Acute liver failure and aplastic crisis due to anorexia nervosa in an adolescent girl: a case report

Abstract

Anorexia nervosa (AN) has a high mortality rate due to the widespread organ dysfunction caused by the underlying severe malnutrition. Malnutrition-induced hepatitis is common among individuals with AN especially as body mass index decreases, while acute liver failure and aplastic crisis related to coagulation disease and encephalopathy rarely occur in AN patients. The supervised increase of caloric intake can quickly improve the elevated aminotransferases caused by starvation and aplastic crisis. This current case report describes a 12-year-old adolescent girl who was admitted with a 3-month history of weight loss. Within 3 months, she had lost 10 kg of weight. The girl was diagnosed with AN, acute liver failure, severe malnutrition with emaciation, electrolyte disorder, bradycardia and aplastic crisis. She was gradually supplemented with vitamins and enteral nutrition to avoid refeeding syndrome. After treatment, her liver function and haematopoietic function returned to normal. In conclusion, acute liver failure and aplastic crisis are rare but potentially life-threatening complications of AN, which could be improved by supervised feeding and timely rehydration. AN should be considered as the potential aetiology of acute liver failure and aplastic crisis.

Keywords

Anorexia nervosa acute liver failure aplastic crisis refeeding syndrome autophagy malnutrition case report

Introduction

Anorexia nervosa (AN) is a psychiatric condition characterized by severe weight loss and secondary problems associated with malnutrition. AN predominantly develops in adolescence in the peripubertal period.¹ AN is a complex psychiatric disorder with a high rate of mortality and a relatively low rate of remission.² Based on the Diagnostic and Statistical Manual of Mental Disorders-V (DSM-V) criteria, the lifetime prevalence of AN in females is estimated to be as high as 4%.³ The lifetime prevalence in males has been estimated to be between 0.1% and 0.3%, although this is likely an underestimate.⁴ The peak age of onset of AN in both men and women is 15–19 years old.⁵ Among young people aged 8–17 years in the UK, the incidence rate per 100 000 population is 13.68.⁶ The prevalence among adolescents in Japan is near that of developed European countries and the United States.⁷ At present, there are no reports on the epidemiology of adolescents with AN in China. Without effective treatment, AN could lead to multiple system dysfunction, such as bradycardia,^8,9 hypoglycaemia,¹⁰ electrolyte disorders,¹¹ osteoporosis,¹² haematopoiesis abnormality¹³ and acute liver failure.¹⁴ The standardized mortality ratio of AN inpatients with the complications of severe malnutrition was found to be as high as 15.9.¹⁵ More than 5% of AN patients have died within 4 years of initial diagnosis.¹⁶ Approximately half of the deaths in AN are attributable to suicide;¹⁷ with the remaining causes of death in these patients being related to medical complications as a result of their eating disorder.¹⁸ Approximately 12%–50% of all AN patients were complicated with liver disfunction.^19–21 Acute liver failure is a rare and life-threatening complication of AN. This current case report describes a case of acute liver failure and aplastic crisis caused by AN.

