Case Report JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY

Hereditary Persistence of Alpha-Fetoprotein in

Chronic Liver Disease-Confusing Genes!
Vaibhav Patil , Dinesh Jothimani , Gomathy Narasimhan , Silas Danielraj , Mohamed Rela
Institute of Liver Disease and Transplantation, Dr. Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research,
Chennai, Tamilnadu, India

Alpha-fetoprotein (AFP) is a glycoprotein secreted by the embryonic liver and is expressed in tumours with high
mitotic index such as hepatocellular carcinoma (HCC) and germ cell tumours. Detection of elevated AFP is
strongly associated with underlying HCC or occasionally germ cell tumour. Modest elevation of AFP can be
observed in patients with chronic viral hepatitis particularly with active replication. Very rarely, incidental detec-
tion of raised AFP in a genetically susceptible individuals has been reported in the absence of the underlying ma-
lignant process. This condition is termed as hereditary persistence of AFP (HPAFP), a rare disorder with an
autosomal dominant pattern of inheritance. HPAFP should be suspected in patients with high AFP in the
absence of radiological evidence of HCC or germ cell tumour. The diagnosis is confirmed by the identification
of AFP gene mutation. AFP gene is located in the long arm of chromosome 4. The most common single-nucle-
otide polymorphism in HPAFP is 119 G > A, rs587776861, interestingly reported only in six family clusters world-
wide. Despite being described as a benign disorder, its implication in patients with underlying chronic liver
disease needs further clarification. Here, we describe 3 patients in their forties with chronic liver disease and
persistently elevated levels of AFP, where genetic studies confirmed HPAFP. None of our patients had HCC
despite extensive investigations. ( J CLIN EXP HEPATOL 2021;11:616–618)
Cirrhosis of Liver

A
lpha-fetoprotein (AFP) is a single-chain glycopro- Rarely, persistent elevation of AFP can be seen in pa-
tein, with a unique bimodal genomic expression. tients without HCC and very rarely with completely
In utero, AFP is secreted by the yolk sac and embry- normal liver. This condition, hereditary persistence of
onic liver and is silenced within a year after birth to unde- alpha-fetoprotein (HPAFP) was first described in 1983 as
tectable levels.1 However, after birth, higher AFP expression an autosomal dominant disorder, characterized by fluctu-
occurs in pathological conditions associated with extensive ating AFP levels amongst family members usually with no
mitosis such as hepatoblastoma, hepatocellular carcinoma underlying pathology.3 It is associated with a single-nucle-
(HCC) and germ cell tumour and in other conditions such otide polymorphism of G to A substitution in the 5’ UTR
as hereditary tyrosinemia, neural tube defects and region (
119 G > A) of the AFP gene and occasionally mu-
Down syndrome. AFP is used as a tumour marker in pa- tations in other loci (
55 C > A and
65C > T) of the gene,
tients for the diagnosis of primary HCC. The level of AFP with complete phenotypic penetrance.4 So far, HPAFP has
correlates with the size and differentiation of HCC,2 but been reported in 20 families around the world; however,
unfortunately, only 60% of HCC express AFP. Thus, the most of these patients were suspected to have non–liver-
combination of abdominal ultrasound and serum AFP related AFP elevation.5
every 6 months is the universally practised modality for Here, we describe for the first time 3 patients with
HCC surveillance in patients with cirrhosis and other HPAFP in the background of chronic liver disease.
high-risk conditions such as chronic hepatitis B infection. Case 1: A 48-year-old gentleman was found to have
Occasionally, low-level AFP expression can be observed in mildly elevated liver function tests on routine health check.
acute and chronic hepatitis which usually settles after liver He had a history of 10-kg weight gain over the last 3 months.
recovery. There was no history of alcohol consumption or native
medication intake. There was no history of diabetes mellitus
or hypertension. Clinically, he was overweight, and his
abdominal examination was unremarkable. His blood tests
Keywords: AFP, hereditary persistence AFP (HPAFP), chronic liver disease,
non-alcoholic fatty liver disease
showed a total bilirubin 0.9 mg%, aspartate aminotrans-
Received: 12.11.2020; Accepted: 24.12.2020; Available online 30 December 2020 ferase 110 U/L, alanine aminotransferase (ALT) 125 U/L,
Address for correspondence. Tel: +919849859508 alkaline phosphatase (ALP) 119 U/L, albumin 3.5 gm/dl, In-
E-mail: silasdaniel@ymail.com ternational Normalized Ratio (INR) 1.0 and platelets
Abbreviations: AFP: Alpha Fetoprotein; HPAFP: Hereditary Persistence of 150  109/L; HBsAg, anti-Hepatitis C virus antibodies and
Alpha Fetoprotein; HCC: Hepatocellular Carcinoma; HNF-1: Hepatocyte
nuclear factor
autoimmune markers were unremarkable. His AFP was
https://doi.org/10.1016/j.jceh.2020.12.008 1027 ng/ml. His abdominal ultrasound showed increased

