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Hepatocyte Nuclear Factor 1-β Gene Mutation: Brief Report and Review of Hepatic Involvement

Hepatic involvement in HNF-1β defects.

Annals of Case Reports and Images. 2018;1(1):2
DOI: 10.24983/scitemed.acri.2018.00054
Article Type: Case Report


Defects in the hepatocyte nuclear factor 1-β (HNF1β) gene result in the development of a constellation of defects including cystic renal disease, maturity-onset diabetes of the young (MODY), and genitourinary abnormalities; and the less common findings include agenesis of the pancreas and liver abnormalities. We report a young girl with an HNF1β mutation (variant c.479T > G (p.M160R)), who had a history of neonatal cholestasis, persistent liver dysfunction, and developed insulin-dependent diabetes without renal involvement. Further, we review the literature related to the hepatic involvement associated with HNF1β mutations.


  • Hepatocyte nuclear factor 1-β; early onset diabetes; transaminitis


Hepatocyte nuclear factor-1β (HNF1β) is a member of the home­odomain-containing family of transcription factors and is encoded by the HNF1β gene located on chromosome 17 [1,2]. HNF1β is involved in the transcriptional and functional regulations of the liver, biliary system, kidney, urogenital tract, and pancreatic β-cells [3,4]. Defects of this gene have been described in a small subgroup of patients with MODY, includ­ing point mutations and whole gene deletions, with the majority being de novo whole gene mutations [5,6]. The phenotypical spectrum of individ­uals with HNF1β mutations varies widely. The major features are MODY and cystic renal disease, however, agenesis of the pancreas, urogenital malformations, hyperparathyroidism, gout, cognitive delay, autism spec­trum disorder, and hepatic disorders have also been described [3,4].

Case Report

An African-American female presented at 6-weeks of age with poor growth and jaundice, which, as the mother stated, had been present since birth. She was born to a prima gravid mother at term via sponta­neous vaginal delivery, following an uncomplicated pregnancy. At pre­sentation, the infant was having pigmented bowel movements. The only abnormal physical findings were jaundice, scleral icterus, a grade 2/6 soft systolic murmur consistent with a Still’s murmur, and mild hepatospleno­megaly. Laboratory examination showed evidence of cholestasis with el­evated levels of transaminases (alanine-amino transaminase, ALT = 110 U/L), total and direct bilirubin (11.8 mg/dl and 8.5 mg/dl, respectively), gamma glutamyl transferase (GGT, 150 U/L), and serum bile acids. Serum albumin and prothrombin time were normal. Further testing for an eti­ology was non-diagnostic, including serum amino acids, serologic testing for human immunodeficiency virus, toxoplasmosis, cytomegalovirus, ru­bella, syphilis, and alpha-1-antitrypsin phenotype. Ultrasound of the liver and gallbladder was normal. Liver biopsy showed mild bile ductule pro­liferation in portal areas with mild inflammatory cell infiltrate, no fibrosis, and rare foci of extramedullary hematopoiesis.

The patient maintained normal hepatic function, as evidenced by normal serum albumin and prothrombin time. Bilirubin normalized at 5 months of age, however, serum levels of transaminases and GGT re­mained elevated, fluctuating over time (Figure 1). Repeat liver biopsy at 15-months of age showed patchy minimal chronic lymphocytic inflamma­tion of the portal areas and patchy fibrosis with portal-to-portal bridging. A third liver biopsy was performed at 6.25 years of age to assess for wors­ening fibrosis due to persistence of biochemical evidence for hepatobili­ary injury and the presence of fibrosis on the previous biopsy. The biopsy showed unremarkable portal tracts with no inflammation, fibrosis, or bile ductular proliferation.

Figure 1. The levels of serum ALT and GGT fluctuated during a period of 15 years. Abbreviations: ALT, alanine-amino transaminase; GGT, gamma glutamyl transferase.

