from China (n = 44) was 18.2%. This comparatively high rate of maternal mortality was predominantly caused by delays in referring the pregnant woman to a perinatal centre [12]. Causes of death from AFL are the consequences of liver/multi-organ failure. Maternal mortality rates from HELLP syndrome are currently around 1% in developed countries but can be as high as 30% in developing countries [23]. The leading cause of maternal death from HELLP syndrome is intracerebral haemorrhage in 26 – 64% of cases; DIC/multi-organ failure, hepatic bleeding or acute kidney failure are less common causes (overview in [46]).

Perinatal mortality from AFL ranges from 9 – 23% [3], [15] and from 7 – 20% in patients with HELLP syndrome [23].

The average risk of recurrence in a subsequent pregnancy is 7% (4 – 19%, [47]) for HELLP syndrome and 12.8% according to a Germanwide study [48]. Recurrence of AFL in subsequent pregnancies has only been reported in individual cases [10]; however, the risk of recurrence is significantly higher in cases with genetic defects of fatty acid oxidation and can be up to 25% [3], [49].

The risk of complications in later life for women with AFL has not been sufficiently investigated to date [15]. Follow-up studies up to an average of 54 months after the event (n = 25) found no significant adverse maternal outcomes [50]. In contrast, women with preeclampsia/HELLP syndrome are at increased risk of cardiovascular and metabolic diseases and neurological disorders in later life [51], [52].


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Discussion

Because of the similarities in terms of clinical findings and lab test results, HELLP syndrome and acute fatty liver of pregnancy are a differential diagnostic challenge for obstetricians [7].

Based on an AFL incidence of 1 : 15 000 pregnancies, HELLP syndrome is 72 times more common In Caucasian populations than AFL [14].

Varying degrees of microvesicular steatosis are a common morphological feature of both diseases [7].

There is no specific risk profile for both entities. With regard to HELLP syndrome, it is worth bearing in mind that the average risk of recurrence in a subsequent pregnancy is 7% (4 – 19%) [47], while the risk of recurrence of AFL is only increased if there are genetic defects of fatty acid oxidation [49].

The prevalence of multiple pregnancies is significantly higher in HELLP syndrome and AFL compared to uncomplicated singleton pregnancies; for AFL the increased risk with multiple pregnancy is ascribed to increased foetal production of fatty acid metabolites which have a hepatotoxic effect [53]; with regard to HELLP syndrome, the increased risk is due to inadequate adaptation of the maternal circulation in placental ischaemia and its complications.

Pregnant women whose foetuses have mitochondrial fatty acid oxidation defects (e.g. LCHAD deficiency) have a significantly higher risk of liver function disorders (overview in [15]). According to studies by Jebbink et al. [19], heterozygous mothers of LCHAD-deficient foetuses have a 77% risk of developing AFL or HELLP syndrome.

The carrier incidence for LCHAD deficiency in the USA is 1 : 675 [54].

A detailed overview of this topic is given in the review by Liu et al. 2017 [15].

Differences between HELLP syndrome and AFL with regard to clinical and laboratory findings as well as the course of disease can be explained by the different pathogenesis of the two diseases. Generalised endothelial dysfunction with vasoconstriction/vasospasms, disturbances of microcirculation and activation of intravascular clotting which occurs with HELLP syndrome lead to microangiopathic haemolytic anaemia with haemolysis and pronounced thrombocytopenia as a consequence of microthrombosis of liver arterioles leading to liver cell necrosis, and elevated aminotransferase levels.

In contrast, dysfunction in AFL is initially limited to the liver and is caused by pronounced microvesicular steatosis; as the liverʼs metabolic capacity progressively decreases, this has a systemic effect (e.g. encephalopathy), potentially leading to multi-organ failure.

The problem is to detect either of the two diseases at an early stage as, initially, patients with HELLP syndrome or AFL present with unspecific symptoms such as general malaise, nausea, vomiting and abdominal pain.

An appropriate action algorithm outlining the procedure which should be followed in cases with suspicion of either of the disorders is shown in [Fig. 1].

Zoom Image
Fig. 1 Action algorithm for women with suspected AFL/HELLP syndrome.

Whether and to what extent the Swansea criteria are useful for diagnosing AFL is still a matter of debate [15]. In their study of 24 pregnant women with AFL, Goel et al. [22] found that the Swansea criteria had high positive and negative predictive values (85 and 100%, respectively). Their findings were confirmed by Knight et al. [10], who reported that the Swansea criteria had a high diagnostic reliability (90%). After critically evaluating this study, Minakami et al. [7] concluded that the Swansea criteria are only suitable to diagnose AFL in critically ill pregnant women. Other problems associated with the Swansea criteria are their lack of standardisation [15] and their use to differentiate AFL from HELLP syndrome which should, in fact, be excluded prior to applying the criteria [21] but occurs concomitantly with AFL in up to 20% of cases [13], [14]. In one study, 8 out of 20 patients with AFL (subsequently confirmed by liver biopsy) who met the Swansea criteria also met the criteria for HELLP syndrome [22]. A closer look at the 14 Swansea criteria shows that up to 8 of these criteria (nausea/vomiting, abdominal pain, ascites, elevated creatinine, aminotransferase, bilirubin and uric acid levels as well as microvesicular steatosis on liver biopsy) can also apply to HELLP syndrome.