Case report

In October 2022, a 12-year-old adolescent girl was admitted to the Department of Gastroenterology, Nanjing Children’s Hospital, Clinical Teaching Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China with a 3-month history of weight loss. Within 3 months, she lost 10 kg of weight. On admission, her weight was 19.5 kg (–3SD), her height was 148 cm (SD) and her body mass index (BMI) was 8.9 kg/m² (–3SD). She usually has normal health, no fever, no vomiting, no diarrhoea, normal stools and urine. Her birth and family history were unremarkable. Influenced by negative comments about obesity 3 months previously, she had developed a restrictive eating behaviour and unreasonable beliefs about low weight and stature. She had refused to eat starchy foods and only ate a little meat every day. She paid too much attention to fat reduction videos. Her BMI fell to within the lowest 5% for the same age and sex, without vomiting, diarrhoea or abdominal distension. The child has been excluded from having the following: (i) liver disease history; (ii) hepatitis virus (HBV or HCV); (iii) drug abuse; (iv) excessive drinking; (v) genetic metabolic disease; (vi) autoimmune liver disease. Her mental and nutritional status was poor (Figure 1). The main laboratory examination results at admission and over the course of her hospitalization are presented in Table 1. Alpha-fetoprotein, carcinoembryonic antigen, neuron-specific enolase, carbohydrate antigen 199, erythrocyte sedimentation rate, syphilis antibody, human immunodeficiency virus antibody, anti-SM antibody, anti-Ro52 antibody, anti-Jo-1 antibody, autoimmune hepatitis antibody, tuberculosis T cell γ interferon release test, urine culture, viral hepatitis antibody, nucleic acid detection of novel coronavirus and ceruloplasmin were all within in the normal range. The abdomen and chest computed tomography (CT) showed the subcutaneous fat was thin (Figure 2). The results of head magnetic resonance imaging (MRI) are shown in Figure 2. Abdominal magnetic resonance cholangiopancreatography showed the bile ducts were normal for both intrahepatic and extrahepatic. The results of bone marrow puncture cytology showed that the proliferation of the bone marrow was extremely reduced. Bone marrow biopsy showed that the proliferation of bone marrow was significantly reduced and no haematopoietic cell islands could be seen (Figure 3). According to the criteria of DSM-V, the girl was diagnosed as AN, acute liver failure, severe malnutrition with emaciation, electrolyte disorder, bradycardia and aplastic crisis. In addition to the acute liver failure, the patient also suffered with multisystemic abnormalities, such as bradycardia, hypotension, anaemia, thrombocytopenia, hyponatraemia, hypokalaemia and hypoglycaemia.

Figure 1.

The physical appearance of a 12-year-old adolescent girl who was admitted with a 3-month history of weight loss (10 kg) and was subsequently diagnosed with anorexia nervosa: (A) scattered ecchymosis and ecchymosis on the trunk (arrows) and (B) dry skin, loss of subcutaneous fat and thin muscle in the lower limbs. The colour version of this figure is available at: http://imr.sagepub.com.

Table 1.

Changes in laboratory parameters over the hospitalization period of a 12-year-old adolescent girl who was admitted with a 3-month history of weight loss (10 kg) and was subsequently diagnosed with anorexia nervosa complicated with an aplastic crisis.