At 11-years of age, she presented with polyuria, polydipsia, and po­lyphagia. Laboratory evaluation showed ketonuria, metabolic acidosis, and hyperglycemia, consistent with a diagnosis of diabetic ketoacidosis. Antibodies to glutamic acid decarboxylase and islet cells were negative. A diagnosis of diabetes mellitus was rendered and treatment initiated with insulin replacement. At this point, it was elected to look for mutations in the HNF1β gene to explain the association between the persistent he­patic disease and the early onset insulin-dependent diabetes mellitus. HNF1β gene sequencing detected two gene defects: c.721G > A; p.A241T and c.479T > G; p.M160R. Due to the known association of renal disease with HNF1β gene defects, the patient underwent testing of renal function and a renal ultrasound, which were normal.

At her most recent follow-up at 17-years of age, she continues to have fluctuating levels of transaminases (ALT = 181 U/L; AST = 163 U/L) and GGT (1147 U/L); her diabetes is under poor control as evidenced by an elevated hemoglobin A1c (14.0%; upper limits of normal is 6.1%). She is presently receiving ursodiol (300 mg BID) and rifampin (300 mg BID) for control or pruritus and remains asymptomatic regarding liver disease.


More than 100 different mutations in the HNF1β gene have been re­ported to cause MODY [7]. The difference in clinical presentation of the HNF1β mutation is thought to be caused by the differences in HNF1β activity in conjunction with the repression of HNF1α activity in selected promoters and tissues [8]. Raile et al, suggested that gene dosage of oth­er genetic factors and/or environmental triggers could play a role in the pattern and severity of the HNF1β-associated MODY [9]. Due to the rarity of patients with HNF1β mutation, the clinical manifestations and correla­tion with gene mutations are not well understood.

To date, 47 individuals have been reported with liver disease associ­ated with HNF1β gene defects, 25 as case reports [6,8-14] and 22 identi­fied in patients with the known renal disease being screened for HNF1β defects [15-17]. Liver involvement may present as cholestasis, elevated liver enzyme levels (ALT and/or GGT), hepatomegaly, or steatosis.

Clinical cholestasis manifested as jaundice has been reported in both children and adults with HNF1β defects. Overall, eight of 25 report­ed patients (32%) presented with cholestasis. Five children, including our patient, have been reported, all identified during the neonatal period. An etiology for cholestasis was not established in four, while one child was diagnosed with biliary atresia and underwent portoenterostomy [8- 10,13]. Long-term follow-up of three patients showed resolution of jaun­dice between 5 and 12 months of age. The diagnosis of an HNF1β defect was not entertained until the children developed insulin-dependent dia­betes mellitus [8-10,13]. The exception is the patient described by Kotalo­va et al, where a defect was found in the HNF1β gene as part of a study looking for genes associated with biliary atresia [13]. In a case series of three adults, cholestasis was seen in association with poorly controlled diabetes and secondary renal insufficiency [14]. Electron microscopy showed paucity or absence of cholangiocyte cilia in these patients, sug­gesting a causative role in cholestasis [14].

Persistent and fluctuating liver enzymes are common findings in patients with defects in HNF1β. The percentage of patients from case reports with biochemical cholestasis (elevated GGT) is 78%, while the percentage with elevated ALT is 76% [6,8-14]. This is probably an over-representation as these patients had known liver disease and were subsequently found to harbor a defect in HNF1β. When search­ing for hepatic injury in patients with known HNF1β defects, the per­centages are lower, ranging from 17% to 56% for GGT and 12% to 56% for ALT [14-18]. The degree of enzyme elevation varies from mild (twice the upper limit of normal) to severe (10-times the upper limit of normal).

Hepatomegaly has been found in 25% of the patients with an HNF1β defect when the liver size was commented on in the physical examination [6,8-10,12]. Steatosis has been reported in four patients, diagnosed by imaging studies and/or liver biopsy.

