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

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). 

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.