Your Health and Fitness Partner: Androxal & FitHub

We are also excited to expand our scope by including valuable information on Androxal, a potent medication beneficial in various medical conditions. This remarkable drug, derived from the testosterone molecule, has made its mark significantly in the field of endocrinology. Patients and medical professionals can rely on our comprehensive, unbiased, and scientifically grounded content on Androxal for gaining a robust understanding of its uses, side effects, and the latest studies related to it. We understand the necessity of accurate information when it comes to medication. Our newly launched section dedicated to Androxal aims at not only educating the readers about its nuances but also at contributing beneficially to their wellbeing. Stay tuned for insightful articles unraveling the potential of Androxal in medical science.

Sitemap | Policies | Feedback    
 About the Journal
Editorial Board
Journal Subscription
Instructions for Authors
E-mail Alerts
Forthcoming Events
Advertise with Us
Contact Us
 
Article Options
FULL TEXT
PDF
Printer Friendly Version
Search Pubmed for
Search Google Scholar for
Article Statistics
Bookmark and Share
Case Report
 
Hereditary Persistence of Alpha Fetoprotein in an Indian Family
Keywords :
Pratin Bhatt, Deepak Kumar Gupta, Dhiraj Agrawal, Sangit Saurav, Abhijeet Karad, Prashant Dhore, Akash Shukla 
Department of Gastroenterology, Seth G S Medical College and KEM Hospital, Mumbai, Maharashtra, India.


Corresponding Author
:
Dr Pratin Bhatt
Email: dr.pratin@gmail.com


DOI: http://dx.doi.org/10.7869/tg.522

48uep6bbphidcol2|ID
48uep6bbphidvals|1906
48uep6bbph|2000F98CTab_Articles|Fulltext
Serum alpha fetoprotein (AFP) is produced in the yolk sac, fetal hepatocytes and developing gastrointestinal tract.1 AFP reaches its peak level during the 3rd  and 4th month of gestation2, and declines after birth. Serum AFP level in healthy adults is lower than 10 ng/ml.3
Raised serum AFP levels are found in a wide range of malignancies, including hepatocellular carcinoma (HCC), as well as benign conditions like pregnancy, acute or chronic hepatitis, cirrhosis, and ataxia-telangiectasia.4 Elevated AFP value in maternal serum is a marker of congenital fetal malformation (anencephaly, spina-bifida, exomphalos, gastroschisis) threatened abortion, fetal death in utero, and multiple pregnancies.4
Although high AFP level in cases of HCC suggest large size, advanced stage, portal vein thrombosis or metastasis, AFP has limited utility as a tumor marker for HCC due to low sensitivity.5
Hereditary persistence of AFP (HPAFP) is a rare autosomal-dominantly inherited condition with raised AFP levels without any symptoms or signs. First described in 19836, only 20 families have been described to date. HPAFP is due to both proximal and distal hepatocyte nuclear factor-1 site mutations.7

Case Report

A 6o year old lady was incidentally detected to have compensated cirrhosis of liver during evaluation for symptomatic chronic calculus cholecystitis nine years ago and underwent an uneventful open cholecystectomy. She was non-diabetic, non-obese with a body mass index of 22 kg/m2, and without history of significant alcohol intake. Etiological workup for other causes of chronic liver disease was negative. A gastroscopy prior to surgery showed 3 small varices with Portal Hypertensive Gastropathy (PHG). Liver biopsy showed complete nodule formation with minimal necroinflammatory activity at the portal tract.   
The patient has been on regular follow-up with clinical examinations, laboratory studies, and imaging. Her baseline serum AFP levels at the time of diagnosis were high (871.81 ng/ml). Her ultrasound examination did not reveal any space-occupying lesion, further confirmed with an MRI abdomen (Figure 1a). Serial liver function tests and AFP levels are depicted in Table 1






On family screening, two of her three children had elevated AFP levels (811.05 ng/ml and 530.68 ng/ml, respectively) without symptoms, signs, and normal blood investigation, including liver function tests, and ultrasonography. On further family screening, the patient’s grandmother (303 ng/ ml) and one grandchild (271 ng/ ml) were also found to have elevated AFP. Familial cases with high AFP are depicted in the pedigree chart (Figure 1b).
In her follow up, the patient had decompensation in the form of ascites for one year. A repeat MRI abdomen at the time of decompensation did not show HCC (Figure 1a). 