Liver biopsies performed during the evaluation of cholestasis or per­sistent elevation in liver enzymes in patients with HNF1β defects showed varied histological findings. In the cholestatic neonate with an HNF1β defect, liver biopsies have shown paucity of bile ducts, bile ductule prolif­eration, extramedullary hematopoiesis, severe biliary stasis, and mild to severe periportal fibrosis [8-10,13]. Liver biopsies in adults with HNF1β defects and cholestasis have shown non-specific findings of steatosis and sinusoidal dilatation [14]. Liver biopsy performed for persistent elevation in liver enzymes in an infant showed mild steatosis and extramedullary hematopoiesis [12], while the liver biopsies performed in adults showed mild cholestasis and normal histology [11]. It appears that the histolog­ic findings are more pronounced in infants when compared to adults, suggesting that there may be an improvement in liver injury over time. Support for this concept is found in a previous report, as well as in our pa­tient. Improvement in liver histology was reported in an infant by repeat biopsy at 21-months of age [10], while our patient had normalization of liver histology at 6.25-years of age.


HNF1β mutations affect multiple organs and the re­sulting defects may be subtle or subclinical, making the diagnosis based on clinical features difficult. There should be a high index of suspicion for an HNF1β gene mutation in children with early onset diabetes and a past history of neonatal cholestasis or persistent elevation in hepatic enzymes.


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Editorial Information

Publication History

Received date: September 30, 2017
Accepted date: November 13, 2017
Published date: March 19, 2018


© 2018 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY).

Division of Pediatric Gastroenterology, University of Mississippi Medical Center, Jackson, MS, USA
Division of Pediatric Gastroenterology, University of Mississippi Medical Center, Jackson, MS, USA
Division of Pediatric Gastroenterology, University of Mississippi Medical Center, Jackson, MS, USA
Figure 1. The levels of serum ALT and GGT fluctuated during a period of 15 years. Abbreviations: ALT, alanine-amino transaminase; GGT, gamma glutamyl transferase.

Peer Review Report: Round 1

Reviewer 1 Comments 

  1. This is a well-done study that should be of interest to the readers of ACRI. I have a few minor concerns/recommendations, but my main criticism is that the authors have not made a strong figure (HNF1β defects in this case or liver biopsies) and table (laboratory values). There is no mention of case informed consent. I am sure this was done, but a sentence or two must be included prior to publication.
    ResponseWe sought the initial biopsies, but they were performed over 16 years ago and could not be recovered from the archives; the biopsy at 6-years of age was normal, as such we do not feel it will add to the story. As for the labs, we have included a graph that depicts the fluctuating levels of two of the hepatic enzymes–ALT [for hepatocellular injury] and GGT [for biliary injury]. If necessary, we could provide a table as well, but thought the pictorial representation was superior. Parental consent information was added at the end of the manuscript along with the Author Declarations.

Reviewer 2 Comments 

  1. Did the patient have any cardiac anomaly (exam revealed systolic murmur)?
    ResponseNo, it was determined to be a Still’s murmur and resolved with age.
  2. What was the patient's age and general condition at follow up?
    ResponseThis was added to the text in the Case Report section.
  3. Is there any dependable familial inheritance pattern worth screening?
    ResponseIt is an autosomal recessive condition; but getting insurance to pay for testing was prohibitive.
  4. Ref no 17 is not as per format.
    ResponseThis has been corrected.

Reviewer 3 Comments 

The authors presented a patient with HNF1b mutation who developed neonatal cholestasis, persistent liver dysfunction and IDDM and review of hepatic involvement of cases of HNF1b mutations. The paper is well-written and has interesting findings.

  1. Why and how does the hepatic involvement including histological findings improve overtime in patients with HNF1b mutation? Possible mechanisms should be discussed.
    ResponseThere is nothing in the literature to explain why there is an improvement over time. Idiopathic neonatal hepatitis improves with time, as the offending cause is removed and there is no further inflammation. In conditions, such as benign recurrent intrahepatic cholestasis [BRIC], there are recurrent bouts of cholestasis with fluctuations in liver enzymes in the absence of hepatic injury. This condition appears to have a clinical course that combines both of these disorders; however, there are insufficient reports to speculate on a mechanism for the findings.

Peer Review Report: Round 2

Reviewer 1 Comments 

Accepted for publication

Reviewer 2 Comments 

The manuscript has been revised as per changes recommended. It is accepted for publication.

Reviewer 3 Comments 

The paper is well-revised and has interesting findings, I accept for publication