Recognizing Mitochondrial Hepatopathy in Acute Fatty Liver of Pregnancy

Ashish Goel; Banumathi Ramakrishna; Manisha Madhai Beck; Thomas Alex; Uday Zachariah; CE Eapen

doi:10.4103/ghep.ghep_35_22

REVIEW ARTICLE

Year : 2023 | Volume : 3 | Issue : 1 | Page : 7-11

Recognizing Mitochondrial Hepatopathy in Acute Fatty Liver of Pregnancy

Ashish Goel¹, Banumathi Ramakrishna², Manisha Madhai Beck³, Thomas Alex⁴, Uday Zachariah¹, CE Eapen¹
¹ Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu, India
² Department of Pathology, Christian Medical College, Vellore; Department of Pathology, SRM Institutes for Medical Science, Chennai, Tamil Nadu, India
³ Department of Obstetrics and Gynecology, Christian Medical College, Vellore, Tamil Nadu, India
⁴ Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India

Date of Submission	30-Nov-2022
Date of Decision	30-Nov-2022
Date of Acceptance	01-Dec-2022
Date of Web Publication	28-Dec-2022

Correspondence Address:
Ashish Goel
Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ghep.ghep_35_22

Abstract

Acute fatty liver of pregnancy (AFLP) is a rare cause of catastrophic liver dysfunction and failure in late pregnancy. Defective mitochondrial fatty acid oxidation (FAO) seems to be the underlying pathogenic mechanism. Stressors of both late pregnancy (increased maternal dependence on fats as energy source) and fetus with homozygous defect in mitochondrial FAO, precipitate AFLP in a woman who was previously asymptomatic. Mitochondrial disorders exhibit significant clinical heterogeneity, but many of these primary and secondary disorders have liver as the primary organ affected. The liver injury pattern in these patients also has a varied spectrum and course. Unlike other primary mitochondrial disorders affecting the liver, AFLP represents a potentially completely reversible form of liver injury. Thus, AFLP behaves as a secondary mitochondrial disorder precipitated by inciting factors from fetus and placenta. In this review, we attempt to highlight the varied aspects of mitochondrial dysfunction in AFLP. Mitochondrial injury is the mainstay of pathogenesis and can be recognized in typical clinical features and histopathological findings in patients with AFLP. We also present the consequent impact of recognizing underlying mitochondrial injury on clinical diagnosis and management strategies employed in AFLP.

Keywords: Acute liver failure, hepatic microvesicular steatosis, pregnancy

How to cite this article:
Goel A, Ramakrishna B, Beck MM, Alex T, Zachariah U, Eapen C E. Recognizing Mitochondrial Hepatopathy in Acute Fatty Liver of Pregnancy. Gastroenterol Hepatol Endosc Pract 2023;3:7-11

How to cite this URL:
Goel A, Ramakrishna B, Beck MM, Alex T, Zachariah U, Eapen C E. Recognizing Mitochondrial Hepatopathy in Acute Fatty Liver of Pregnancy. Gastroenterol Hepatol Endosc Pract [serial online] 2023 [cited 2023 Jan 27];3:7-11. Available from: http://www.ghepjournal.com/text.asp?2023/3/1/7/365726

Introduction

Acute fatty liver of pregnancy (AFLP), or “acute yellow atrophy of liver,” is a rare disorder characterized by acute liver dysfunction in women occurring during late pregnancy.^[1] Early recognition and institution of timely management ensures optimal outcome in these patients.

Mitochondrial or respiratory chain disorders are a rare group of autosomal recessive disorders usually presenting in early childhood. As liver (hepatocytes) is the factory of the body with varied biosynthetic and detoxifying functions, it is highly dependent on cellular power source (mitochondria-derived adenosine triphosphate).^[2] Consequently, hepatocytes have a high density of mitochondria and most mitochondrial disorders primarily affect liver.

Mitochondria generate energy by metabolizing nutrients. Fatty acid oxidation (FAO), which is a major energy source for muscles, contributes only during stress (e.g., prolonged fasting) to energy requirements of liver. Injury to mitochondria (both primary and secondary to an insult) negatively impacts its functions – respiratory chain activity and also FAO.^[3],[4]

Mitochondrial disorders exhibit clinical heterogeneity in the organ(s) involved and also as to the severity of manifestations. Liver manifestations can range from mild cholestasis or steatosis to liver failure.^[3] Unlike other primary mitochondrial hepatopathies, AFLP is characterized by a sudden “power cut” that is experienced by pregnant women only during late pregnancy.