Laboratory parameter	Reference range	Day of hospitalization
Laboratory parameter	Reference range	Day 1	Day 2	Day 3	Day 5	Day 7	Day 9	Day 14	Day 18	Day 20	Day 42
ALT, U/l	7–30	2713	2590	2261	1630	1035	468	193	90	50	16
AST, U/l	14–44	5570	4430	3410	1308	529	94	23	21	21	19
γ-GGT, U/l	5–19	172	172	197	194	160	118	80	67	52	25
T-Bil, µmol/l	5–19	80.78	89.14	110.23	109.87	75.02	35.06	22.75	18	20.4	16.15
D-Bil, µmol/l	0–6.8	39.17	41.47	56.87	68.44	49.45	25.55	13.92	13.1	11.9	7.38
I-Bil, µmol/l	1.7–13.7	41.61	47.67	53.36	41.43	29.57	9.51	8.83	4.9	8.5	8.77
Glucose, mmol/l	3.5–5.6	0.98	6.87	3.93	4.47	4.67	7.02	6	5.06	3.49	4.14
Albumin, g/l	39–54	43.5	41.6	41.6	37.4	36.2	26.6	30.6	36.9	36.4	44.6
Urea, mmol/l	2.5–6.5	11.4	8.88	5.34	4.23	2.53	2.53	2.79	2.33	5.8	5.69
K, mmol/l	3.7–5.2	3.07	3.69	4.23	4.04	3.81	4.26	4.34	4.64	4.61	4.11
Na, mmol/l	135–145	134	138	138	138	135	142	144	138.3	137.1	138
Cl, mmol/l	98–110	93.9	99	101.2	102.1	99.9	111.7	106.8	98.9	102.5	102.9
Total cholesterol, mmol/l	0–5.18	6.24	6.33	6.92	5.99	4.85	2.95	3.4	3.92	4.35	6.7
HDL, mmol/l	2.33–5.69	2.51	2.64	2.84	2.34	1.73	0.78	0.6	1.11	1.26	1.89
WBC, *10⁹/l	4.3–11.3	13.96	11.8	NA	4.63	3.57	2.93	3.84	5.78	4.5	4.44
RBC, *10¹²/l	4.2–5.7	4.16	4.13	NA	4.15	3.41	2.8	2.46	2.63	2.65	3.23
HGB, g/l	118–156	120	120	NA	120	99	78	70	80	80	102
PLT, *10⁹/l	150–407	91	66	NA	32	29	46	96	447	611	194
Neutrophil,*10⁹/l	1.6–7.8	9.53	7.08	NA	2.63	2.64	1.94	2.12	3.97	2.43	2.02
Lymphocyte, *10⁹/l	1.5–4.6	3.96	4.17	NA	1.88	0.91	0.84	1.31	1.29	1.61	2.15
PT, s	10–14	24.2	17	14.7	12.7	14.7	13.1	NA	11.6	NA	13.6
INR	0.82–1.15	2.13	1.48	1.25	1.11	1.28	1.15	NA	1.02	NA	1.19
APTT, s	20–45	35.9	26.9	27.7	29.1	32.5	33.8	NA	32.6	NA	35.3
PTA, %	>40%	27.74	51.81	71.67	107.5	71.67	97.73	NA	148.28	NA	87.76

ALT, alanine aminotransferase; AST, aspartate aminotransferase; γ-GGT, gamma-glutamyl transferase; T-Bil, total bilirubin; D-Bil, direct bilirubin; I-Bil, indirect bilirubin; K, potassium; Na, sodium; Cl, chloride; HDL, high-density lipoprotein; WBC, white blood cell; NA, not assessed; RBC, red blood cell; HGB, haemoglobin; PLT, platelet; PT, prothrombin time; INR, international normalized ratio; APTT, partially activated thrombin time; PTA, prothrombin activity.

Figure 2.

Cranial magnetic resonance images and abdominal computed tomography (CT) image of a 12-year-old adolescent girl who was admitted with a 3-month history of weight loss (10 kg) and was subsequently diagnosed with anorexia nervosa: (A) T1 weighted image and (B) T2-weighted-fluid-attenuated inversion recovery image showed mild brain atrophy-like changes, the bilateral lateral ventricles were full and the ventricles were deep; (C) the abdominal CT scan showed that the subcutaneous fat layer of the abdomen was relatively thin but there was no significant abnormality in the density of the liver morphology.

Figure 3.

Bone marrow cytology smear and biopsy from a 12-year-old adolescent girl who was admitted with a 3-month history of weight loss (10 kg) and was subsequently diagnosed with anorexia nervosa complicated with an aplastic crisis: (A) bone marrow cytology (haematoxylin & eosin [H & E], scale bar 2.5 µm) showed that proliferation was extremely reduced and scattered platelets were rare; (B & C) bone marrow biopsy showed significantly reduced (20%) hyperplasia, adipose tissue hyperplasia and no haematopoietic cell islands (B, H & E, scale bar 10 µm; C, H&E, scale bar 2.5 µm). The colour version of this figure is available at: http://imr.sagepub.com.