Differences in clinical presentation between the two entities include the absence of polydipsia/polyuria in HELLP syndrome. Jaundice is more common and more pronounced in AFL while the incidence of hypertension/proteinuria is lower. With increasing liver failure, patients with AFL may also develop encephalopathy. In contrast, the most prominent symptoms of HELLP syndrome are neurological symptoms such as severe headache and/or visual disturbances. Potential organ complications (e.g. acute renal failure, lung oedema) are similar for both diseases, although they occur more commonly with AFL than with HELLP syndrome (cf. [Table 2]).

The diagnosis of HELLP syndrome is based on laboratory findings, while the diagnosis of AFL is based on a combination of clinical symptoms and laboratory findings. The differences with regard to clinical and laboratory findings and the differentiation between these entities and other liver diseases are shown in [Table 3].

Table 3 Differential diagnosis for HELLP syndrome – liver disorders in pregnancy (data from [23], [27], [46]).

Criteria

HELLP syndrome

Acute fatty liver of pregnancy

Hepatitis

Intrahepatic pregnancy cholestasis

pp.: post partum

+/−: occasionally (0 – 20%)

+: moderately often/often (> 20 – 50%)

++: often (> 50 – 80%)

+++: very often/constantly (> 80 – 100%)

Peak manifestation

3rd trimester/pp.

3rd trimester/pp.

at any time

> 60% in 3rd trimester

Haemolysis

+++

+/−

Aminotransferases ↑

+++

+++

+++

+(+)

Hypertension

++

+

Proteinuria

++(+)

+

Leucocytosis

+++

+(+)

Thrombocytopenia

+++

+ → ++ secondary

Neurological symptoms

+ → +++

++

Renal insufficiency

+

++ secondary

Jaundice

+/−

++

++

+(+)

Other

DIC

liver haematoma/
liver rupture

hypoglycaemia

encephalopathy

coagulopathy → bleeding

Swansea criteria

serology

pruritus

bile acid in blood ↑

Laboratory findings are the most effective way of differentiating AFL from HELLP syndrome, with AFL characterised by leucocytosis, hypoglycaemia, a less common incidence of proteinuria, elevated direct bilirubin levels indicating intrahepatic cholestasis (HELLP syndrome: elevation of indirect bilirubin levels as a consequence of haemolysis), an initial absence of haemolysis, thrombocytopenia < 100 G/l, decreased antithrombin by < 65% and prolonged prothrombin times [15], [27], [28], [35]. In addition, a pathologically elevated sFlT-1/PIGF ratio may facilitate the differentiation between HELLP syndrome and AFL. Coagulopathy with prolongation of clotting times (prothrombin time, aPTT) due to reduced liver synthesis of clotting factors is more common with AFL [7] but occurs less common with HELLP syndrome where it is caused by DIC as a consequence of severe disease progression [5], [55].

While HELLP syndrome takes a fluctuating course with transient remissions or acute exacerbation of disease within a few hours, AFL will progress to acute liver failure if the pregnancy is not terminated [5], [35]. The postoperative course is similar for both diseases, and normalisation of clinical and laboratory findings usually occurs within 1 – 2 weeks.

Early termination of the pregnancy is the only causal therapy for both entities [15], [27], [35]. Immediate delivery irrespective of the week of gestation is mandatory for AFL. In contrast, conservative management is recommended for HELLP syndrome [6] between 24 + 0 and 33 + 6 weeks of gestation, as long as the mother can be stabilised with antihypertensive and anticonvulsive medication and there are no signs of foetal compromise. The recommendations of AWMF guideline 015/018 [6] on terminating pregnancy for fetal and/or maternal indications should be followed.

The latency period between making the diagnosis and delivery has a significant impact on prognosis for AFL and acute HELLP syndrome [5], [12]. The advances in intensive care and the more rapid time to establish diagnosis followed by immediate delivery has significantly reduced maternal mortality rates for both entities in the last 20 – 30 years [2], [15], with the maternal mortality rate for AFL decreasing to 1.8 – 18% [10], [12] and the mortality rate for HELLP syndrome dropping to around 1% in developed countries [23].

Perinatal mortality rates for HELLP syndrome are 7 – 20% [23] and 9 – 23% for AFL [3].

The long-term effects of AFL on the later life of mother and child have not yet been sufficiently studied [15], [56]. It is known that HELLP syndrome is associated with an increased risk of cardiovascular disease/stroke for mother and child in later life [52].


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Conclusion

HELLP syndrome and AFL are acute life-threatening complications of pregnancy. Similarities in their clinical and laboratory findings may lead to significant problems in differential diagnosis. Obstetricians must therefore be aware of the important differences between both diseases. Early diagnosis and immediate delivery have a significant impact on prognosis for both AFL and acute HELLP syndrome.

Important topics for future studies should include further investigations on predisposing factors (e.g. genetics, concomitant diseases, environmental factors), the development of predictive models to determine the course and progression of disease and, for AFL, studies on the long-term impact of the disorder on mother and child.


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Conflict of Interest/Interessenkonflikt

The authors declare that they have no conflict of interest./Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.


Correspondence/Korrespondenzadresse

Univ.-Prof. Dr. med. Dr. h. c. Werner Rath
Medizinische Fakultät Gynäkologie und Geburtshilfe
Universitätsklinikum Schleswig-Holstein, Campus Kiel
Arnold-Heller Straße 3
24105 Kiel
Germany   


  
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Fig. 1 Action algorithm for women with suspected AFL/HELLP syndrome.
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Abb. 1 Handlungsalgorithmus bei Verdacht auf akute Schwangerschaftsfettleber/HELLP-Syndrom.