In this review, we focus on understanding and recognizing mitochondrial dysfunction in patients with AFLP.

Mitochondrial Dysfunction Underlies the Pathogenesis of Acute Fatty Liver of Pregnancy

AFLP is a manifestation of defect in fatty acid beta-oxidation (FAO). In the late 2^nd or 3^rd trimesters of pregnancy, a pregnant woman increasingly relies on fats for meeting her energy requirement. In such a scenario, a hitherto compensated FAO defect becomes overtly manifest.^[1],[5],[6]

Genetic defects in various enzymes (mainly long-chain hydroxyacyl-CoA dehydrogenase) of mitochondrial beta-oxidation pathway of fatty acids, although often recognized in a mother with AFLP (heterozygous) and also the fetus (often homozygous), are not always present.^[7],[8] Similarly, only a small proportion (~1/5^th) of patients with known FAO defects develop AFLP.^[7] These genetic defects, if present, although affect FAO enzymes which are located on the inner mitochondrial membrane, are inherited autosomal recessively not by mitochondrial pattern.

The pathogenesis is thus heterogeneous, and our previous study suggested a central role of placenta in these patients. Impaired placental mitochondrial beta FAO preferentially channels fats toward peroxisomal beta FAO leading to generation of free radicals and release of toxic metabolites (e.g., high levels of arachidonic acid) in the maternal serum. This toxic and stressful environment exacerbates microvesicular liver steatosis (pathologic hallmark for mitochondrial hepatopathy) in these patients.^[9]

Mitochondrial dysfunction of the placenta is thus postulated to lead to mitochondrial dysfunction in the liver and causes acute liver failure in patients with AFLP. It appears that placenta (and fetus) release inciting factors causing liver mitochondrial dysfunction in AFLP.^[2] This is supported by the clinical observation that patients with AFLP improve rapidly after delivery of fetus (and placenta).

Other examples of secondary mitochondrial hepatopathy are Reye's syndrome, valproic acid toxicity, and Wilson's disease.^[2],[3] Multiple nucleoside analogs, developed for hepatitis B virus, have mitochondrial dysfunction (especially myopathy and lactic acidosis), as a prominent adverse event, leading to their nonapproval or discontinuation from the market.^{[10],[11],[12]}

Clinical Picture

As the mother is heterozygous for FAO defect and is essentially asymptomatic prior to the decompensating stressor (late pregnancy), most clinical features and presentation are of a reversible acute illness involving primarily only the liver.^[13],[14]

Mitochondrial hepatopathies are notoriously heterogeneous in their presentation and severity. The presence of seizures, vomiting, and encephalopathy can be a manifestation of mitochondrial dysfunction in these patients with liver failure. These symptoms form part of “Swansea” criteria for diagnosis of AFLP but are nonspecific and can be seen in a variety of other etiologies of liver failure.^[15],[16]

Other system involvement (e.g., neuromuscular, pancreas, and gastrointestinal tract) and chronic liver damage, seen in some mitochondrial hepatopathies, are not commonly seen in patients with AFLP.

During 1998–2006, from the cohort of patients suspected to have pregnancy-related liver disorders who underwent postpartum (transjugular) or immediate postmortem biopsies at our center, we studied patients with pregnancy-related liver disease (n = 24), diagnosed as possible AFLP. [Table 1] shows the application of individual parameters of “Swansea” criteria in these patients.^[16]

Table 1: Application of Swansea criteria in patients presented with 24 patients with pregnancy-related liver disease-acute fatty liver of pregnancy, in late pregnancy. The features that can suggest mitochondrial dysfunction are highlighted^[16]

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Some drugs (e.g., valproic acid and nucleoside analogs) can present with mitochondrial dysfunction, and a plethora of other drugs (including complementary and alternative medications) can present with idiosyncratic liver dysfunction and failure.^[17] These have to be carefully interrogated about in all patients suspected to have AFLP.

Laboratory Parameters

Hypoglycemia, lactic acidosis, and hyperammonemia are commonly seen in patients with multiple types of mitochondrial dysfunction.^[2],[3] In addition, raised bilirubin, raised aminotransferases, and coagulopathy are also seen in patients with liver involvement. [Table 1] lists the laboratory abnormalities noted in our patients diagnosed with AFLP.