The patient was administered intravenous and enteral nutrition starting from 40% of the target calorie intake (720 kcal/day for calories, 21.6 g/day for protein, 27.2 g/day for fat and 99.35 g/day for carbohydrate) and the amount provided was gradually increased to reach the target calorie intake over 5–7 days. Meanwhile, psychological counselling was provided to the girl. The amount of liquid (in and out), electrolyte level, blood sugar, weight, pulse and blood pressure were monitored. Gradually, a positive feedback link was established between eating behaviour and physical strength. Also, vitamins were supplied to avoid refeeding syndrome. She also received rapid glucose infusion when hypoglycaemia occurred and red blood cell infusions when her haemoglobin fell below 70 g/l. With all the treatment, the weight increased to 23 kg and the BMI was 10.5 kg/m² at the 18th day of admission. In addition, her liver and haematopoietic function improved gradually, so the liver failure and aplastic crisis were considered to have been caused by AN. Before discharge, a liver ultrasound was confirmed as normal and refeeding syndrome was excluded. At the same time, the patient's bone marrow was rechecked and her haematopoietic function had returned to normal. After the patient was discharged, a follow-up call was undertaken and the patient was reported to have recovered well after discharge. The patient and her family were satisfied with the treatment.

The treatment reported in this case report was approved by the patient and her family members. The patient's details have been de-identified. Written informed consent was obtained from the parents of the patient for publication of this case report. This study was approved by the Ethics Committee of Nanjing Children's Hospital, Nanjing, China. The reporting of this study conforms to CARE guidelines.²²

Discussion

Anorexia nervosa is an eating disorder characterized by a strong fear of weight gain and distorted body image. The clinical presentation includes severe weight loss and secondary problems related to malnutrition. Weight loss is mainly due to reduced food intake, but other behaviours will increase energy consumption, such as exercise, taking metabolic stimulants and cold exposure, or chewing, spitting and washing and other methods to reduce energy intake may also lead to AN. Although the most common explanation for this behaviour is the fear of being overweight, other reasons include the pursuit of perfection and low self-worth (that is, not worth eating).²³ In the US, the lifetime prevalence of this disease is approximately 0.80% and approximately 92% of patients are women.²⁴ At present, the global incidence rate is rising, especially in Asia and the Middle East.²⁵

In some patients, it is impossible to determine the reason why they are unwilling to eat, but patients usually resist attempts to help restore nutrition and weight.³ Patients often fail to recognize the severity of their significantly low weight.¹ However, the genetic characteristics, pre-disease characteristics, brain structure and function of AN patients are similar to those of other psychiatric conditions, which is in contrast with obesity and metabolic disorders.¹AN even leads to acute liver failure and death.²⁶ The prevalence of abnormal liver enzymes is related to the development of lower BMI, hypoglycaemia and refeeding hypophosphataemia.²⁷ Acute liver failure is a rare and life-threatening complication of AN.²⁸ Acute liver failure with coagulation disorder and encephalopathy caused by AN is uncommon, but it has been described in a previous case report.²⁹ According to the 2022 North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition's position paper on the diagnosis and management of paediatric acute liver failure, the diagnostic criteria for paediatric acute liver failure are as follows: (i) acute onset of liver disease without evidence of chronic liver disease; (ii) biochemical evidence of severe liver injury; (iii) coagulopathy not corrected by vitamin K with prothrombin time (PT) ≥15 s or international normalized ratio (INR) ≥1.5 with evidence of hepatic encephalopathy or PT ≥ 20 s or INR > 2 with or without encephalopathy.³⁰ The pathological mechanisms of liver complications due to AN are hunger hepatitis or refeeding syndrome, which should be treated differently. Patients with hunger hepatitis need adequate caloric supplementation. However, excessive calories should be avoided because patients with AN often have low cardiac output due to decreased cardiac mass and blood volume. In contrast, patients with refeeding syndrome need to reduce nutritional support in order to avoid the progress of refeeding-induced fatty liver.¹⁹