© 2021 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.
Journal of Clinical and Experimental Hepatology | September–October 2021 | Vol. 11 | No. 5 | 616–618
 JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY

lance abdominal ultrasound showed fatty liver disease. In

addition, there were 2 small hypoechoic lesions in segment
V and VI of the liver. His AFP was 1475 ng/ml. His other
blood tests showed total bilirubin 1.5 mg/dl, ALT 28 U/
L, ALP 118 U/L, albumin 3.7 g/dl and INR 1.3.
A triple-phase abdominal CT showed changes of altered
liver intensity, with no radiological evidence of cirrhosis or
portal hypertension. The lesions did not show arterialising
nor washing out features, and similar findings were
confirmed with a gadolinium-enhanced MRI abdomen. A
repeat contrast abdominal CT preformed on 3 monthly in-
tervals on 2 occasions did not show an increase in size or
Figure 1 Explant liver histology of case 2 showing a cirrhotic liver with nature of those lesions. His AFP follow-up measures over
no HCC. a period of 1 year were 1475.4 ng/ml, 894.9 ng/ml and
1113 ng/ml. Genetic studies confirmed heterozygous pos-
hepatic echotexture consistent with fatty liver disease. There itivity for
119 G > A, rs587776861 of AFP gene point mu-
was no evidence of portal hypertension, and importantly tation. His son's (aged 16 years) AFP was 420 ng/ml with
there was no HCC. A triphasic contrast abdominal no evidence of liver disease.
computed tomography (CT) scan and a subsequent mag-
netic resonance imaging (MRI) abdomen confirmed an
enlarged hypointense liver and no evidence of HCC. A DISCUSSION
scrotal ultrasound revealed normal testicles. A repeat AFP AFP was first discovered by Bergstrand and Czar in 1956 as
at 3 months and 6 months showed 1209.5 ng/ml and a glycoprotein produced by yolk sac and foetal liver, quan-
854.9 ng/ml, respectively. A percutaneous nontargeted liver tifiable from 30 days after conception with peak at around
biopsy showed hepatic steatosis, lobular inflammation and 30–32 weeks and subsequent decline.6 Loci of AFP gene is

Cirrhosis of Liver
hepatocyte ballooning consistent with nonalcoholic steato- located in chromosome 4 and is regulated by three factor
hepatitis (NASH). His Ishak fibrosis score was 3/6. In the enhancers, promoters and silencers located on 50 -UTR in
absence of demonstrable mitotic lesion, a genetic analysis the proximal portion of the gene.5 A hepatocyte nuclear fac-
was carried out, and it confirmed the presence of AFP tor (HNF-1) is a transcriptional factor which activates AFP
119 G > A, rs587776861 mutation. AFP analysis in his son gene, whereas a non–tissue-specific factor (NF-1) acts as a
showed (aged 23 years) 830.4 ng/ml. suppressor. AFP is involved in drug conjugation and
Case 2: A 44-year-old diabetic and obese gentleman was drug-induced cytotoxicity, control of growth, upregulation
diagnosed with NASH-related liver cirrhosis. His HCC sur- and downregulation, ligand binding and transport.7 The
veillance revealed a high AFP (1298 ng/ml), but his abdom- level of AFP in adult ranges from 1 to 5 ng/ml. Under phys-
inal ultrasound did not show HCC. Clinical examination iological conditions, serum AFP was less than 10 ng/ml.8
revealed mild jaundice, ascites and bilateral leg oedema. HPAFP is a rare autosomal dominant disorder charac-
There were no signs of hepatic encephalopathy. His blood terised by high AFP in the absence of pathological condi-
tests showed total bilirubin 4.3 mg/dl, ALT 45 U/L, ALT 53 tions. Three types of single-nucleotide polymorphisms
U/L, ALP 108, albumin 2.4 g/dl, platelets 60  109/L and have been described at the HNF-1 binding site of AFP
INR 1.6. His MELD was 17. A triple phase abdominal CT gene promoter associated with increase in the expression
and an MRI showed cirrhotic liver, ascites, splenomegaly of HPAFP.9 These point mutations are
55 C > A and
and patent portal vein. There was no arterialising/washing
65 C > T substitution in the proximal HNF-1 binding
out lesion. In view of hepatic decompensation, he under- site and
119 G > A substitution in distal HNF-1 binding
went living-related liver transplantation. His explant liver site.10 Owing to these point mutations, there is overbind-
histology showed cirrhotic liver (Figure 1), but there was ing of HNF-1 to AFP gene and relative underbinding of
no HCC. After liver transplantation, his AFP remained NF-1, leading to AFP overproduction.4
detectable between 25 and 30 ng/ml. A subsequent HPAFP HPAFP was first time described in 1983 during an ante-
test showed heterozygote 119 G > A, rs587776861 muta- natal screening program for spina bifida in pregnant
tion. Furthermore, his son's (aged 9 years) and father's women by Ferguson-Smith et al.3
(aged 71 years) AFP were 630.2 ng/ml and 3275 ng/ml, Our cases are unique that they all had high AFP in the
respectively. Interestingly, both have elevated liver enzymes background of chronic liver disease including cirrhosis.
and radiological evidence of fatty liver disease. Elevated AFP in a patient with cirrhosis or chronic hepa-
Case 3: A 43-year-old gentleman was diagnosed with titis B is highly indicative of underlying HCC. Interest-
hepatitis B–related chronic liver disease in 2016. He was ingly, none of our patients described previously had
otherwise asymptomatic, managed on entecavir. A surveil- underlying HCC despite extensive investigations and

Journal of Clinical and Experimental Hepatology | September–October 2021 | Vol. 11 | No. 5 | 616–618 617
 HEREDITARY PERSISTENCE OF ALPHA FETOPROTEIN PATIL ET AL

follow-up. Presence of chronic liver disease and high AFP FUNDING

without HCC can be confusing for the treating clinicians. None.
It is unclear when to suspect HPAFP in patients with high
AFP, particularly if they have underlying liver disease.
Although HPAFP has been described as a benign disorder, INFORMED CONSENT
its significance and association in patients with chronic Obtained.
liver disease needs clarification. We do not know the nat-
ural history of HPAFP in patients with chronic liver dis-
ease. Whether these patients are at high risk of ETHICAL COMMITTEE APPROVAL
developing chronic liver disease is unclear because all Institutional Ethical committee approval obtained.
our patients including some of the family members had
underlying NAFLD. In addition, it is unknown whether REFERENCES
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All authors have none to declare

618 © 2021 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.