Lactic acidosis is not currently a part of the diagnostic criteria but is often seen in a patient with acute liver failure, irrespective of etiology. Most of the other laboratory abnormalities are also shared between mitochondrial dysfunction and liver failure. Disproportionate hypoglycemia, coagulopathy, and encephalopathy (possibly secondary to hyperammonemia) characterize AFLP. This has been described by us in the “Simplified” criteria [Table 2] used to reach a rapid presumptive diagnosis of AFLP to facilitate the timely institution of vital therapy.^{[1],[18],[19]}

Table 2: Simplified criteria for diagnosis of acute fatty liver of pregnancy. The presence of all three criteria is required for presumptive diagnosis of AFLP

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In this situation, laboratory evaluation is to be fine-tuned to achieve a rapid presumptive diagnosis of AFLP. Commonly prevalent etiologies of liver failure (e.g., hepatitis B/E and malaria infection in India) have to be ruled out expeditiously prior to entertaining a diagnosis of AFLP.^[1],[20]

Pathology

Timing and need

Liver biopsy is not needed for reaching a presumptive diagnosis of AFLP, and we found both “Swansea” and “Simplified” criteria extremely sensitive for achieving this aim. High negative predictive value for these noninvasive criteria (against a gold standard of microvesicular steatosis on liver biopsy), suggests utility in reaching a rapid diagnosis of AFLP.^{[1],[16],[19]}

Liver biopsy, even if considered, is difficult due to the presence of coagulopathy (often severe) and need for urgent institution of treatment. Most guidelines suggest immediate delivery in any patient with suspected AFLP. We utilize “Simplified” criteria for rapid diagnosis of AFLP in labor room setting and institute delivery, preferably within 12 h of admission. It is not prudent to rely on liver biopsy findings for clinical decision-making.

To understand and prognosticate, a small proportion of our patients underwent immediate postpartum (transjugular) or postmortem liver biopsies. It is known that liver histology (especially microvesicular steatosis) tends to resolve (as also clinical parameters) starting immediately after delivery, thus correctly timing liver biopsy is of essence. A normal liver biopsy late after delivery does not rule out the possibility of AFLP.^[1]

Gross findings

Grossly, the liver is smaller than normal in size with pale yellow color and was first defined by Sheehan in 1940 as obstetric acute yellow atrophy. Sheehan noted a gross fatty change affecting the entire lobule except for a sharply defined rim of normal hepatocytes around the portal tracts.^[21],[22] This gross pathology term which was used over years to describe atrophy associated with acute liver failure due to various causes including AFLP to massive viral infection is not used now.^[22],[23]

Light microscopic findings

Microscopically, the presence of microvesicular steatosis is considered the diagnostic hallmark of AFLP.^[22],[24] The affected cells are enlarged with numerous tiny cytoplasmic vacuoles and may involve only the perivenular region or affect the entire lobule without sparing periportal hepatocytes. Various other microscopic abnormalities have been reported in a large series of cases by Rolfes and Ishak.^[25] Intrahepatic cholestasis with canalicular bile plugs and acute cholangiolitis, hypertrophied Kupffer cells containing aggregates of ceroid-laden macrophages, mild lobular and portal inflammation, and extramedullary hematopoiesis with megakaryocytes and erythroids, may be present [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d. Fibrin deposition along the sinusoids has been reported occasionally. In patients who survive, serial biopsies have shown progressive disappearance of fat from the periportal to the perivenular region within days of parturition and normal histology is restored.^{[22],[23],[24]}

Figure 1: Histological features in AFLP: (a) Microvesicular steatosis - Diffusely enlarged hepatocytes with numerous tiny cytoplasmic vacuoles (inset - macrovesicular steatosis). (b) Extramedullary hemopoiesis with clusters of erythroid cells. (c) Megakaryocyte and ceroid-laden macrophages (H and E, 400). (d) Canalicular cholestasis (Van Gieson - ×400). AFLP: Acute fatty liver of pregnancy

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Electron microscopic findings

Ultrastructurally, the liver shows nonmembrane-bound fat droplets. The mitochondria are frequently enlarged with variable size and shape and inclusion bearing. These changes do not appear to be specific but likely represent secondary phenomenon. There is dilatation of rough endoplasmic reticulum^[22],[24] [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d.