The possible causes of hunger hepatitis are autophagy and hepatic circulatory disorder (also known as shock liver, hypoxic hepatitis and ischemic hepatitis).^31–33 Low BMI (<12 kg/m²) is a risk factor for severe hunger hepatitis.³⁴ Hunger is an effective inducer of autophagy. Autophagy is a cellular process in which excessive or old cytosolic proteins and organelles are degraded. The resultant breakdown products can then be recycled.³² In patients with AN, autophagy plays a protective role in the early stage of the disease and prevents hepatocyte death, provides amino acids and participates in glucose metabolism after starvation, ensuring nutrition and energy to maintain survival. There is evidence that autophagy is also beneficial to trace element deficiency, because it enhances innate immunity and plays a role in quality control in cells with a long half-life.³⁵ As AN-induced hunger intensifies and BMI further decreases (≤13 kg/m²), over activation of autophagy leads to increased liver cell damage and death, leading to liver failure.^31,32 Insulin inhibits autophagy by activating mammalian protorapamycin protein targets through the class I phosphatidylinositol 3-kinase/Akt pathway.³⁶ The liver biopsy of individuals with severe AN and transaminase elevation (mean value >1900 IU/ml) found rare apoptotic bodies and there was no obvious hepatocyte necrosis in histopathology.³¹ Electron microscopy showed that numerous autophagosomes with morphological features of autophagy; the mitochondria, endoplasmic reticulum and nuclei were normal in most cells.³¹ Aminotransferases normalized singularly with increased caloric intake and weight restoration, suggesting that improved nutrition likely halts the autophagy process that led to hepatocyte injury and death.²⁹ Therefore, it is an effective strategy to treat hunger hepatitis patients by giving glucose to increase the serum insulin level. Moreover, the significant elevation of transaminase levels and liver dysfunction were associated with systemic dehydration, subsequent hypovolemia and hypotension, and fusion of hypoxaemia and hepatic hypoperfusion.³⁷ Liver dysfunction and secondary ischaemia caused by low blood volume usually occur in haemorrhagic shock, leading to a significant increase in serum transaminase and lactate dehydrogenase levels.³⁸ A previous study reported that the ratio of blood urea nitrogen/creatinine increased significantly in AN patients with high serum alanine aminotransferase (ALT) levels, which may reflect severe dehydration caused by malnutrition.¹⁴ The treatment of ischaemic hepatitis should aim at restoring cardiac output and reversing the root causes of haemodynamic instability. It is noteworthy that the cardiac output of patients with AN secondary to cardiac atrophy may decrease. Therefore, it is necessary to replenish water carefully to avoid capacity overload. The treatment strategy of patients with hunger hepatitis should include the restoration of cardiac output and proper calorie supplement.

Images from patients with hunger hepatitis showed that there was no detailed abnormality in liver morphology, while, images from patients with refeeding hepatitis might show that the liver was enlarged and bright.^29,39 So, liver imaging including ultrasound, CT and MRI can identify liver injury caused by hunger or refeeding.³³ Refeeding syndrome is a serious metabolic complication related to nutritional recovery in AN patients with severe malnutrition.³⁹ Starvation leads to reduced serum insulin and elevated glucagon levels. The body obtains energy from glycogen storage and biochemical transformation into gluconeogenesis. After long-term malnutrition, the patient suddenly resumes normal eating, increases carbohydrate intake, stimulates insulin secretion and promotes the transport of phosphorus from the cell membrane.^40,41 It may lead to cardiac decompensation, pre-renal failure with metabolic acidosis or even sudden death.⁴⁰ Histopathological examination of liver tissue in patients with refeeding syndrome showed fatty liver and moderate portal vein inflammation, liver cell swelling and increased glycogen deposition.³⁵ In addition to the paradoxical weight fluctuations against nutrient administration, normal electrolytes, hypoglycaemia and absence of a fatty liver were thought to suggest starvation rather than refeeding syndrome.⁴¹