Discussion

Raised serum AFP levels are associated with malignant conditions like HCC, hepatoblastoma, and non-seminomatous germ cell tumors. The cut-off value of AFP should be set at 200 ng/ml for surveillance programs when used in combination with ultrasonography.8 AFP helps diagnose an additional 6% to 8% of cases of HCC. 
HPAFP is a benign disease with autosomal dominance. It is essential to keep a differential of HPAFP in mind in an otherwise healthy person. The diagnosis of HPAFP avoids unnecessary investigation. Patients with undiagnosed HPAFP have been reported to receive chemotherapy or undergo surgery due to misdiagnoses.9 These patients have persistently raised AFP after chemotherapy or surgery, and subsequently diagnosed to have benign HPAFP. HPAFP is a diagnosis of exclusion and is associated with a urological disorder like seminoma testis, non-seminoma testis, or testicular cysts.9 Family screening for high AFP helps to reach a diagnosis. Alternatively, HPAFP can be diagnosed by identifying a mutation in the 5’- regulatory region of the AFP gene in the index patient.
The genetic basis of HPAFP was first described in 1993.10 Hepatocyte nuclear factor (HNF-1) stimulates the AFP gene activation. Point mutations in the HNF-1 binding sites of the AFP gene promoter increase AFP gene transcription leading to HPAFP. A-55 C> A substitution in the proximal HNF-1 binding site and a -119 G > A substitution in the distal HNF-1 binding site lead to HPAFP.7,10
Only one case report of HPAFP with chronic hepatitis C is reported in the literature.11 Our patient is the only case of HPAFP with diagnosed liver cirrhosis. Our patient has persistent elevated AFP without HCC with a follow up of 9 years. There is only one case report of HPAFP in Bangladesh national from the Indian subcontinent.12 To our knowledge, this is the first case report of HPAFP from India and in a patient with cirrhosis. The limitation of our case report is the lack of genetic testing.
To conclude, high AFP in the background of cirrhosis always creates doubts about HCC in the mind of physicians. Once HCC and other urological disorders are ruled out, HPAFP is diagnosed easily with family screening for high AFP or identifying a mutation in the AFP gene in the index patient. This approach helps the physician to avoid unnecessary investigation and the patient to assure the benign nature of the disease.

Reference
  1. Gitlin D, Perricelli A, Gitlin GM. Synthesis of alpha-fetoprotein by liver, yolk sac, and gastrointestinal tract of the human conceptus. Cancer Res 1972;32:979–982.
  2. Van Furth R, Adinolfi M. In vitro synthesis of the fetala1-globulin in man. Nature 1969;222:1296–1299.
  3. Ball D, Rose E, Alpert E. Alpha-fetoprotein levels in normal adults. Am J Med Sci 1992;303:157–159
  4. Wong et al. Elevated alpha fetoprotein. Clin Liver Dis-(2015).
  5. Marrero JA, Feng Z, Wang Y, et al. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology 2009; 137:110-8.
  6. Ferguson-Smith MA, May HM, O’Hare E, Aitken DA. Hereditary persistence of alphafetoprotein: a new autosomal dominant trait identified in an antenatal screening programme for spina bifida. J Med Genet. 1983;20(6):454-8.
  7. Alj Y et al. Hereditary persistence of alpha-fetoprotein is due to both proximal and distal hepatocyte nuclear factor-1 site mutations. Gastroenterology. 2004 Jan;126(1):308-17.
  8. Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, Tateishi R, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int. 2017 Jul;11(4):317-370.
  9. Houwert AC, Giltay JC, Lentjes EG, Lock MT Hereditary persistence of alpha-fetoprotein (HPAFP): review of the literature. Neth J Med.2010 Nov;68(11):354-8.
  10. McVey JH, Michaelides K, Hansen LP, Ferguson-Smith M, Tilghman S, Krumlauf R, et al. A G-->A substitution in an HNF I binding site in the human alpha-fetoprotein gene is associated with hereditary persistence of alpha-fetoprotein (HPAFP). Hum Mol Genet. 1993 Apr;2(4):379-84.
  11. Hsu SX, Siegel AB, Berk PD. A 70-year-old woman with 10 years of markedly elevated alpha-fetoprotein measurements. In Seminars disease 2010 Feb (Vol. 30, No. 01, pp. 099-106).
  12. Deshpande N, Chavan R, Bale G, Avanthi US, Aslam M, Ramchandani M, et al. Hereditary Persistence of Alpha-Fetoprotein Is Associated with the -119G>A Polymorphism in AFP Gene. ACG Case Rep J. 2017 Mar 1;4:e33.