Figure 2: (a-d) Ultrastructural features in AFLP RER. AFLP: Acute fatty liver of pregnancy, RER: Rough endoplasmic reticulum

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Macrovesicular versus microvesicular hepatic steatosis

Macrovesicular steatosis [large intracytoplasmic fat droplet pushing the nucleus to the side, [Figure 1]a inset] is commonly seen in patients with metabolic syndrome (nonalcoholic fatty liver disease) and alcohol-related liver injury. The primary cause of increased triglycerides in hepatocytes in these patients is an imbalance between input (fatty acid delivery from gut due to insulin resistance, de novo lipogenesis within hepatocytes, and recirculation from adipose/skeletal tissue) and output (very low-density lipoprotein production and secretion from hepatocytes).^[26],[27] In contrast, microvesicular steatosis is secondary to defective mitochondrial beta FAO.

How Accurate are These Clinical Observations in Diagnosing Mitochondrial Hepatopathy in Patients with Acute Fatty Liver of Pregnancy?

There is considerable overlap in the diagnostic criteria for AFLP, preeclamptic liver dysfunction, and Hemolysis, Elevated Liver enzymes, and Low Platelets (HELLP) syndrome (these are the three pregnancy-related liver disorders which manifest in late pregnancy). Thus, a patient who presents with liver dysfunction in late pregnancy may meet diagnostic criteria for AFLP and for preeclamptic liver dysfunction. In a series of 20 patients with diagnostic criteria of AFLP, we noted considerable overlap with HELLP syndrome (13 patients) and preeclampsia (2 patients).^[16]

Mitochondria and its abnormalities are seen only on electron microscopy, while microvesicular steatosis is seen both on light microscopy and electron microscopy of the liver. Hepatic mitochondrial abnormalities seen on electron microscopy in AFLP patients are accompanied by microvesicular steatosis [Figure 2]. Swansea diagnostic criteria for AFLP include the presence of hepatic microvesicular steatosis (seen on light microscopy) and do not include hepatic mitochondrial abnormalities (which can be visualized only on electron microscopy).

In patients suspected to have AFLP, How good are the Swansea criteria for AFLP in detecting hepatic microvesicular steatosis? We attempted to answer this question by analyzing these findings in 34 patients who underwent liver biopsy (either postpartum transjugular or postmortem) for liver failure in late pregnancy. We found that Swansea criteria had 100% sensitivity and negative predictive value with a 57% specificity and 85% positive predictive value in predicting diffuse/perivenular hepatic microvesicular steatosis. Thus, in patients suspected to have AFLP, in the setting of late pregnancy, the Swansea criteria help detect hepatic microvesicular steatosis (which is an accompaniment of mitochondrial hepatopathy).^[16]

Management

Detailed discussion of management is beyond the scope of the current review, and the readers are referred to a more exhaustive review and guidelines on the topic.^{[1],[28],[29],[30]}

For want of specific treatment, most mitochondrial disorders are managed by supportive treatment strategy and ameliorating the aggravating factors. Similarly, urgent delivery (as inciting factors originate from the fetoplacental unit) offers the best chance of successful outcome in AFLP mothers. Maternal health takes a priority in AFLP and guides decision-making. We have demonstrated a significant decrease in mortality due to AFLP with early recognition, teamwork, and urgent delivery of these patients.^[1]

Supportive and expectant management of hypoglycemia, hyperammonemia, coagulopathy, and encephalopathy are the hallmarks of a composite management strategy for AFLP as is the case with any mitochondrial disorder. Loading with glucose, to provide alternative energy source, is proposed as a management strategy that needs to be tested prospectively.^[18] The supportive management often requires a trained multidisciplinary team for complex management of these patients.

Unlike other primary mitochondrial disorders, AFLP is completely reversible (although catastrophic) and preferentially involves only liver. Thus, multivitamins, cofactors, respiratory substrates, or antioxidant compounds do not have much role in AFLP management. As a corollary, liver transplant and liver support strategies (therapeutic plasma exchange) can be considered in these patients.^[30],[31]

Perinatal outcome remains poor even with optimal management. Whether loading with glucose will positively impact perinatal outcome, needs to be studied. P presence of Defective mitochondrial beta FAO in the baby and regular clinical assessment and a high-carbohydrate, low-fat diet are also necessary.^{[1],[18],[29]} It is prudent to avoid and ameliorate any catabolic stress, e.g., fasting and intercurrent infection, in these children.

Mothers need to be counseled regarding the risk of recurrence of AFLP in subsequent pregnancies and genetic testing can be considered.^[1],[18]

Conclusion

AFLP represents a specific form of reversible, catastrophic, and liver-limited mitochondrial hepatopathy secondary to pregnant state. There are many features in clinical presentation, laboratory parameters, light, and electron microscopy which suggest severe mitochondrial dysfunction in AFLP patients. This understanding guides our current treatment strategy and should lead us in future research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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