In this current case, her liver failure could not be explained as secondary to any toxin, drug intake, autoimmune or infectious factors. After fluid infusion and nutrition treatment, the child's liver function gradually returned to normal. The peak of liver function in the early stage of the disease supports the hunger mediated process, which may be the cause of liver failure rather than excessive glucose deposition (steatosis) in the liver due to refeeding. By hospital discharge, ALT and aspartate aminotransferase had improved significantly (Table 1). As all the clinical symptoms and psychological condition were resolved, she refused a liver biopsy. Although this current patient was severely dehydrated, she also had bradycardia. This phenomenon may be due to the fact that patients with AN usually have hypertonic parasympathetic nerves and hypotonic sympathetic nerves, which leads to a sluggish response to the sympathetic nervous system stimulation caused by dehydration.⁴² The current case had severe hypoglycaemia at admission. So far, there is no authoritative report on AN-related hypoglycaemia and liver injury, although hypoglycaemia can affect the systemic circulation, thereby affecting the liver circulation and leading to liver injury. Hypoglycaemia is also common in patients with hypoxic hepatitis. In summary, the current patient suffered from hunger liver failure caused by AN.

Haematological disease is one of the complications of AN and malnutrition leads to the decline of the overall bone marrow function and metabolism.³⁷ Patients with AN often present with pancytopenia. With the aggravation of AN, whole blood cell counts decrease, resulting in anaemia, leukopenia and thrombocytopenia. Pancytopenia involves approximately 3% of patients with AN; 40% of patients have anaemia, 30% have leukopenia and approximately 10% have thrombocytopenia.³⁷ Haematological abnormalities are not only common at admission, but also more likely to occur in patients with severe elevation of liver enzymes during hospitalization.⁴³ In patients with severe elevation of liver enzymes, liver dysfunction itself may lead to a high incidence of thrombocytopenia.²⁰ AN with pancytopenia showed gel-like bone marrow transformation (GMT), which is a typical bone marrow feature of malnutrition.⁴⁴ At present, no other literature has reported cases of AN patients diagnosed with aplastic anaemia (AA). The differentiation between AN associated pancytopenia and other types of pancytopenia, especially idiopathic AA, has not been studied. A previous case report described a patient with AN with relatively poor nutritional status that was accompanied by pancytopenia.⁴⁴ The bone marrow biopsy findings were similar to AA, especially adipose tissue hyperplasia, but no GMT was found.⁴⁴ As the blood and bone marrow were found to be improved after only nutritional treatment, the final diagnosis was modified as pancytopenia secondary to malnutrition.⁴⁴ The current case was similar to this previous patient.⁴⁴ After hospitalization, the white blood cell count decreased gradually in the current patient. It is reported that there is a significant correlation between BMI, white blood cell and red blood cell counts, as well as between weight loss and the degree of bone marrow abnormality in patients with eating disorders.⁴⁵ In this current patient, haemocytopenia gradually developed while weight recovered.⁴⁶ Therefore, it was difficult at the beginning to determine whether the current patient's diagnosis was AN associated pancytopenia or AA. After further nutritional support, a follow-up examination of the patient's peripheral blood and bone marrow was undertaken after discharge and they had returned to normal.

In conclusion, acute liver failure and aplastic crisis are rare but potentially life-threatening complications of AN. For the AN patient with acute liver failure, it is important to start feeding and provide timely rehydration. As the incidence of AN is increasing, it should be considered as the potential aetiology of acute liver failure and aplastic crisis.

Footnotes

Acknowledgement

Our sincere thanks to the patient and her family members for their participation.

Author contributions

L.C. and Y.Z. contributed to the study design, data collection, data analysis and manuscript preparation. Y.Z. also revised the manuscript. Z.L. contributed to the study design and critically revised the manuscript.

Declaration of conflicting interests

The authors declare that there are no conflicts of interest.

Funding

This research received no specific grant from funding agency in the public, commercial, or not-for-profit sectors.

ORCID iD

Zhifeng Liu

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